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Dong MQ, Xie Y, Tang ZL, Zhao XW, Lin FZ, Zhang GY, Huang ZH, Liu ZM, Lin Y, Liu FY, Zhou WJ. Leukocyte cell-derived chemotaxin 2 (LECT2) regulates liver ischemia-reperfusion injury. LIVER RESEARCH 2024; 8:165-171. [PMID: 39957753 PMCID: PMC11771270 DOI: 10.1016/j.livres.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/26/2024] [Accepted: 09/10/2024] [Indexed: 02/18/2025]
Abstract
Background and aim Hepatic ischemia-reperfusion injury (IRI) is a significant challenge in liver transplantation, trauma, hypovolemic shock, and hepatectomy, with limited effective interventions available. This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2 (LECT2) in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA (shRNA) delivered through adeno-associated virus (AAV) vectors. Materials and methods This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver. Lect2-knockout and C57BL/6J mice were used. Hepatic IRI was induced by clamping the hepatic pedicle. Treatments included recombinant human LECT2 (rLECT2) and AAV-Lect2-shRNA. LECT2 expression levels and serum biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) were measured. Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed. Results Serum and liver LECT2 levels were elevated during hepatic IRI. Serum LECT2 protein and mRNA levels increased post reperfusion. Lect2-knockout mice had reduced weight loss; hepatic necrosis; and serum ALT, AST, creatinine, and BUN levels. rLECT2 treatment exacerbated weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN). AAV-Lect2-shRNA treatment significantly reduced weight loss, hepatic necrosis, and serum biomarkers (ALT, AST, creatinine, and BUN), indicating therapeutic potential. Conclusions Elevated LECT2 levels during hepatic IRI increased liver damage. Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage, indicating its therapeutic potential. AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI, offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.
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Affiliation(s)
- Meng-Qi Dong
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuan Xie
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Zhi-Liang Tang
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Xue-Wen Zhao
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Fu-Zhen Lin
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Guang-Yu Zhang
- Department of Hepato-Biliary-Pancreatic and Hernia Surgery, The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China
| | - Zhi-Hao Huang
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Min Liu
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuan Lin
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Lao J, Zhu H, You Q, Nie M, Lal Pathak J. Updates on the role of leukocyte cell-derived chemotaxin-2 in inflammation regulation and immunomodulation. Cytokine 2024; 181:156697. [PMID: 39024680 DOI: 10.1016/j.cyto.2024.156697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/24/2024] [Accepted: 07/02/2024] [Indexed: 07/20/2024]
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2), originally identified as a novel neutrophil chemokine, is a multifunctional secreted factor primarily produced in hepatocytes. However, many studies have shown that LECT2 is a pleiotropic protein that not only exerts chemotaxis properties as a cytokine but also plays an important role in inflammatory regulation and immune regulation. Pathogens such as bacteria and the role of the host immune system are key factors in the inflammatory response. In antibacterial, LECT2 can directly destroy bacterial structure or affect the normal metabolism of bacteria to inactivate bacteria and can also achieve this effect by activating immune cells and regulating cytokines. In immunomodulation, LECT2 has neutrophil chemotactic activity and regulates the quantities of Natural killer T (NKT) cells, regulatory T cells, monocytes/macrophages, granulocytes, and/or the expression of associated cytokines, thereby influencing their effect in immune reaction. Inflammation and immune regulation are closely related to a variety of diseases, such as bacterial infection, liver cirrhosis, dermatitis, coronary atherosclerotic heart disease, and so on. This review summarizes the basic and clinical studies of LECT2 in antibacterial effects and its effects on immune cells to explore the mechanism of LECT in inflammatory regulation and immune regulation in physiological and pathological conditions better.
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Affiliation(s)
- Jiaying Lao
- School of Stomatology, Guangzhou Medical University, Guangzhou, China
| | - Haohui Zhu
- School of Stomatology, Guangzhou Medical University, Guangzhou, China
| | - Qianhui You
- School of Stomatology, Guangzhou Medical University, Guangzhou, China
| | - Min Nie
- Department of Basic Oral Medicine, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China; Department of Periodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China.
| | - Janak Lal Pathak
- Department of Basic Oral Medicine, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China.
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Liu W, Wang Q, Yeerlan J, Yan Y, Xu L, Jia C, Liu X, Zhang L. Global research trends and hotspots for leukocyte cell-derived chemotaxin-2 from the past to 2023: a combined bibliometric review. Front Immunol 2024; 15:1413466. [PMID: 38881894 PMCID: PMC11176436 DOI: 10.3389/fimmu.2024.1413466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2) is an important cytokine synthesized by liver. Significant research interest is stimulated by its crucial involvement in inflammatory response, immune regulation, disease occurrence and development. However, bibliometric study on LECT2 is lacking. In order to comprehend the function and operation of LECT2 in human illnesses, we examined pertinent studies on LECT2 investigation in the Web of Science database, followed by utilizing CiteSpace, VOSview, and Scimago Graphica for assessing the yearly quantity of papers, countries/regions involved, establishments, authors, publications, citations, and key terms. Then we summarized the current research hotspots in this field. Our study found that the literature related to LECT2 has a fluctuating upward trend. "Angiogenesis", "ALECT2", "diagnosis", and "biliary atresia" are the current investigative frontiers. Our findings indicated that liver diseases (e.g. liver fibrosis and hepatic cell carcinoma), systemic inflammatory disease, and amyloidosis are the current research focus of LECT2. The current LECT2 research outcomes are not exceptional. We hope to promote the scientific research of LECT2 and exploit its potential for clinical diagnosis and treatment of related diseases through a comprehensive bibliometric review.
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Affiliation(s)
- Wei Liu
- Department of Neurology, Nanbu People’s Hospital, Nanbu, China
| | - Qin Wang
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | | | - Yirui Yan
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Luke Xu
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Cui Jia
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Xinlian Liu
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Lushun Zhang
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
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Kim JW, Fedorov EA, Zon LI. G-CSF-induced hematopoietic stem cell mobilization from the embryonic hematopoietic niche does not require neutrophils and macrophages. Exp Hematol 2024; 131:104147. [PMID: 38160994 PMCID: PMC10939783 DOI: 10.1016/j.exphem.2023.104147] [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: 08/11/2023] [Revised: 12/14/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Hematopoietic stem cell transplantation requires the collection of hematopoietic cells from patients or stem cell donors. Granulocyte colony-stimulating factor (G-CSF) is widely used in the clinic to mobilize hematopoietic stem and progenitor cells (HSPCs) from the adult bone marrow niche into circulation, allowing a collection of HSPCs from the blood. The mechanism by which G-CSF acts to mobilize HSPCs is unclear, with some studies showing a direct stimulation of stem cells and others suggesting that myeloid cells are required. In this study, we developed a heat-inducible G-CSF transgenic zebrafish line to study HSPC mobilization in vivo. Live imaging of HSPCs after G-CSF induction revealed an increase in circulating HSPCs, demonstrating a successful HSPC mobilization. These mobilized HSPCs went on to prematurely colonize the kidney marrow, the adult zebrafish hematopoietic niche. We eliminated neutrophils or macrophages using a nitroreductase-based cell ablation system and found that G-CSF still mobilizes HSPCs from the niche. Our findings indicate that neutrophils and macrophages are not required for G-CSF-induced HSPC mobilization from the embryonic hematopoietic niche.
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Affiliation(s)
- Ji Wook Kim
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | - Evan A Fedorov
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | - Leonard I Zon
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA.
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Zhao J, Zhang X, Li Y, Yu J, Chen Z, Niu Y, Ran S, Wang S, Ye W, Luo Z, Li X, Hao Y, Zong J, Xia C, Xia J, Wu J. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front Immunol 2023; 14:1314123. [PMID: 38155961 PMCID: PMC10754533 DOI: 10.3389/fimmu.2023.1314123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023] Open
Abstract
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
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Affiliation(s)
- Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Liu YJ, Lu XJ, Hauton C, Yang GJ, Chen J. Editorial: Emerging talents in comparative immunology: 2022. Front Immunol 2023; 14:1318852. [PMID: 37965318 PMCID: PMC10641830 DOI: 10.3389/fimmu.2023.1318852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 10/20/2023] [Indexed: 11/16/2023] Open
Affiliation(s)
- Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
| | - Xin-Jiang Lu
- Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chris Hauton
- School of Ocean and Earth Science, National Oceanography Centre, University of Southampton, Southampton, United Kingdom
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultral Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultral Biotechnology Ministry of Education, Ningbo University, Ningbo, China
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Zhu MH, Liu YJ, Li CY, Tao F, Yang GJ, Chen J. The emerging roles of leukocyte cell-derived chemotaxin-2 in immune diseases: From mechanisms to therapeutic potential. Front Immunol 2023; 14:1158083. [PMID: 36969200 PMCID: PMC10034042 DOI: 10.3389/fimmu.2023.1158083] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2, also named ChM-II), initially identified as a chemokine mediating neutrophil migration, is a multifunctional secreted factor involved in diverse physiological and pathological processes. The high sequence similarity of LECT2 among different vertebrates makes it possible to explore its functions by using comparative biology. LECT2 is associated with many immune processes and immune-related diseases via its binding to cell surface receptors such as CD209a, Tie1, and Met in various cell types. In addition, the misfolding LECT2 leads to the amyloidosis of several crucial tissues (kidney, liver, and lung, etc.) by inducing the formation of insoluble fibrils. However, the mechanisms of LECT2-mediated diverse immune pathogenic conditions in various tissues remain to be fully elucidated due to the functional and signaling heterogeneity. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of LECT2 in immune diseases, as well as the potential applications of LECT2 in therapeutic interventions in preclinical or clinical trials. This review provides an integrated perspective on the current understanding of how LECT2 is associated with immune diseases, with the aim of facilitating the development of drugs or probes against LECT2 for the theranostics of immune-related diseases.
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Affiliation(s)
- Ming-Hui Zhu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Chang-Yun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Fan Tao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
- *Correspondence: Jiong Chen, ; ; Guan-Jun Yang,
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, China
- *Correspondence: Jiong Chen, ; ; Guan-Jun Yang,
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Nowicki M, Wierzbowska A, Szymańska B, Nowicki G, Szmigielska-Kapło A. Inflammation-related mRNA expression in patients with multiple myeloma undergoing hematopoietic stem cell mobilization. Exp Hematol 2023:S0301-472X(23)00069-3. [PMID: 36906219 DOI: 10.1016/j.exphem.2023.03.001] [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: 11/30/2022] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/11/2023]
Abstract
Mobilization of CD34+ cells is a key element in the therapy of patients with multiple myeloma undergoing autologous stem cell transplantation. The use of chemotherapy and the granulocyte colony-stimulating factor can significantly affect the expression of inflammation-related proteins and the migration of hematopoietic stem cells. We assessed the mRNA expression of selected proteins involved in the inflammatory landscape in MM patients (n=71). The aim of the study was to evaluate C-C motif chemokine ligand 3, 4, 5 (CCL3, CCL4, CCL5), leukocyte cell-derived chemotaxin 2 (LECT2), tumor necrosis factor (TNF), and formyl peptide receptor 2 (FPR2) levels in the course of mobilization and their role in the CD34+ collection efficacy. mRNA expression from peripheral blood plasma was evaluated by RT-PCR. We observed a deep decline in CCL3, CCL4, LECT2, and TNF mRNA expression on the day of the first apheresis (day A) as compared to baseline. A negative correlation was observed between CCL3, FPR2, LECT2, TNF level, and the CD34+ cells count in peripheral blood on day A, and the number of CD34+ cells obtained at first apheresis . Our results indicate that the investigated mRNAs significantly alter and may regulate the migration of CD34+ cells during mobilization. Moreover, in case of FPR2 and LECT2, the results obtained in patients differ from the murine models.
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Affiliation(s)
- Mateusz Nowicki
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz Comprehensive Cancer Center and Traumatology, Poland; Department of Hematology, Medical University of Lodz, Poland.
| | - Agnieszka Wierzbowska
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz Comprehensive Cancer Center and Traumatology, Poland; Department of Hematology, Medical University of Lodz, Poland
| | - Bożena Szymańska
- Central Scientific Laboratory, Medical University of Lodz, Poland
| | | | - Anna Szmigielska-Kapło
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz Comprehensive Cancer Center and Traumatology, Poland; Department of Hematology, Medical University of Lodz, Poland
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Yu M, He X, Song X, Gao J, Pan J, Zhou T, Wang Q, Zhu W, Ma H, Zeng H, Xu C, Yu C. Biglycan promotes hepatic fibrosis through activating heat shock protein 47. Liver Int 2023; 43:500-512. [PMID: 36371672 DOI: 10.1111/liv.15477] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/07/2022] [Accepted: 11/11/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Biglycan (BGN) is a small leucine-rich proteoglycan that participates in the production of excess extracellular matrix (ECM) and is related to fibrosis in many organs. However, the role of BGN in liver fibrosis remains poorly understood. This study aimed to investigate the role and mechanism of BGN in liver fibrosis. METHODS Human liver samples, Bgn-/0 (BGN KO) mice and a human LX-2 hepatic stellate cells (HSCs) model were applied for the study of experimental fibrosis. GEO data and single-cell RNA-seq data of human liver tissue were analysed as a bioinformatic approach. Coimmunoprecipitation, immunofluorescence staining, western blotting and qRT-PCR were conducted to identify the regulatory effects of BGN on heat shock protein 47 (HSP47) expression and liver fibrosis. RESULTS We observed that hepatic BGN expression was significantly increased in patients with fibrosis and in a mouse model of liver fibrosis. Genetic deletion of BGN disrupted TGF-β1 pathway signalling and alleviated liver fibrosis in mice administered carbon tetrachloride (CCl4 ). siRNA-mediated knockdown of BGN significantly reduced TGF-β1-induced ECM deposition and fibroblastic activation in LX-2 cells. Mechanistically, BGN directly interacted with and positively regulated the collagen synthesis chaperon protein HSP47. Rescue experiments showed that BGN promoted hepatic fibrosis by regulating ECM deposition and HSC activation by positively regulating HSP47. CONCLUSION Our data indicate that BGN promotes hepatic fibrosis by regulating ECM deposition and HSC activation through an HSP47-dependent mechanism. BGN may be a new biomarker of hepatic fibrosis and a novel target for disease prevention and treatment.
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Affiliation(s)
- Mengli Yu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinjue He
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Song
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Gao
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiaqi Pan
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tianyu Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qinqiu Wang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Zhu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huijian Ma
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hang Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengfu Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Wang Q, Xu F, Chen J, Xie YQ, Xu SL, He WM. Serum Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Level Is Associated with Osteoporosis. Lab Med 2023; 54:106-111. [PMID: 35976970 DOI: 10.1093/labmed/lmac080] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE The aim of this study was to examine serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in osteoporosis subjects to confirm its association with osteoporosis. METHODS A total of 204 adult subjects were recruited. Bone mineral densities (BMD) were assessed and blood samples were collected for measurements of biomedical parameters and the bone turnover markers. Serum LECT2 levels were measured by enzyme-linked immunosorbent assay. The relationships between serum LECT2 levels and other parameters were analyzed using the Spearman correlation coefficient. RESULTS Serum LECT2 levels were significantly increased in osteoporosis subjects over controls. We found a significantly negative correlation of serum LECT2 with BMD, 25-hydroxy-vitamin D, and creatinine and a significantly positive correlation with C-terminal telopeptide of type 1 collagen and total cholesterol. CONCLUSION Serum LECT2 levels were significantly upregulated in osteoporosis subjects and correlated with the severity of bone loss. Serum LECT2 could be a potential biomarker to assess the risk of bone loss.
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Affiliation(s)
- Qiang Wang
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Feng Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang, China.,State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China
| | - Yan-Qing Xie
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Su-Ling Xu
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
| | - Wen-Ming He
- Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China
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11
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Xie Y, Zhong KB, Hu Y, Xi YL, Guan SX, Xu M, Lin Y, Liu FY, Zhou WJ, Gao Y. Liver infiltration of multiple immune cells during the process of acute liver injury and repair. World J Gastroenterol 2022; 28:6537-6550. [PMID: 36569272 PMCID: PMC9782841 DOI: 10.3748/wjg.v28.i46.6537] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/29/2022] [Accepted: 11/18/2022] [Indexed: 12/08/2022] Open
Abstract
BACKGROUND Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic recovery. To date, there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.
AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time, and to study the relationship between the changes in leukocyte cell-derived chemotaxin 2 (LECT2) and the infiltration of several immune cells.
METHODS Carbon tetrachloride- and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively. The quantitative changes in various immune cells were monitored at different time points. Serum samples were collected, and liver tissues were harvested. Ly6G, CD161, CD4, CD8 and F4/80 staining were used to indicate neutrophils, NK/NKT cells, CD4+ T cells, CD8+ T cells and macrophages, respectively. Lect2-KO mice were used to detect the function of LECT2.
RESULTS During the injury and repair process, different types of immune cells began to increase, reached their peaks and fell into decline at different time points. Furthermore, when the serum alanine transaminase (ALT) and aspartate transaminase (AST) indices reverted to normal levels 7 d after the injury, the infiltration of immune cells still existed even 14 d after the injury, showing an obvious lag effect. We found that the expression of LECT2 was upregulated in acute liver injury mouse models, and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice. Compared with wild-type mice, Lect2-KO mice had different immune cell infiltration.
CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair. LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.
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Affiliation(s)
- Yuan Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Ke-Bo Zhong
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Yang Hu
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yong-Lun Xi
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shi-Xing Guan
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Meng Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yuan Lin
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing 100853, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of Pathology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510280, Guangdong Province, China
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12
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Meteorin links the bone marrow hypoxic state to hematopoietic stem/progenitor cell mobilization. Cell Rep 2022; 40:111361. [PMID: 36130501 DOI: 10.1016/j.celrep.2022.111361] [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: 04/13/2022] [Revised: 07/20/2022] [Accepted: 08/23/2022] [Indexed: 11/21/2022] Open
Abstract
Hematopoietic stem/progenitor cells (HSPCs) are supported and regulated by niche cells in the bone marrow with an important characterization of physiological hypoxia. However, how hypoxia regulates HSPCs is still unclear. Here, we find that meteorin (Metrn) from hypoxic macrophages restrains HSPC mobilization. Hypoxia-induced factor 1α and Yin Yang 1 induce the high expression of Metrn in macrophages, and macrophage-specific Metrn knockout increases HSPC mobilization through modulating HSPC proliferation and migration. Mechanistically, Metrn interacts with its receptor 5-hydroxytryptamine receptor 2b (Htr2b) to regulate the reactive oxygen species levels in HSPCs through targeting phospholipase C signaling. The reactive oxygen species levels are reduced in HSPCs of macrophage-specific Metrn knockout mice with activated phospholipase C signaling. Targeting the Metrn/Htr2b axis could therefore be a potential strategy to improve HSPC mobilization for stem cell-based therapy.
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13
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Lin Y, Dong M, Liu Z, Xu M, Huang Z, Liu H, Gao Y, Zhou W. A strategy of vascular-targeted therapy for liver fibrosis. Hepatology 2022; 76:660-675. [PMID: 34940991 PMCID: PMC9543235 DOI: 10.1002/hep.32299] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
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Affiliation(s)
- Yuan Lin
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng‐Qi Dong
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Min Liu
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Hao Huang
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Hong‐Juan Liu
- Department of BioinformationSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina,Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina,General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Microbiome Medicine CenterZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
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14
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Kim J, Lee SK, Kim D, Lee E, Park CY, Choe H, Kang MJ, Kim HJ, Kim JH, Hong JP, Lee YJ, Park HS, Heo Y, Jang YJ. Adipose tissue LECT2 expression is associated with obesity and insulin resistance in Korean women. Obesity (Silver Spring) 2022; 30:1430-1441. [PMID: 35722819 DOI: 10.1002/oby.23445] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Leukocyte cell-derived chemotaxin 2 (LECT2) is an obesity-upregulated hepatokine inducing skeletal muscle insulin resistance. The study's aim was to explore whether LECT2 is expressed in human adipose tissue and whether the expression is dysregulated during obesity and associated with obesity-related metabolic disorders. METHODS This study measured metabolic parameters, serum LECT2, and expression of LECT2 and CD209, a gene encoding a putative receptor for LECT2, in abdominal subcutaneous and visceral adipose tissues in women with obesity (with or without type 2 diabetes) and women with normal weight. The expression/secretion of LECT2 and its putative effects were assessed in human adipocytes. RESULTS Adipose tissue LECT2 mRNA and serum LECT2 were higher in women with obesity and were significantly correlated with parameters related to insulin resistance. LECT2 was mainly expressed by adipocytes. Both LECT2 and CD209 expression was higher in adipocytes from women with obesity. Incubating adipocytes with substances mimicking the microenvironment of obesity adipose tissue increased LECT2 expression/secretion. LECT2 treatment of adipocytes suppressed insulin-stimulated Akt phosphorylation; it reduced adiponectin (ADIPOQ) and increased leptin (LEP) expression in a CD209-dependent manner. CONCLUSIONS This study demonstrates that LECT2 expression in adipose tissue is high in patients with obesity and associated with insulin resistance and suggests that adipocyte-derived LECT2 may contribute to adipose tissue dysfunction.
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Affiliation(s)
- Jimin Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Brexogen Research Center, Brexogen Inc., Seoul, South Korea
| | - Seul Ki Lee
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Brexogen Research Center, Brexogen Inc., Seoul, South Korea
| | - Donguk Kim
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eunyoung Lee
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chan Yoon Park
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Food and Nutrition, College of Health Science, The University of Suwon, Hwaseong-si, South Korea
| | - Han Choe
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Min-Ji Kang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hwa Jung Kim
- Department of Preventive Medicine, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Clinical Epidemiology and Biostatistics, ASAN Medical Center, Seoul, South Korea
| | - Jong-Hyeok Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Joon Pio Hong
- Department of Plastic Surgery, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yeon Ji Lee
- Department of Family Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Hye Soon Park
- Department of Family Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoonseok Heo
- Department of General Surgery, Inha University School of Medicine, Incheon, South Korea
| | - Yeon Jin Jang
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
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15
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Xie Y, Fan K, Guan S, Hu Y, Gao Y, Zhou W. LECT2: A pleiotropic and promising hepatokine, from bench to bedside. J Cell Mol Med 2022; 26:3598-3607. [PMID: 35656863 PMCID: PMC9258709 DOI: 10.1111/jcmm.17407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/12/2022] [Accepted: 05/02/2022] [Indexed: 11/28/2022] Open
Abstract
LECT2 (leucocyte cell-derived chemotaxin 2) is a 16-kDa protein mainly produced by hepatocytes. It was first isolated in PHA-activated human T-cell leukaemia SKW-3 cells and originally identified as a novel neutrophil chemotactic factor. However, many lines of studies suggested that LECT2 was a pleiotropic protein, it not only functioned as a cytokine to exhibit chemotactic property, but also played multifunctional roles in some physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC(haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. Among the above studies, it was discovered that LECT2 could be a promising molecular biomarker and therapeutic target. This review summarizes LECT2-related receptors and pathways, basic and clinical researches, primarily in mice and human, for a better comprehension and management of these diseases in the future.
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Affiliation(s)
- Yuan Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of General Surgery IIThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Kai‐Wei Fan
- Department of Cerebrovascular DiseaseThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Shi‐Xing Guan
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yang Hu
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
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16
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Hu YZ, Ma ZY, Wu CS, Wang J, Zhang YA, Zhang XJ. LECT2 Is a Novel Antibacterial Protein in Vertebrates. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2037-2053. [PMID: 35365566 DOI: 10.4049/jimmunol.2100812] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 02/09/2022] [Indexed: 06/14/2023]
Abstract
In vertebrates, leukocyte-derived chemotaxin-2 (LECT2) is an important immunoregulator with conserved chemotactic and phagocytosis-stimulating activities to leukocytes during bacterial infection. However, whether LECT2 possesses direct antibacterial activity remains unknown. In this article, we show that, unlike tetrapods with a single LECT2 gene, two LECT2 genes exist in teleost fish, named LECT2-a and LECT2-b Using grass carp as a research model, we found that the expression pattern of grass carp LECT2-a (gcLECT2-a) is more similar to that of LECT2 in tetrapods, while gcLECT2-b has evolved to be highly expressed in mucosal immune organs, including the intestine and skin. Interestingly, we found that gcLECT2-b, with conserved chemotactic and phagocytosis-stimulating activities, can also kill Gram-negative and Gram-positive bacteria directly in a membrane-dependent and a non-membrane-dependent manner, respectively. Moreover, gcLECT2-b could prevent the adherence of bacteria to epithelial cells through agglutination by targeting peptidoglycan and lipoteichoic acid. Further study revealed that gcLECT2-b can protect grass carp from Aeromonas hydrophila infection in vivo, because it significantly reduces intestinal necrosis and tissue bacterial load. More importantly, we found that LECT2 from representative tetrapods, except human, also possesses direct antibacterial activities, indicating that the direct antibacterial property of LECT2 is generally conserved in vertebrates. Taken together, to our knowledge, our study discovered a novel function of LECT2 in the antibacterial immunity of vertebrates, especially teleost fish, greatly enhancing our knowledge of this important molecule.
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Affiliation(s)
- Ya-Zhen Hu
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Zi-You Ma
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Chang-Song Wu
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Jie Wang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Yong-An Zhang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China;
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
- Hubei Hongshan Laboratory, Wuhan, China; and
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xu-Jie Zhang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China;
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
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17
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Zhao J, Xu X, Gou Q, Zheng Q, Ge L, Chen L, Zhang C, Ma H, Lin S, Hu X, Zhan J. TGF-β1-Mediated Leukocyte Cell-Derived Chemotaxin 2 Is Associated With Liver Fibrosis in Biliary Atresia. Front Pediatr 2022; 10:901888. [PMID: 35928681 PMCID: PMC9345500 DOI: 10.3389/fped.2022.901888] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/20/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Biliary atresia (BA) presents as a severe infantile cholangiopathy disease, characterized by progressive liver fibrosis and the resulting poor prognosis. Leukocyte cell-derived chemotaxin 2 (LECT2) was proposed as the key gene associated with hepatic fibrosis in BA, but the molecular mechanism is unclear. This study aims to investigate the function of LECT2 in BA. METHODS A total of 53 patients were enrolled in this study; 36 patients with BA, and 17 control patients with cholestasis, including congenital biliary dilations, biliary hypoplasia, and inspissated bile syndrome. The role of LECT2 in BA was analyzed using histological and cytological tests. The correlation between LECT2 and infiltrating immune cells was further analyzed by bioinformatics. The analyses were conducted using correlational analyses and ROC curves. RESULTS LECT2 was highly expressed in infants with BA and positively related with fibrosis (0.1644 ± 0.0608 vs. 0.0779 ± 0.0053, p < 0.0001; r s = 0.85, p < 0.0001). Serum levels of LECT2 showed high distinguishing features for patients with BA having an AUC of 0.95 (95% CI: 0.90-1.00). CD163 was highly expressed in the aggravation of fibrosis (0.158 ± 0.062 vs. 0.29 ± 0.078, p < 0.0001), and the expression of LECT2 was positively correlated with the accumulation of CD163+ macrophages (r = 0.48, p = 0.003). The bioinformatic analysis also showed that LECT2 was positively correlated with macrophage M2 (r = 0.34, p = 0.03). TGF-β1 and CD163 colocalized to the portal area in the livers of patients with BA. Moreover, TGF-β1 upregulated the expression of LECT2. CONCLUSION LECT2 is highly expressed in both BA liver tissue and serum, and serum LECT2 is a potential diagnostic biomarker of BA. Meanwhile, TGF-β1 is secreted by macrophages to regulate LECT2 associated with BA liver fibrosis.
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Affiliation(s)
- Jinfeng Zhao
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Xiaodan Xu
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Qingyun Gou
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Qipeng Zheng
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Liang Ge
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Lingzhi Chen
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Cong Zhang
- Graduate College, Tianjin Medical University, Tianjin, China.,Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
| | - Hui Ma
- Department of Laboratory Medicine, Tianjin Children's Hospital, Tianjin, China
| | - Shuxiang Lin
- Department of Pediatric Research Institute, Tianjin Children's Hospital, Tianjin, China
| | - Xiaoli Hu
- Department of Pathology, Tianjin Children's Hospital, Tianjin, China
| | - Jianghua Zhan
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
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18
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Zhu S, Bennett S, Li Y, Liu M, Xu J. The molecular structure and role of LECT2 or CHM-II in arthritis, cancer, and other diseases. J Cell Physiol 2021; 237:480-488. [PMID: 34550600 DOI: 10.1002/jcp.30593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/31/2021] [Accepted: 09/11/2021] [Indexed: 12/20/2022]
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2 or LECT-2), also called chondromodulin II (ChM-II or CHM2) plays a versatile role in various tissues. It was first identified as a chemotactic factor to promote the migration of neutrophils. It was also reported as a hepatokine to regulate glucose metabolism, obesity, and nonalcoholic fatty liver disease. As a secreted factor, LECT2 binds to several cell surface receptors CD209a, Tie1, and Met to regulate inflammatory reaction, fibrogenesis, vascular invasion, and tumor metastasis in various cell types. As an intracellular molecule, it is associated with LECT2-mediated amyloidosis, in which LECT2 misfolding results in insoluble fibrils in multiple tissues such as the kidney, liver, and lung. Recently, LECT2 was found to be associated with the development of rheumatoid arthritis and osteoarthritis, involving the dysregulation of osteoclasts, mesenchymal stem cells, osteoblasts, chondrocytes, and endothelial cells in the bone microenvironment. LECT2 is implicated in the development of cancers, such as hepatocellular carcinoma via MET-mediated PTP1B/Raf1/ERK signaling pathways and is proposed as a biomarker. The mechanisms by which LECT2 regulates diverse pathogenic conditions in various tissues remain to be fully elucidated. Further research to understand the role of LECT2 in a tissue tropism-dependent manner would facilitate the development of LECT2 as a biomarker for diagnosis and therapeutic target.
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Affiliation(s)
- Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Samuel Bennett
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Yihe Li
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Mei Liu
- School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jiake Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia
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19
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Luo C, Wang L, Wu G, Huang X, Zhang Y, Ma Y, Xie M, Sun Y, Huang Y, Huang Z, Song Q, Li H, Hou Y, Li X, Xu S, Chen J. Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies. Stem Cell Res Ther 2021; 12:310. [PMID: 34051862 PMCID: PMC8164253 DOI: 10.1186/s13287-021-02379-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies. METHODS We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin- Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200-250 μg/kg/day) group and the LD (low dose, 100-150 μg/kg/day) group based on doses, and were classified into the short-term (2-3 days) group and the long-term (4-5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen. RESULTS We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0-2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0-2733.0). CONCLUSIONS Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.
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Affiliation(s)
- Chengxin Luo
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guixian Wu
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Xiangtao Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Yali Zhang
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Yanni Ma
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Mingling Xie
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Yanni Sun
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Yarui Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Zhen Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Qiuyue Song
- Department of Health Statistics, Third Military Medical University, Chongqing, China
| | - Hui Li
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Yu Hou
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China
| | - Xi Li
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
| | - Shuangnian Xu
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China. .,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China.
| | - Jieping Chen
- Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China. .,Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China.
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20
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Ha JH, Tu HC, Wilkens S, Loh SN. Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2). J Biol Chem 2021; 296:100446. [PMID: 33617884 PMCID: PMC8039541 DOI: 10.1016/j.jbc.2021.100446] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/05/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Aggregation of the circulating protein leukocyte-cell-derived chemotaxin 2 (LECT2) causes amyloidosis of LECT2 (ALECT2), one of the most prevalent forms of systemic amyloidosis affecting the kidney and liver. The I40V mutation is thought to be necessary but not sufficient for ALECT2, with a second, as-yet undetermined condition being required for the disease. EM, X-ray diffraction, NMR, and fluorescence experiments demonstrate that LECT2 forms amyloid fibrils in vitro in the absence of other proteins. Removal of LECT2's single bound Zn2+ appears to be obligatory for fibril formation. Zinc-binding affinity is strongly dependent on pH: 9-13 % of LECT2 is calculated to exist in the zinc-free state over the normal pH range of blood, with this fraction rising to 80 % at pH 6.5. The I40V mutation does not alter zinc-binding affinity or kinetics but destabilizes the zinc-free conformation. These results suggest a mechanism in which loss of zinc together with the I40V mutation leads to ALECT2.
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Affiliation(s)
- Jeung-Hoi Ha
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Ho-Chou Tu
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Stephan Wilkens
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Stewart N Loh
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA.
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21
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Xu Z, He J, Zhou X, Zhang Y, Huang Y, Xu N, Yang H. Down-regulation of LECT2 promotes osteogenic differentiation of MSCs via activating Wnt/β-catenin pathway. Biomed Pharmacother 2020; 130:110593. [PMID: 32763823 DOI: 10.1016/j.biopha.2020.110593] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/21/2020] [Accepted: 07/29/2020] [Indexed: 12/22/2022] Open
Abstract
Osteoporosis is a result of the imbalance between osteoblasts and osteoclasts quantities, which is closely correlated with osteogenic differentiation (OD). Leucocyte cell-derived chemotaxin 2 (LECT2) has been reported as a regulatory factor in some chronic diseases such as hepatitis through mediating downstream target gene β-catenin. Additionally, Wnt/β-catenin is also the crucial modulatory signal pathway in OD. Mesenchymal stem cells (MSC) is a kind of mesodermal stem cells; its differentiation direction is discovered affected by Wnt/β-catenin. However, the function of LECT2 in osteoporosis still remains exploration, which encourages us to lucubrate its functional effect in regulating the OD of MSCs. In this study, we found that LECT2 was expressed at low level in MSCs with osteogenic differentiation, and knockdown of LECT2 would activate Wnt/β-catenin pathway and therefore promoting OD in MSCs. It is the first time to report that LECT2 participates in regulating OD via mediating Wnt/β-catenin. Our discovery would affirmatively help provide a novel strategy for the diagnosis and therapy methods for osteoporosis.
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Affiliation(s)
- Zhonghua Xu
- Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou, 213200, China
| | - Jin He
- Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou, 213200, China
| | - Xindie Zhou
- Department of Orthopedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China.
| | - Yi Zhang
- Department of Orthopedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Yong Huang
- Department of Orthopedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Nanwei Xu
- Department of Orthopedics, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Haoyu Yang
- Department of Orthopedics, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, 214000, China.
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22
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Lu XJ, Zhu K, Shen HX, Nie L, Chen J. CXCR4s in Teleosts: Two Paralogous Chemokine Receptors and Their Roles in Hematopoietic Stem/Progenitor Cell Homeostasis. THE JOURNAL OF IMMUNOLOGY 2020; 204:1225-1241. [DOI: 10.4049/jimmunol.1901100] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/11/2019] [Indexed: 12/20/2022]
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23
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Zhu K, Lu XJ, Chen J. The interleukin-6 regulates the function of monocytes/macrophages (MO/MФ) via the interleukin-6 receptor β in ayu (Plecoglossus altivelis). FISH & SHELLFISH IMMUNOLOGY 2019; 93:191-199. [PMID: 31326589 DOI: 10.1016/j.fsi.2019.07.049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/11/2019] [Accepted: 07/17/2019] [Indexed: 06/10/2023]
Abstract
Interleukin-6 (IL-6) is one of the most pleiotropic cytokines because of its wide range of effects on cells of the immune and non-immune systems in the body. However, the role of IL-6 in fish monocytes/macrophages (MO/MФ) is poorly understood. In this study, we cloned the cDNA sequence of the IL-6 gene from ayu (Plecoglossus altivelis) and demonstrated using a tissue distribution assay that ayu interleukin-6 (PaIL-6) mRNA is expressed in all tested tissues. Changes in expression were observed in immune tissues as well as in MO/MФ after a Vibrio anguillarum infection; subsequently, PaIL-6 was expressed and purified to prepare anti-PaIL-6 antibodies. Recombinant PaIL-6 protein (rPaIL-6) treatment enhanced pro-inflammatory cytokine expression. Ayu interleukin-6 receptor β (PaIL-6Rβ) knockdown resulted in decreased pro-inflammatory cytokine expression in MO/MФ treated with rPaIL-6, whereas no significant changes were observed after ayu interleukin-6 receptor α (PaIL-6Rα) knockdown in MO/MФ. PaIL-6 and PaIL-6Rβ knockdown in MO/MФ inhibited the phosphorylation of signal transducer and activator of transcription 1. Moreover, PaIL-6Rβ knockdown inhibited the phagocytic and bactericidal ability of ayu MO/MФ treated with rPaIL-6. These data indicate that PaIL-6 may be able to regulate the function of ayu MO/MФ.
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Affiliation(s)
- Kai Zhu
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Xin-Jiang Lu
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
| | - Jiong Chen
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China.
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24
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Xu M, Xu HH, Lin Y, Sun X, Wang LJ, Fang ZP, Su XH, Liang XJ, Hu Y, Liu ZM, Cheng Y, Wei Y, Li J, Li L, Liu HJ, Cheng Z, Tang N, Peng C, Li T, Liu T, Qiao L, Wu D, Ding YQ, Zhou WJ. LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis. Cell 2019; 178:1478-1492.e20. [PMID: 31474362 DOI: 10.1016/j.cell.2019.07.021] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 04/23/2019] [Accepted: 07/12/2019] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
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Affiliation(s)
- Meng Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Hong-Hai Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Yuan Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Guangdong 528333, China
| | - Xiangnan Sun
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Li-Jing Wang
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
| | - Zhe-Ping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Xue-Han Su
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Xiang-Jing Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Yang Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Zhi-Min Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Yuanxiong Cheng
- Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, China
| | - Yuanyuan Wei
- The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Jiabin Li
- The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Li Li
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
| | - Hong-Juan Liu
- Department of Bioinformation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zhiqiang Cheng
- Department of Pathology, Shenzhen People's Hospital, Shenzhen, Guangdong 515020, China
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital, Shenzhen, Guangdong 515020, China
| | - Chao Peng
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai 201210, China
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Tengfei Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital and Western Clinical School, Westmead, NSW 2145, Australia
| | - Dalei Wu
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China.
| | - Wei-Jie Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Guangdong 528333, China; Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong 510005, China.
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He WM, Dai T, Chen J, Wang JA. Leukocyte cell-derived chemotaxin 2 inhibits development of atherosclerosis in mice. Zool Res 2019; 40:317-323. [PMID: 31310065 PMCID: PMC6680125 DOI: 10.24272/j.issn.2095-8137.2019.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditions. However, its role in atherosclerosis remains undefined. In this study, we administered vehicle or LECT2 to male Apoe-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8, IL-1β, and TNF-α were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-α, IL-1β, IL-8, MCP-1, and MMP-1 concentrations were measured by enzyme-linked immunosorbent assay. CD68, CD31, and α-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immunostaining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-α, IL-8, and IL-1β mRNA abundance. Furthermore, LECT2 decreased CD68, but increased α-SMA in atherosclerotic lesions, suggesting an increase in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.
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Affiliation(s)
- Wen-Ming He
- Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang 310009, China.,Department of Cardiology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo Zhejiang 315010, China
| | - Ting Dai
- Department of Cardiology, the Affiliated Hospital of Medical School of Ningbo University, Ningbo Zhejiang 315010, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo Zhejiang 315832, China
| | - Jian-An Wang
- Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang 310009, China
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de Kruijf EJFM, Fibbe WE, van Pel M. Cytokine-induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche. Ann N Y Acad Sci 2019; 1466:24-38. [PMID: 31006885 PMCID: PMC7217176 DOI: 10.1111/nyas.14059] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/15/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
Peripheral blood hematopoietic stem and progenitor cells (HSPCs), mobilized by granulocyte colony‐stimulating factor, are widely used as a source for both autologous and allogeneic stem cell transplantation. The use of mobilized HSPCs has several advantages over traditional bone marrow–derived HSPCs, including a less invasive harvesting process for the donor, higher HSPC yields, and faster hematopoietic reconstitution in the recipient. For years, the mechanisms by which cytokines and other agents mobilize HSPCs from the bone marrow were not fully understood. The field of stem cell mobilization research has advanced significantly over the past decade, with major breakthroughs in the elucidation of the complex mechanisms that underlie stem cell mobilization. In this review, we provide an overview of the events that underlie HSPC mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed.
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Affiliation(s)
- Evert-Jan F M de Kruijf
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Willem E Fibbe
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Melissa van Pel
- Section of Stem Cell Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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Liu H, Lu XJ, Chen J. Full-length and a smaller globular fragment of adiponectin have opposite roles in regulating monocyte/macrophage functions in ayu, Plecoglossus altivelis. FISH & SHELLFISH IMMUNOLOGY 2018; 82:319-329. [PMID: 30130657 DOI: 10.1016/j.fsi.2018.08.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 08/17/2018] [Accepted: 08/18/2018] [Indexed: 06/08/2023]
Abstract
Adiponectin (ADP), a regulator of the innate immune system, plays a role in the progression of inflammation and metabolic disorders in mammals. However, the role of ADP in fish is poorly understood. Here, we cloned the cDNA sequence of a ADP homolog (PaADP) gene from ayu. Multiple sequence alignment revealed that PaADP presented typical characteristics of ADPs. Phylogenetic tree analysis showed that PaADP was most closely related to that of rainbow trout. In healthy ayu, the transcripts of PaADP were detected in most of the tested tissues and cells, with the highest level in the adipose tissue. Upon V. anguillarum infection, the mRNA expression of PaADP was significantly up-regulated in the tissues and cells except adipose tissue. Subsequently, the full-length mature PaADP (fPaADP) and the globular domain fragment (gPaADP) were prokaryotically expressed in bacteria and purified, and anti-PaADP antibodies were produced. Western blot analysis revealed that three fragments including fPaADP and gPaADP were existed in ayu serum. The recombinant fPaADP (rfPaADP) had an anti-inflammatory effect on ayu MO/MФ by upregulating anti-inflammatory cytokine expressions, downregulating pro-inflammatory cytokine expressions, inhibiting the phagocytosis and subsequent bacterial killing. In contrast, the recombinant gPaADP (rgPaADP) presented a pro-inflammatory effect on ayu MO/MФ by upregulating pro-inflammatory cytokine expression, downregulating anti-inflammatory cytokine expressions, enhancing the phagocytosis and subsequent bacterial killing. These results suggested that fPaADP and gPaADP have opposite roles in the regulation of MO/MФ functions in ayu.
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Affiliation(s)
- He Liu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China
| | - Xin-Jiang Lu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo 315211, China.
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Chai Y, Cong B, Yu S, Liu Y, Man X, Wang L, Zhu Q. Effect of a LECT2 on the immune response of peritoneal lecukocytes against Vibrio anguillarum in roughskin sculpin. FISH & SHELLFISH IMMUNOLOGY 2018; 74:620-626. [PMID: 29331349 DOI: 10.1016/j.fsi.2017.12.069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 12/28/2017] [Accepted: 12/31/2017] [Indexed: 06/07/2023]
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) is a multi-functional protein that is mainly synthesized by the liver. However, its role in roughskin scalping is less known. Here, we cloned a leukocyte cell-derived chemotaxin 2 (TfLECT2) genes in the liver of roughskin scalping, Trachidermus fasciatus, and studied its possible role involved in the immune response against Vibrio anguillarum (V. anguillarum) of peritoneal lecukocytes under in vivo conditions. The cDNA sequence of TfLECT2 is 566 bp in size. Its deduced amino acid (aa) sequence comprises 151 residues, of which the first 16 residues form a putative signal peptide and 101 residues compose a typical peptidase M23 domain in the C-terminal region. The domain structure is conserved in all LECT2 proteins, which suggests a close phylogenetic relationship between TfLECT2 and LECT2 in other fish species. Real-time quantitative PCR analysis revealed that TfLECT2 gene expression was dramatically increased in liver after V. anguillarum stimulation. Subsequently, TfLECT2 was prokaryotic expressed and purified to prepare anti-TfLECT2 antibody. After V. anguillarum challenge, leukocytes recruitment and LECT2 levels in peritoneal exudates were increased, and positively correlated with each other. Moreover, recombinant TfLECT2 administration significantly improved immune responses after infection, principally in stimulating the recruitment, phagocytosis and respiratory burst of leukocytes at the site of infection; however, anti-TfLECT2 treatment neutralized these abilities. Therefore, TfLECT2 may trigger the early immune events of peritoneal leukocytes and it will be useful to induce innate immune response of fish.
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Affiliation(s)
- Yingmei Chai
- Marine College, Shandong University (Weihai), Weihai 264209, PR China.
| | - Bailin Cong
- The First Institute of Oceanography, Marine Ecological Center, State Oceanic Administration, Qingdao, 266061, PR China
| | - Shanshan Yu
- Marine College, Shandong University (Weihai), Weihai 264209, PR China
| | - Yingying Liu
- Marine College, Shandong University (Weihai), Weihai 264209, PR China
| | - Xin Man
- Marine College, Shandong University (Weihai), Weihai 264209, PR China
| | - Lujie Wang
- Marine College, Shandong University (Weihai), Weihai 264209, PR China
| | - Qian Zhu
- Marine College, Shandong University (Weihai), Weihai 264209, PR China.
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Molecular characterization of mudskipper (Boleophthalmus pectinirostris) hypoxia-inducible factor-1α (HIF-1α) and analysis of its function in monocytes/macrophages. PLoS One 2017; 12:e0177960. [PMID: 28542591 PMCID: PMC5443510 DOI: 10.1371/journal.pone.0177960] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 05/05/2017] [Indexed: 01/13/2023] Open
Abstract
Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses and is important in controlling a variety of processes in monocytes and macrophages. However, very little information is available about the functions of HIF-1α in fish monocytes/macrophages (MO/MФ). In this study, the cDNA sequence of the mudskipper (Boleophthalmus pectinirostris) HIF-1α gene (BpHIF-1α) was determined. Sequence comparison and phylogenetic tree analysis showed that BpHIF-1α is clustered in the fish HIF-1α tree. Constitutive expression of BpHIF-1α mRNA was detected by real-time quantitative PCR in all tested tissues, and the expression was found to be dramatically increased in the skin, liver, spleen, and kidney after Edwardsiella tarda infection. In addition, hypoxia and infection induced the expression of the BpHIF-1α transcript and protein in MO/MФ, respectively. Hypoxia caused an increase in phagocytic and bactericidal capacity of mudskipper MO/MФ in a BpHIF-1α-dependent manner. BpHIF-1α induced an anti-inflammatory status in MO/MФ upon E. tarda infection and hypoxia. Therefore, BpHIF-1α may play a predominant role in the modulation of mudskipper MO/MФ function in the innate immune system.
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Lu XJ, Chen Q, Rong YJ, Chen F, Chen J. CXCR3.1 and CXCR3.2 Differentially Contribute to Macrophage Polarization in Teleost Fish. THE JOURNAL OF IMMUNOLOGY 2017; 198:4692-4706. [PMID: 28500070 DOI: 10.4049/jimmunol.1700101] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/18/2017] [Indexed: 12/29/2022]
Abstract
The study of multiple copies of chemokine receptor genes in various teleosts has long appealed to investigators seeking to understand the evolution of the immune system. The CXCR CXCR3 gene has two isoforms, CXCR3.1 and CXCR3.2, which are both expressed in macrophages. The distinct roles of teleost CXCR3s have not been identified previously. In this article, we found that CXCR3.1 and CXCR3.2 differentially contributed to macrophage polarization in the teleosts: ayu (Plecoglossus altivelis), grass carp (Ctenopharyngodon idella), and spotted green pufferfish (Tetraodon nigroviridis). In ayu macrophages, the P. altivelis CXCR3.1 (PaCXCR3.1) gene was constitutively expressed, whereas the P. altivelis CXCR3.2 (PaCXCR3.2) gene was induced postinfection with Escherichia coli Upon E. coli infection, PaCXCR3.1+ and PaCXCR3.2+ macrophages showed an M1 and an M2 phenotype, respectively. CXCL9-11-like proteins mediated M1 and M2 polarization by interacting with the PaCXCR3.1 and PaCXCR3.2 proteins on macrophages, respectively. The transcription factors P. altivelis STAT1 and P. altivelis STAT3 were activated in PaCXCR3.1+ and PaCXCR3.2+ macrophages, respectively. Furthermore, the prognosis of septic ayu adoptively transferred with PaCXCR3.2+ macrophages was improved. Our data reveal a previously unknown mechanism for macrophage polarization, suggesting that redundant genes may regulate crucial functions in the teleost immune system.
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Affiliation(s)
- Xin-Jiang Lu
- Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo 315211, People's Republic of China
| | - Qiang Chen
- Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo 315211, People's Republic of China
| | - Ye-Jing Rong
- Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo 315211, People's Republic of China
| | - Feng Chen
- Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo 315211, People's Republic of China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo 315211, People's Republic of China
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Lu XJ, Chen Q, Chen J, Chen J. Molecular identification and functional analysis of KLF2 in Plecoglossus altivelis (ayu): It's regulatory role in monocyte/macrophage activation. FISH & SHELLFISH IMMUNOLOGY 2017; 62:257-264. [PMID: 28130078 DOI: 10.1016/j.fsi.2017.01.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/22/2017] [Accepted: 01/23/2017] [Indexed: 06/06/2023]
Abstract
Monocytes/macrophages (MO/MФ) play an important role in the response to infection in Plecoglossus altivelis (ayu). However, the role of transcription factors in the function of ayu MO/MФ is poorly understood. Here, we cloned the cDNA sequence of the Kruppel-like factor 2 (PaKLF2) gene from ayu. Phylogenetic analysis indicated that PaKLF2 was closest to that of Atlantic salmon (Salmo salar). Real time quantitative PCR (RT-qPCR) revealed that the PaKLF2 mRNA level was highest in the peripheral blood mononuclear cells among all tested tissues. The mRNA expression of PaKLF2 was upregulated in the head kidney, liver, spleen, and brain after Listonella anguillarum infection. Subsequently, PaKLF2 was expressed and purified to prepare anti-PaKLF2 antibodies. After L. anguillarum challenge, the PaKLF2 mRNA and protein levels were significantly upregulated in ayu MO/MФ. Moreover, PaKLF2 knockdown in MO/MФ resulted in the enhancement of cytokine production as well as phagocytotic and bactericidal capability. Therefore, PaKLF2 may modulate the immune response in ayu by suppressing the function of MO/MФ.
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Affiliation(s)
- Xin-Jiang Lu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China
| | - Qiang Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China
| | - Jie Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China; Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China.
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32
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Bozec A, Soulat D. Latest perspectives on macrophages in bone homeostasis. Pflugers Arch 2017; 469:517-525. [PMID: 28247013 DOI: 10.1007/s00424-017-1952-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/02/2017] [Accepted: 02/07/2017] [Indexed: 12/17/2022]
Abstract
Knowledge about macrophages residing in the bone, also known as osteal macrophages or osteomacs, is still limited. A hallmark of this peculiar myeloid population is the expression of macrophage markers distinct from the markers found on osteoclast surface. In bone, osteomacs are in contact with osteoblasts, where they are involved in regulating bone homeostasis. However, additional macrophage subtypes already present in the bone marrow or recruited from the blood circulation could have further functions, which could be all important for the maintenance of the bone architecture and its associated functions. Indeed, bone marrow macrophages have been found to eliminate apoptotic cells, particularly apoptotic osteoblasts through a process named efferocytosis. This phagocytic process plays an essential role in bone tissue homeostasis and new bone formation. In addition, bone marrow macrophages can influence the hematopoietic stem cell (HSC) niches. They contribute to the regulation of the HSC progenitor cell maintenance, mobilization, and function. To do so, macrophages secrete cytokines in steady state or during stress conditions. These cytokines influence hematopoiesis either by a direct effect on HSCs or through the control of stromal cells that are essential for the HSC niches. Interestingly, the similarities between the niches for HSCs and the niche for metastatic tumor cells support the possibility that bone-resident macrophages could control the homing of tumor cells and their proliferation within the bone. In general, macrophage role during metastatic processes is well described; however, their direct involvement in bone metastasis is a rising research area. In this review, we will highlight the macrophage functions in the skeleton, in the maintenance of the HCS niches, and their importance in bone metastasis.
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Affiliation(s)
- Aline Bozec
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.
| | - Didier Soulat
- Department of Microbiology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, 91054, Germany
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Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. Int J Hematol 2016; 105:129-140. [PMID: 27943116 DOI: 10.1007/s12185-016-2162-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 11/21/2016] [Accepted: 11/29/2016] [Indexed: 12/23/2022]
Abstract
Hematopoietic stem cells (HSC) reside in perivascular regions of the bone marrow (BM) embedded within a complex regulatory unit called the niche. Cellular components of HSC niches include vascular endothelial cells, mesenchymal stromal progenitor cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes-further regulated by sympathetic nerves and complement components as described in this review. Three decades ago the discovery that cytokines induce a large number of HSC to mobilize from the BM into the blood where they are easily harvested, revolutionised the field of HSC transplantation-curative for immune-deficiencies and some malignancies. However, despite now routine use of granulocyte-colony stimulating factor (G-CSF) to mobilise HSC for transplant, only in last 15 years has research on the mechanisms behind why and how HSC can be induced to move into the blood began. These studies have revealed the complexity of the niche that retains HSC in the BM. This review describes how BM niches and HSC themselves change during administration of G-CSF-or in the recovery phase of chemotherapy-to facilitate movement of HSC into the blood, and research now leading to development of novel therapeutics to further boost HSC mobilization and transplant success.
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Bendall L. Extracellular molecules in hematopoietic stem cell mobilisation. Int J Hematol 2016; 105:118-128. [PMID: 27826715 DOI: 10.1007/s12185-016-2123-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 11/01/2016] [Indexed: 01/11/2023]
Abstract
Hematopoietic stem cells are a remarkable resource currently used for the life saving treatment, hematopoietic stem cell transplantation. Today, hematopoietic stem cells are primarily obtained from mobilized peripheral blood following treatment of the donor with the cytokine G-CSF, and in some settings, chemotherapy and/or the CXCR4 antagonist plerixafor. The collection of hematopoietic stem cells is contingent on adequate and timely mobilization of these cells into the peripheral blood. The use of healthy donors, particularly when unrelated to the patient, requires mobilization strategies be safe for the donor. While current mobilization strategies are largely successful, adequate mobilization fails to occur in a significant portion of donors. Understanding the mechanisms involved in the egress of stem cells from the bone marrow provides opportunities to further improve the process of collecting hematopoietic stem cells. Here, the role extracellular components of the blood and bone marrow in the mobilization process are discussed.
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Affiliation(s)
- Linda Bendall
- Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, 176 Hawkesbury Rd, Westmead, Sydney, NSW, 2145, Australia.
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