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Zheng Y, Bai B, Wei Z, Zhang M, Zhang Q, Li X. Plasma Exosomal-Derived SERPINA1 and GNAI2 Downregulation as Potential Diagnostic Biomarkers of Kawasaki Disease with Coronary Artery Aneurysms. Int J Mol Sci 2025; 26:2668. [PMID: 40141310 PMCID: PMC11942354 DOI: 10.3390/ijms26062668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Kawasaki disease (KD) with coronary artery aneurysms (CAAs) is currently the primary cause of childhood acquired heart disease with an unclear pathogenesis. We established five groups for the discovery of differentially expressed proteins (DEPs): healthy control, febrile control, KD without CAAs, KD with small and medium CAAs, and KD with giant CAAs (n = 8 in each group). The validation of selected DEPs was conducted in another five groups (n = 4 in each group). We conducted comprehensive bioinformatics analyses to elucidate the functional roles of the DEPs in the groups of KD with CAAs and KD without CAAs. A total of 104 DEPs were identified in KD patients, which were primarily associated with complement-related pathways. A trend analysis of these 104 DEPs revealed 54 significantly changed DEPs associated with increased disease severity, which were primarily associated with G-protein-related functions. The alterations in α-1-antitrypsin short peptide (SERPINA1) and guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2), which were selected from complement-related and G-protein-related pathways, respectively, were validated by Western blotting, and they were significantly decreased in KD patients with vs. without CAAs. In addition, we conducted an analysis of the DEPs in the groups of KD with CAAs and KD without CAAs, separately. There were 91 DEPs specifically expressed in KD patients with CAAs, associated with the neutrophil extracellular trap and complement pathways, while 16 DEPs were specific to those without CAAs, associated with viral infection and immunity pathways. Additionally, for DEPs among different severities of CAAs, there were 102 DEPs in KD patients with small and medium CAAs, associated with complement pathways and platelet activation pathways, whereas 34 DEPs were specific to giant CAAs, associated with the Rap1 signaling pathway and cell functions. In conclusion, this study provides plasmatic exosomal protein profiles in KD patients with CAAs, suggesting that SERPINA1 and GNIA2 might serve as novel potential diagnostic biomarkers for KD with CAAs.
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Affiliation(s)
- Yang Zheng
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Peking Union Medical College Graduate School, Beijing 100020, China;
| | - Baoling Bai
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China;
| | - Zhimiao Wei
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
| | - Mingming Zhang
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
| | - Qin Zhang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China;
| | - Xiaohui Li
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Peking Union Medical College Graduate School, Beijing 100020, China;
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
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Zhuo W, Zhang M, Tan J, Gao Y, Wang Y, Wang N, Ma J, Zhang J, Liu Z, Lv H, Liu Y. Lysine lactylation analysis of proteins in the heart of the Kawasaki disease mouse model. Front Cell Dev Biol 2025; 13:1550220. [PMID: 40114965 PMCID: PMC11922914 DOI: 10.3389/fcell.2025.1550220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction Kawasaki disease (KD) is a medium-vessel vasculitis predominantly affecting children under 5 years of age and may involve the coronary arteries. Methods A mouse KD model was induced by Candida albicans cell wall extracts (CAWS), cardiac tissues were analyzed through integrated lactylomic and proteomic profiling. The lysine lactylation (Kla) results were normalized to the proteomic data. Results Elevated serum lactate and lactate dehydrogenase (LDH) levels were observed in KD patients. Given lactate's role as a substrate for Kla, this study investigated Kla modifications in KD. Proteomic analysis identified 150 upregulated proteins and 18 downregulated proteins, with 38.1% located in the cytoplasm and significant enrichment in immune-related pathways. After normalization, 41 sites in 37 proteins were found to be upregulated in the Kla data, with no downregulated sites. Approximately 67.57% of the altered proteins were localized in the mitochondria. Bioinformatics analysis indicated alterations in aerobic respiration, energy production and conversion, and key immune- and metabolism-related pathways. Discussion This study enhances the understanding of Kla modifications in the development of KD and may inform targeted therapies for its prevention and improved prognosis.
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Affiliation(s)
- Wenyu Zhuo
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mingyang Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jiajia Tan
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yang Gao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Pediatrics, The First People's Hospital of Lianyungang, Xuzhou Medical University Affiliated Hospital of Lianyungang (Lianyungang Clinical College of Nanjing Medical University), Lianyungang, China
| | - Yan Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Cardiology, The Affiliated Xuzhou Children's Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Nana Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jin Ma
- Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jiaying Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhiheng Liu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Haitao Lv
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ying Liu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
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Kumrah R, Jindal AK, Rawat A, Singh S. Proteomics approach for biomarker discovery in Kawasaki disease. Expert Rev Clin Immunol 2024; 20:1449-1460. [PMID: 39041312 DOI: 10.1080/1744666x.2024.2383236] [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: 04/15/2024] [Revised: 06/07/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Kawasaki disease (KD) is a medium vessel vasculitis mainly affecting children below the age of 5. KD is the leading cause of acquired heart disease in developed countries. Diagnosis of KD is clinical, and there are no pathognomonic laboratory tests to confirm the diagnosis. There is a paucity of studies that have utilized proteomic approach for biomarker discovery in KD. Identification of these biomarkers may be helpful for early and more effective diagnosis and may aid in the treatment of KD. AREA COVERED The present review focuses on studies that have utilized the proteomic approach in the identification of biomarkers in patients with KD. We have divided these biomarkers into three different categories: the biomarkers used for (a) assessment of risk of KD; (b) assessment of risk of coronary artery aneurysms; and (c) assessment of treatment resistance. EXPERT OPINION Efforts to improve the clinical and diagnostic evaluation of KD have focused on general markers of inflammation that are not specific for KD. Identification of a proteomic-based biomarker can reliably and specifically differentiate KD from other diseases and could help in the prompt diagnosis. Comprehensive analysis of the serum proteome of patients with KD may be helpful in identifying candidate protein biomarkers.
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Affiliation(s)
- Rajni Kumrah
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ankur Kumar Jindal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Surjit Singh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Zhou Z, Zhang R, Zhou A, Lv J, Chen S, Zou H, Zhang G, Lin T, Wang Z, Zhang Y, Weng S, Han X, Liu Z. Proteomics appending a complementary dimension to precision oncotherapy. Comput Struct Biotechnol J 2024; 23:1725-1739. [PMID: 38689716 PMCID: PMC11058087 DOI: 10.1016/j.csbj.2024.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024] Open
Abstract
Recent advances in high-throughput proteomic profiling technologies have facilitated the precise quantification of numerous proteins across multiple specimens concurrently. Researchers have the opportunity to comprehensively analyze the molecular signatures in plentiful medical specimens or disease pattern cell lines. Along with advances in data analysis and integration, proteomics data could be efficiently consolidated and employed to recognize precise elementary molecular mechanisms and decode individual biomarkers, guiding the precision treatment of tumors. Herein, we review a broad array of proteomics technologies and the progress and methods for the integration of proteomics data and further discuss how to better merge proteomics in precision medicine and clinical settings.
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Affiliation(s)
- Zhaokai Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Ruiqi Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Aoyang Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jinxiang Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shuang Chen
- Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Haijiao Zou
- Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ge Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ting Lin
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhan Wang
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Henan 450052, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Matsuyama K, Yamada S, Sato H, Zhan J, Shoda T. Advances in omics data for eosinophilic esophagitis: moving towards multi-omics analyses. J Gastroenterol 2024; 59:963-978. [PMID: 39297956 PMCID: PMC11496339 DOI: 10.1007/s00535-024-02151-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/07/2024] [Indexed: 09/21/2024]
Abstract
Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus characterized by eosinophil accumulation and has a growing global prevalence. EoE significantly impairs quality of life and poses a substantial burden on healthcare resources. Currently, only two FDA-approved medications exist for EoE, highlighting the need for broader research into its management and prevention. Recent advancements in omics technologies, such as genomics, epigenetics, transcriptomics, proteomics, and others, offer new insights into the genetic and immunologic mechanisms underlying EoE. Genomic studies have identified genetic loci and mutations associated with EoE, revealing predispositions that vary by ancestry and indicating EoE's complex genetic basis. Epigenetic studies have uncovered changes in DNA methylation and chromatin structure that affect gene expression, influencing EoE pathology. Transcriptomic analyses have revealed a distinct gene expression profile in EoE, dominated by genes involved in activated type 2 immunity and epithelial barrier function. Proteomic approaches have furthered the understanding of EoE mechanisms, identifying potential new biomarkers and therapeutic targets. However, challenges in integrating diverse omics data persist, largely due to their complexity and the need for advanced computational methods. Machine learning is emerging as a valuable tool for analyzing extensive and intricate datasets, potentially revealing new aspects of EoE pathogenesis. The integration of multi-omics data through sophisticated computational approaches promises significant advancements in our understanding of EoE, improving diagnostics, and enhancing treatment effectiveness. This review synthesizes current omics research and explores future directions for comprehensively understanding the disease mechanisms in EoE.
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Affiliation(s)
- Kazuhiro Matsuyama
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7028, Cincinnati, OH, 45229, USA
- Department of Computer Science, University of Cincinnati, Cincinnati, USA
| | - Shingo Yamada
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7028, Cincinnati, OH, 45229, USA
| | - Hironori Sato
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7028, Cincinnati, OH, 45229, USA
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Justin Zhan
- Department of Computer Science, University of Cincinnati, Cincinnati, USA
| | - Tetsuo Shoda
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 7028, Cincinnati, OH, 45229, USA.
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Gu W, Mirsaidi-Madjdabadi S, Ramirez F, Simonson TS, Makino A. Transcriptome meta-analysis of Kawasaki disease in humans and mice. Front Pediatr 2024; 12:1423958. [PMID: 39350793 PMCID: PMC11440715 DOI: 10.3389/fped.2024.1423958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 08/29/2024] [Indexed: 10/04/2024] Open
Abstract
Kawasaki Disease (KD) affects young children less than five years old with severe blood vessel inflammation. Despite being treatable, the causes and mechanisms remain elusive. This study conducted a meta-analysis of RNA sequencing (RNA-seq) data from human and animal models to explore KD's transcriptomic profile and evaluate animal models. We retrieved bulk and single-cell RNA-seq data from Gene Expression Omnibus, with blood and coronary artery samples from KD patients, aorta samples from KD mouse models (Lactobacillus casei cell wall extract-injected mice), and their controls. Upon consistent quality control, we applied Fisher's exact test to assess differential gene expression, followed by an enrichment analysis of overlapping genes. These studies identified 400 differentially expressed genes in blood samples of KD patients compared to controls and 413 genes in coronary artery samples. The data from KD blood and KD coronary artery samples shared only 16 differentially expressed genes. Eighty-one genes overlapped between KD human coronary arteries and KD mouse aortas, and 67 of these 81 genes were regulated in parallel in both humans and mice: 30 genes were up-regulated, and 37 were down-regulated. These included previously identified KD-upregulated genes: CD74, SFRP4, ITGA4, and IKZF1. Gene enrichment analysis revealed significant alterations in the cardiomyopathy pathway. Single-cell RNAseq showed a few significant markers, with known KD markers like S100A9, S100A8, CD74, CD14, IFITM2, and IFITM3, being overexpressed in KD cohorts. Gene profiles obtained from KD human coronary artery are more compatible with data from aorta samples of KD mice than blood samples of KD humans, validating KD animal models for identifying therapeutic targets. Although blood samples can be utilized to discover novel biomarkers, more comprehensive single-cell sequencing is required to detail gene expression in different blood cell populations. This study identifies critical genes from human and mouse tissues to help develop new treatment strategies for KD.
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Affiliation(s)
- Wanjun Gu
- Department of Medicine, University of California, San Diego, CA, United States
| | | | - Francisco Ramirez
- Department of Medicine, University of California, San Diego, CA, United States
- Center for Inflammation Science and Systems Medicine, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, United States
| | - Tatum S. Simonson
- Department of Medicine, University of California, San Diego, CA, United States
| | - Ayako Makino
- Department of Medicine, University of California, San Diego, CA, United States
- Center for Inflammation Science and Systems Medicine, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, United States
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Sapountzi E, Kotanidou EP, Tsinopoulou VR, Kalinderi K, Fidani L, Giannopoulos A, Galli-Tsinopoulou A. Kawasaki Disease: An update on Genetics and Pathophysiology. Genet Test Mol Biomarkers 2024; 28:373-383. [PMID: 39185556 DOI: 10.1089/gtmb.2024.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024] Open
Abstract
Kawasaki disease (KD), a systemic vasculitic condition predominantly affecting children, remains a significant challenge in pediatric health care. First identified in 1967, KD is now recognized as the primary cause of pediatric ischemic heart disease in developed countries. This review provides a comprehensive update of KD, focusing on biomarkers, pathophysiology, and genetic associations. KD's clinical manifestation, including symptoms such as persistent fever and mucocutaneous changes, often overlaps with other pediatric conditions, complicating its diagnosis. This ambiguity, especially in cases of incomplete KD, highlights the critical need for specific biomarkers and more precise diagnostic methods. Recent studies have made promising advancements in identifying serum biomarkers and microRNAs, contributing to the development of rapid diagnostic tools. However, these are yet to be fully integrated into clinical practice. The article focuses on the pathophysiological aspects of KD, highlighting the potential for targeted therapies and personalized medicine approaches based on genetic predispositions. Collaborative efforts in global research and raising public awareness about KD are emphasized as key strategies for improving its management. This review presents the current understanding of KD while pointing out the gaps and future directions in research and clinical care. The ultimate goal is to enhance diagnostic accuracy, optimize treatment strategies, and improve patient outcomes, thereby addressing the complexities of this enigmatic and potentially life-threatening condition in pediatric medicine.
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Affiliation(s)
- Evdoxia Sapountzi
- Outpatient Rheumatology Unit, 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Eleni P Kotanidou
- 2 Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Vasiliki-Rengina Tsinopoulou
- 2 Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Kallirhoe Kalinderi
- Laboratory of Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Liana Fidani
- 2 Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
- Laboratory of Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Giannopoulos
- 2 Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 2 Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
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Pugh D, Patel D, Macnaught G, Czopek A, Bruce L, Donachie J, Gallacher PJ, Tan S, Ahlman M, Grayson PC, Basu N, Dhaun N. 18F-FDG-PET/MR imaging to monitor disease activity in large vessel vasculitis. Nat Commun 2024; 15:7314. [PMID: 39183340 PMCID: PMC11345444 DOI: 10.1038/s41467-024-51613-1] [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: 11/23/2023] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Disease-monitoring in large vessel vasculitis (LVV) is challenging. Simultaneous 18F-fluorodeoxyglucose positron emission tomography with magnetic resonance imaging (PET/MRI) provides functional assessment of vascular inflammation alongside high-definition structural imaging with a relatively low burden of radiation exposure. Here, we investigate the ability of PET/MRI to monitor LVV disease activity longitudinally in a prospective cohort of patients with active LVV. We demonstrate that both the PET and MRI components of the scan can distinguish active from inactive disease using established quantification methods. Using logistic-regression modelling of PET/MRI metrics, we devise a novel PET/MRI-specific Vasculitis Activity using MR PET (VAMP) score which is able to distinguish active from inactive disease with more accuracy than established methods and detects changes in disease activity longitudinally. These findings are evaluated in an independent validation cohort. Finally, PET/MRI improves clinicians' assessment of LVV disease activity and confidence in disease management, as assessed via clinician survey. In summary, PET/MRI may be useful in tracking disease activity and assessing treatment-response in LVV. Based on our findings, larger, prospective studies assessing PET/MRI in LVV are now warranted.
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Affiliation(s)
- Dan Pugh
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Dilip Patel
- Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | | | - Alicja Czopek
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Lorraine Bruce
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - James Donachie
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Peter J Gallacher
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Sovira Tan
- National Institute of Arthritis & Musculoskeletal & Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark Ahlman
- Department of Radiology & Imaging, Medical College of Georgia, Georgia, USA
| | - Peter C Grayson
- National Institute of Arthritis & Musculoskeletal & Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Neil Basu
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK
| | - Neeraj Dhaun
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
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Dritsoula A, Camilli C, Moss SE, Greenwood J. The disruptive role of LRG1 on the vasculature and perivascular microenvironment. Front Cardiovasc Med 2024; 11:1386177. [PMID: 38745756 PMCID: PMC11091338 DOI: 10.3389/fcvm.2024.1386177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024] Open
Abstract
The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.
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Affiliation(s)
- Athina Dritsoula
- UCL Institute of Ophthalmology, University College London, London, United Kingdom
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Özer E, Yilmaz HE, Narin F, Sağlam M. The evaluation of salivary leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in humans with periodontal health or periodontal disease. J Periodontal Res 2024; 59:387-394. [PMID: 38126217 DOI: 10.1111/jre.13223] [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: 08/17/2023] [Revised: 11/29/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE The purpose of the present research is to evaluate the salivary levels of leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in periodontal health and disease (gingivitis and stage III periodontitis) and also to compare the discriminative efficiencies of both biomarkers in periodontal disease. BACKGROUND LRG is a new acute-phase protein whose functions are still being investigated. LRG and CRP are both biomarkers that are increased by inflammation. No clinical study has yet investigated the comparison of the level of LRG and CRP in periodontal health, gingivitis and periodontitis in saliva samples. METHODS A total of 60 individuals, including 20 periodontally healthy (control group/group C), 20 with gingivitis (group G), and 20 with Stage III periodontitis (group P), who were systemically healthy and non-smokers, participated in this study. Periodontal charts were used for recording clinical periodontal parameters and saliva LRG and CRP levels were measured by ELISA. Analyzing the area under the curve (AUC) was performed by the receiver-operating characteristics curve. RESULTS Salivary levels of LRG and CRP were significantly higher in disease groups than in group C (p < .05). Positive statistically significant correlations were observed between both biomarkers and clinical parameters (p < .05). There was also a strong positive correlation between two biomarkers (p < .05). In distinguishing periodontal disease from periodontal health, LRG (AUC = 0.833) and CRP (AUC = 0.826) were found to have similar accuracy (p = .923). CONCLUSION LRG and CRP may be useful and similarly effective biomarkers in the diagnosis of periodontal diseases based on the findings of this study.
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Affiliation(s)
- Ece Özer
- Department of Periodontology, Faculty of Dentistry, Izmir Katip Celebi University, Izmir, Turkey
| | - Huriye Erbak Yilmaz
- Department of Medical Biochemistry, School of Medicine, Izmir Katip Celebi University, Izmir, Turkey
- Izmir Biomedicine Genome Center, Dokuz Eylul University, Izmir, Turkey
| | - Figen Narin
- Department of Medical Biochemistry, School of Medicine, Izmir Katip Celebi University, Izmir, Turkey
| | - Mehmet Sağlam
- Department of Periodontology, Faculty of Dentistry, Izmir Katip Celebi University, Izmir, Turkey
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11
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Zhang J, Yang P, Liu Y, Chen Z, Wu J, Feng S, Yi Q. Serum levels of PDGF-CC as a potential biomarker for the diagnosis of Kawasaki disease. Ital J Pediatr 2024; 50:16. [PMID: 38273388 PMCID: PMC10809580 DOI: 10.1186/s13052-024-01580-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/07/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that predominantly affects children, and no specific diagnostic biomarkers for KD are available. Platelet-derived growth factor CC (PDGF-CC) is a peptide with angiogenic properties that has been amply demonstrated to play a critical role in the cardiovascular system. This study aimed to investigate the serum expression of PDGF-CC in children with KD and to evaluate the ability of PDGF-CC to diagnose KD. METHODS A total of 96 subjects, including 59 KD patients, 17 febrile controls (FC), and 20 healthy controls (HC), were enrolled. Serum levels of PDGF-CC were measured via enzyme-linked immunosorbent assay. The associations between PDGF-CC and clinical laboratory parameters were investigated by correlation analysis. The diagnostic performance was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS Serum PDGF-CC levels in the KD group were significantly higher than in the FC and HC groups. Serum PDGF-CC levels in the KD group were positively correlated with white blood cell counts, percentage of neutrophils, IL-2, IL-12p70, TNF-α, and IL-1β levels, and negatively correlated with the percentage of lymphocytes. In the analysis of ROC curves, the area under the curve was 0.796 (95% confidence interval 0.688-0.880; P < 0.0001) for PDGF-CC and increased to 0.900 (95% confidence interval 0.808-0.957; P < 0.0001) in combination with white blood cell counts and C-reactive protein. CONCLUSIONS PDGF-CC is a potential biomarker for KD diagnosis, and the combination with white blood cell counts and C-reactive protein can further improve diagnostic performance.
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Affiliation(s)
- Jing Zhang
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Penghui Yang
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Yihao Liu
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Zhuo Chen
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Jinhui Wu
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China
| | - Siqi Feng
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
| | - Qijian Yi
- Department of Cardiovascular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, National Clinical Research Center for Child Health and Disorders, National Clinical Key Cardiovascular Specialty, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
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12
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Kumar Barik A, Mathew C, Sanoop PM, John RV, Adigal SS, Bhat S, Pai KM, Bhandary SV, Devasia T, Upadhya R, Kartha VB, Chidangil S. Protein profile pattern analysis: A multifarious, in vitro diagnosis technique for universal screening. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1232:123944. [PMID: 38056315 DOI: 10.1016/j.jchromb.2023.123944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 12/08/2023]
Abstract
Universal health care is attracting increased attention nowadays, because of the large increase in population all over the world, and a similar increase in life expectancy, leading to an increase in the incidence of non-communicable (various cancers, coronary diseases, neurological and old-age-related diseases) and communicable diseases/pandemics like SARS-COVID 19. This has led to an immediate need for a healthcare technology that should be cost-effective and accessible to all. A technology being considered as a possible one at present is liquid biopsy, which looks for markers in readily available samples like body fluids which can be accessed non- or minimally- invasive manner. Two approaches are being tried now towards this objective. The first involves the identification of suitable, specific markers for each condition, using established methods like various Mass Spectroscopy techniques (Surface-Enhanced Laser Desorption/Ionization Mass Spectroscopy (SELDI-MS), Matrix-Assisted Laser Desorption/Ionization (MALDI-MS), etc., immunoassays (Enzyme-Linked Immunoassay (ELISA), Proximity Extension Assays, etc.) and separation methods like 2-Dimensional Polyacrylamide Gel Electrophoresis (2-D PAGE), Sodium Dodecyl-Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE), Capillary Electrophoresis (CE), etc. In the second approach, no attempt is made the identification of specific markers; rather an efficient separation method like High-Performance Liquid Chromatography/ Ultra-High-Performance Liquid Chromatography (HPLC/UPLC) is used to separate the protein markers, and a profile of the protein pattern is recorded, which is analysed by Artificial Intelligence (AI)/Machine Learning (MI) methods to derive characteristic patterns and use them for identifying the disease condition. The present report gives a summary of the current status of these two approaches and compares the two in the use of their suitability for universal healthcare.
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Affiliation(s)
- Ajaya Kumar Barik
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Clint Mathew
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Pavithran M Sanoop
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Reena V John
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sphurti S Adigal
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sujatha Bhat
- Division of Microbiology, Department of Basic Medical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Keerthilatha M Pai
- Department of Dental Surgery, Sikkim Manipal Institute of Medical Sciences, Sikkim Manipal University, Gangtok, Sikkim 737102, India
| | - Sulatha V Bhandary
- Department of Ophthalmology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Tom Devasia
- Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Rekha Upadhya
- Department of Obstetrics and Gynecology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - V B Kartha
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Santhosh Chidangil
- Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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13
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Amir O, Prajjwal P, Inban P, Gadam S, Aleti S, Sunasra RR, Gupta K, Elhag M, Mahmoud M, Alsir O. Neurological involvement, immune response, and biomarkers in Kawasaki disease along with its pathogenesis, therapeutic and diagnostic updates. F1000Res 2023; 12:235. [PMID: 37065507 PMCID: PMC10102713 DOI: 10.12688/f1000research.130169.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/05/2023] Open
Abstract
Kawasaki disease is an acute, febrile disease that is not typically fatal if treated and affects infants and children more commonly. More than 80% of the afflicted patients are under the age of four. This disease most commonly affects coronary arteries. In a minority of cases, Aneurysms can burst or produce thrombosis, and they can cause infarction. The distinctive redness in the palms and soles of the feet might result from a delayed-type hypersensitivity reaction to a cross-reactive or recently discovered antigen (s). Autoantibodies against epithelial cells and smooth muscle cells are produced as a result of subsequent macromolecule synthesis and polyclonal white blood cell activation, which intensifies the redness. Kawasaki disease's clinical manifestations range from oral skin disease to the blistering of the mucosa, symptoms involving the hands and the feet, skin disease of the palms and soles, a desquamative rash, and cervical lymphatic tissue enlargement (so it is also referred to as tissue layer lymphatic tissue syndrome). Most untreated patients develop some vessel sequelae, from well-organized coronary inflammation to severe arterial blood vessel dilatation to giant artery aneurysms with rupture or occlusion, infarction, and thrombosis. With human gamma globulin administration, reasonable standards of medical care, and the use of analgesics, the speed of symptomatic progression and inflammatory artery changes are reduced. In this review, we have covered the immunology of Kawasaki disease, its biomarkers, and the neurological manifestations of this multisystem illness. We have also included a discussion on its pathogenesis, diagnosis, and treatment.
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Affiliation(s)
| | - Priyadarshi Prajjwal
- Neurology, Bharati Vidyapeeth University Medical College and Hospital, Pune, India
| | | | | | - Soumya Aleti
- Internal Medicine, Berkshire Medical Center, Pittsfield, Massachusetts, USA
| | | | - Karan Gupta
- Orthopedics, Government medical college, Patiala, India
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Amir O, Prajjwal P, Inban P, Gadam S, Aleti S, Sunasra RR, Gupta K, Elhag M, Mahmoud M, Alsir O. Neurological involvement, immune response, and biomarkers in Kawasaki disease along with its pathogenesis, therapeutic and diagnostic updates. F1000Res 2023; 12:235. [PMID: 37065507 PMCID: PMC10102713 DOI: 10.12688/f1000research.130169.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Kawasaki disease is an acute, febrile disease that is not typically fatal if treated and affects infants and children more commonly. More than 80% of the afflicted patients are under the age of four. This disease most commonly affects coronary arteries. In a minority of cases, Aneurysms can burst or produce thrombosis, and they can cause infarction. The distinctive redness in the palms and soles of the feet might result from a delayed-type hypersensitivity reaction to a cross-reactive or recently discovered antigen (s). Autoantibodies against epithelial cells and smooth muscle cells are produced as a result of subsequent macromolecule synthesis and polyclonal white blood cell activation, which intensifies the redness. Kawasaki disease's clinical manifestations range from oral skin disease to the blistering of the mucosa, symptoms involving the hands and the feet, skin disease of the palms and soles, a desquamative rash, and cervical lymphatic tissue enlargement (so it is also referred to as tissue layer lymphatic tissue syndrome). Most untreated patients develop some vessel sequelae, from well-organized coronary inflammation to severe arterial blood vessel dilatation to giant artery aneurysms with rupture or occlusion, infarction, and thrombosis. With human gamma globulin administration, reasonable standards of medical care, and the use of analgesics, the speed of symptomatic progression and inflammatory artery changes are reduced. In this review, we have covered the immunology of Kawasaki disease, its biomarkers, and the neurological manifestations of this multisystem illness. We have also included a discussion on its pathogenesis, diagnosis, and treatment.
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Affiliation(s)
| | - Priyadarshi Prajjwal
- Neurology, Bharati Vidyapeeth University Medical College and Hospital, Pune, India
| | | | | | - Soumya Aleti
- Internal Medicine, Berkshire Medical Center, Pittsfield, Massachusetts, USA
| | | | - Karan Gupta
- Orthopedics, Government medical college, Patiala, India
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15
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Fang H, Greening DW. An Optimized Data-Independent Acquisition Strategy for Comprehensive Analysis of Human Plasma Proteome. Methods Mol Biol 2023; 2628:93-107. [PMID: 36781781 DOI: 10.1007/978-1-0716-2978-9_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Cartography of the plasma proteome remains technically challenging, primarily due to the abundance and dynamic range of plasma proteins and their concentrations, exceeding ten orders of magnitude, including low-abundant tissue-derived proteins in the pg/mL range. Data-independent acquisition mass spectrometry (DIA-MS) has seen advances in unbiased mass spectrometry-based proteomic analysis of the plasma proteome. Here, we describe a comprehensive proteomic workflow of human plasma from clinically relevant sample (10 μL) that includes anti-protein immunodepletion and highly sensitive sample preparation workflow, with optimized scheduled isolation DIA-MS and deep learning analysis. This approach results in over 960 proteins quantified from a single-shot analysis of broad dynamic range, across 8 orders of magnitude (8.2 ng/L to 0.67 g/L). We further compare data-dependent acquisition (DDA) MS to highlight the advantage in protein quantification and inter-sample variation. These developments have provided streamlined identification of the human plasma proteome, including low-abundant tissue-enriched proteins, and applications toward understanding the plasma proteome.
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Affiliation(s)
- Haoyun Fang
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
| | - David W Greening
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. .,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia. .,Central Clinical School, Monash University, Melbourne, VIC, Australia. .,Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, VIC, Australia.
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Yamashita K, Kanazawa T, Abe Y, Naruto T, Mori M. Kawasaki disease without changes in inflammatory biomarkers: A case report. World J Clin Cases 2022; 10:13038-13043. [PMID: 36569014 PMCID: PMC9782948 DOI: 10.12998/wjcc.v10.i35.13038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Kawasaki disease (KD) is diagnosed based on clinical features. Blood tests and other tests are auxiliary diagnostic tools. Since KD is a disease caused by arterial inflammation, many patients with KD have elevated levels of inflammatory biomarkers, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A protein (SAA) in blood tests. We report our experience of a patient with KD who did not have elevated levels of inflammatory biomarkers.
CASE SUMMARY A 1-year-old boy presented with a 3-day history of fever. Five of the six symptoms of KD were observed, except for changes in the lips and oral cavity. Blood tests revealed no elevation in CRP, ESR, or SAA levels. Although the blood test results were atypical, the patient was diagnosed with KD based on clinical symptoms and was admitted to the hospital for treatment. The patient was administered intravenous immunoglobulin (IVIG) and aspirin. Despite commencing treatment, the fever persisted; therefore, additional IVIG was administered, the dosage of aspirin was increased, and ulinastatin was added. Three doses of IVIG were administered and the fever resolved on day 11 of KD symptoms started. Blood tests performed during hospitalization showed normal levels of inflammatory biomarkers. We examined leucine-rich alpha-2-glycoprotein 1 - a protein that is elevated during the acute phase of KD. The protein levels did not increase during hospitalization.
CONCLUSION This case suggests the need to identify criteria and biomarkers for detecting KD conditions that do not require KD treatment.
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Affiliation(s)
- Kosei Yamashita
- Children’s Medical Center, Showa University Koto Toyosu Hospital, Tokyo 135-8577, Japan
| | - Takeru Kanazawa
- Children’s Medical Center, Showa University Koto Toyosu Hospital, Tokyo 135-8577, Japan
| | - Yoshifusa Abe
- Children’s Medical Center, Showa University Koto Toyosu Hospital, Tokyo 135-8577, Japan
| | - Takuya Naruto
- Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masaaki Mori
- Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Rheumatology, Clinical Immunology and Allergology, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan
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Wu J, Cao L, Wang J, Wang Y, Hao H, Huang L. Characterization of serum protein expression profiles in the early sarcopenia older adults with low grip strength: a cross-sectional study. BMC Musculoskelet Disord 2022; 23:894. [PMID: 36192674 PMCID: PMC9528053 DOI: 10.1186/s12891-022-05844-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
Background Sarcopenia refers to the progressive loss of skeletal muscle mass and muscle function, which seriously threatens the quality of life of the older adults. Therefore, early diagnosis is urgently needed. This study aimed to explore the changes of serum protein profiles in sarcopenia patients through a cross-sectional study, and to provide the reference for clinical diagnosis. Methods This study was a cross-sectional study carried out in the Tianjin institute of physical education teaching experiment training center from December 2019 to December 2020. Ten older adults were recruited, including 5 sarcopenia and 5 healthy older adults. After a detailed diagnostic evaluation, blood samples were collected to prepare serum for proteomic analysis using the HPLC System Easy nLC method. The differentially expressed proteins (DEPs) were screened by the limma package of R software (version 4.1.0). Results A total of 114 DEPs were identified between the patients and healthy older adults, including 48 up-regulated proteins and 66 down-regulated proteins. The functional enrichment analysis showed that the 114 DEPs were significantly enriched in 153 GO terms, which mainly involved in low-density lipoprotein particle remodeling, and negative regulation of immune response,etc. The PPI network further suggested that the cholesteryl ester transfer protein and Apolipoprotein A2 could serve as biomarkers to facilitate diagnosis of sarcopenia. Conclusions This study provided a serum proteomic profile of sarcopenia patients, and identified two proteins with diagnostic value, which might help to improve the diagnostic accuracy of sarcopenia. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-022-05844-2.
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Affiliation(s)
- Jingqiong Wu
- TianJin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, 301617, PR China.,Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Longjun Cao
- TianJin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, 301617, PR China
| | - Jiazhi Wang
- TianJin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, 301617, PR China
| | - Yizhao Wang
- Tianjin Huanhu Hospital, Tianjin, 300350, PR China
| | - Huimin Hao
- TianJin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, 301617, PR China
| | - Liping Huang
- TianJin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, 301617, PR China.
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Rajasekaran K, Duraiyarasan S, Adefuye M, Manjunatha N, Ganduri V. Kawasaki Disease and Coronary Artery Involvement: A Narrative Review. Cureus 2022; 14:e28358. [PMID: 36185934 PMCID: PMC9514671 DOI: 10.7759/cureus.28358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
Kawasaki disease is a systemic vasculitis with a risk of developing coronary artery lesions if left untreated. Kawasaki disease can be diagnosed clinically with classical symptoms (conjunctivitis, rash, lymphadenopathy, mucositis, edema of hands and feet), but predicting the risk of developing coronary artery aneurysm remains challenging. The coronary sequelae of Kawasaki disease have significant morbidity and mortality and are the second most common cause of acquired cardiac disease in children. Several genetic and immune factors are involved in the inflammation of coronary artery lesions in Kawasaki disease. Inositol trisphosphate 3-Kinase (ITPKC), Foxp3+, circular RNAs, mannose-binding lectin 2 (MBL2), complement factor H (CFH), kininogen 1 (KNG1), serpin family C member 1 (SERPINC1) and fibronectin 1 (FN1) are the essential genes identified in the pathogenesis of coronary artery lesions in Kawasaki disease. The addition of methylprednisolone to a combination of aspirin and intravenous immunoglobulins and biological agents like anakinra, etanercept, infliximab, and immunosuppressants like cyclosporine prevents the occurrence of coronary artery aneurysms in Kawasaki disease. Since the coronary artery lesions form the second most common cause of acquired cardiac disease in children and the incidence of myocardial infarction is a late complication, the risk stratification for coronary artery aneurysms and follow-up protocols for the prevention of cardiac thrombosis were proposed by the American Heart Association in 2017.
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An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial. J Clin Immunol 2022; 42:1330-1341. [PMID: 35699824 PMCID: PMC9537216 DOI: 10.1007/s10875-022-01301-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 05/30/2022] [Indexed: 11/20/2022]
Abstract
Purpose A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. Methods Patients’ and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. Results Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release. Conclusion Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01301-w.
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Improper Proteostasis: Can It Serve as Biomarkers for Neurodegenerative Diseases? Mol Neurobiol 2022; 59:3382-3401. [PMID: 35305242 DOI: 10.1007/s12035-022-02775-w] [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: 10/22/2021] [Accepted: 02/19/2022] [Indexed: 10/18/2022]
Abstract
Cells synthesize new proteins after multiple molecular decisions. Damage of existing proteins, accumulation of abnormal proteins, and basic requirement of new proteins trigger protein quality control (PQC)-based alternative strategies to cope against proteostasis imbalance. Accumulation of misfolded proteins is linked with various neurodegenerative disorders. However, how deregulated components of this quality control system and their lack of general mechanism-based long-term changes can serve as biomarkers for neurodegeneration remains largely unexplored. Here, our article summarizes the chief findings, which may facilitate the search of novel and relevant proteostasis mechanism-based biomarkers associated with neuronal disorders. Understanding the abnormalities of PQC coupled molecules as possible biomarkers can help to determine neuronal fate and their contribution to the aetiology of several nervous system disorders.
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Hirano H, Shirakawa J. Recent developments in Phos-tag electrophoresis for the analysis of phosphoproteins in proteomics. Expert Rev Proteomics 2022; 19:103-114. [PMID: 35285370 DOI: 10.1080/14789450.2022.2052850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Phosphate-binding tag (Phos-tag) sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) is an important development capable of analyzing the phosphorylation state of proteins. Conventionally, proteins were separated via SDS-PAGE and Phos-tag SDS-PAGE that use different gels to identify phosphorylated proteins. However, it was often difficult to compare the electrophoretic mobility of the proteins in the different gels used. The recently developed Phos-tag diagonal electrophoresis has been able to solve this problem. It can indicate the SDS-PAGE and Phos-tag SDS-PAGE patterns on a single gel; therefore, phosphorylated proteins can be distinguished easily from non-phosphorylated proteins. AREAS COVERED This review assesses the importance of Phos-tag electrophoresis, which enables the analysis of protein phosphorylation states, in the field of proteomics. Additionally, this review describes the significance and actual experimental technique of Phos-tag diagonal electrophoresis, which was recently developed to overcome the drawbacks of Phos-tag SDS-PAGE. EXPERT OPINION Although shotgun analysis of proteins allows detecting many phosphorylation sites, it is challenging to clarify the differences in the phosphorylation states of protein molecules using this technique. Therefore, Phos-tag SDS-PAGE is frequently used to determine the phosphorylation state of proteins. This technique has become more powerful with the recent development of Phos-tag diagonal electrophoresis.
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Affiliation(s)
- Hisashi Hirano
- Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Jun Shirakawa
- Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
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22
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Kawamura Y, Miura H, Saito K, Kanno T, Yokoyama T, Aizawa Y, Yoshikawa T. An atypical case of Kawasaki disease with severe pneumonia in a neonate. BMC Pediatr 2022; 22:132. [PMID: 35287620 PMCID: PMC8918903 DOI: 10.1186/s12887-022-03203-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 03/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Kawasaki disease (KD) is an acute, febrile, systemic vasculitis of unknown etiology that primarily affects the coronary arteries and generally occurs at around 1 year of age. Although the diagnosis of KD is generally not difficult, it is challenging in cases of incomplete KD lacking characteristic clinical manifestations. The incidence of incomplete KD is higher in infants younger than 6 months of age. Pneumonia is an extremely rare complication of KD and can be misinterpreted as atypical pneumonia rather than KD. Herein, we report a neonate with atypical KD and severe pneumonia who required mechanical ventilation. CASE PRESENTATION Japanese one-month-old infant had only fever and rash on admission (day 1), and he was transferred to the intensive care unit for severe pneumonia on day 2. Although pneumonia improved following intensive care, he was diagnosed with KD on day 14 because of emerging typical clinical manifestations such as fever, bulbar nonexudative conjunctival injection, desquamation of the fingers, and coronary artery aneurysm. KD symptoms improved after three doses of intravenous immunoglobulin plus cyclosporine. However, small coronary aneurysms were present at the time of discharge. In a retrospective analysis, no pathogens were detected by multiplex real-time PCR in samples collected at admission, and the serum cytokine profile demonstrated prominent elevation of IL-6 as well as elevation of neopterin, sTNF-RI, and sTNF-RII, which suggested KD. CONCLUSIONS The patient's entire clinical course, including the severe pneumonia, was caused by KD. As in this case, neonatal KD may exhibit atypical manifestations such as severe pneumonia requiring mechanical ventilation.
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Affiliation(s)
- Yoshiki Kawamura
- Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake, Aichi, 47-01192, Japan.
| | - Hiroki Miura
- Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake, Aichi, 47-01192, Japan
| | - Kazuyoshi Saito
- Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake, Aichi, 47-01192, Japan
| | - Takayuki Kanno
- Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Tadafumi Yokoyama
- Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuta Aizawa
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Tetsushi Yoshikawa
- Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake, Aichi, 47-01192, Japan
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23
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Sato H, Inoue Y, Kawashima Y, Nakajima D, Ishikawa M, Konno R, Nakamura R, Kato D, Mitsunaga K, Yamamoto T, Yamaide A, Tomiita M, Hoshioka A, Ohara O, Shimojo N. In-Depth Serum Proteomics by DIA-MS with In Silico Spectral Libraries Reveals Dynamics during the Active Phase of Systemic Juvenile Idiopathic Arthritis. ACS OMEGA 2022; 7:7012-7023. [PMID: 35252692 PMCID: PMC8892657 DOI: 10.1021/acsomega.1c06681] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 05/09/2023]
Abstract
In serum proteomics using mass spectrometry, the number of detectable proteins is reduced due to high-abundance proteins, such as albumin. However, recently developed data-independent acquisition mass spectrometry (DIA-MS) proteomics technology has made it possible to remarkably improve the number of proteins in a serum analysis by removing high-abundance proteins. Using this technology, we analyzed sera from patients with systemic juvenile idiopathic arthritis (sJIA), a rare pediatric disease. As a result, we identified 2727 proteins with a wide dynamic range derived from various tissue leakages. We also selected 591 proteins that differed significantly in their active phases. These proteins were involved in many inflammatory processes, and we also identified immunoproteasomes, which were not previously found in serum, suggesting that they may be involved in the pathogenesis of sJIA. A detailed high-depth DIA-MS proteomic analysis of serum may be useful for understanding the pathogenesis of sJIA and may provide clues for the development of new biomarkers.
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Affiliation(s)
- Hironori Sato
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
- Department
of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8677, Japan
| | - Yuzaburo Inoue
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
- Division
of Cancer Genetics, Chiba Cancer Center
Research Institute, Chiba, Chiba 260-8717, Japan
| | - Yusuke Kawashima
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Daisuke Nakajima
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Masaki Ishikawa
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Ryo Konno
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Ren Nakamura
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Daigo Kato
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
| | - Kanako Mitsunaga
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
| | - Takeshi Yamamoto
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
- Benaroya
Research Institute at Virginia Mason, Seattle, Washington 98101-2795, United States
| | - Akiko Yamaide
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
| | - Minako Tomiita
- Department
of Clinical Research, National Hospital
Organization Shimoshizu National Hospital, Yotsukaido, Chiba 284-0003, Japan
| | - Akira Hoshioka
- Department
of Allergy and Rheumatology, Chiba Children’s
Hospital, Chiba, Chiba 266-0007, Japan
| | - Osamu Ohara
- Department
of Applied Genomics, Kazusa DNA Research
Institute, Kisarazu, Chiba 292-0818, Japan
| | - Naoki Shimojo
- Center for
Preventive Medical Sciences, Chiba University, Chiba, Chiba 263-8522, Japan
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24
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Zou Y, Xu Y, Chen X, Wu Y, Fu L, Lv Y. Research Progress on Leucine-Rich Alpha-2 Glycoprotein 1: A Review. Front Pharmacol 2022; 12:809225. [PMID: 35095520 PMCID: PMC8797156 DOI: 10.3389/fphar.2021.809225] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/13/2021] [Indexed: 12/18/2022] Open
Abstract
Leucine-rich alpha⁃2 glycoprotein 1 (LRG1) is an important member of the leucine-rich repetitive sequence protein family. LRG1 was mainly involved in normal physiological activities of the nervous system, such as synapse formation, synapse growth, the development of nerve processes, neurotransmitter transfer and release, and cell adhesion molecules or ligand-binding proteins. Also, LRG1 affected the development of respiratory diseases, hematological diseases, endocrine diseases, tumor diseases, eye diseases, cardiovascular diseases, rheumatic immune diseases, infectious diseases, etc. LRG1 was a newly discovered important upstream signaling molecule of transforming growth factor⁃β (TGF⁃β) that affected various pathological processes through the TGF⁃β signaling pathway. However, research on LRG1 and its involvement in the occurrence and development of diseases was still in its infancy and the current studies were mainly focused on proteomic detection and basic animal experimental reports. We could reasonably predict that LRG1 might act as a new direction and strategy for the treatment of many diseases.
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Affiliation(s)
- Yonghui Zou
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.,School of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yi Xu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.,School of Clinical Medicine, Nanchang University, Nanchang, China
| | - Xiaofeng Chen
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.,School of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yaoqi Wu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.,College of Pharmacy, Nanchang University, Nanchang, China
| | - Longsheng Fu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yanni Lv
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
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25
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Mohan B, Kumar S, Xi H, Ma S, Tao Z, Xing T, You H, Zhang Y, Ren P. Fabricated Metal-Organic Frameworks (MOFs) as luminescent and electrochemical biosensors for cancer biomarkers detection. Biosens Bioelectron 2022; 197:113738. [PMID: 34740120 DOI: 10.1016/j.bios.2021.113738] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/03/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023]
Abstract
In the health domain, a major challenge is the detection of diseases using rapid and cost-effective techniques. Most of the existing cancer detection methods show poor sensitivity and selectivity and are time consuming with high cost. To overcome this challenge, we analyzed porous fabricated metal-organic frameworks (MOFs) that have better structures and porosities for enhanced biomarker sensing. Here, we summarize the use of fabricated MOF luminescence and electrochemical sensors in devices for cancer biomarker detection. Various strategies of fabrication and the role of fabricated materials in sensing cancer biomarkers have been studied and described. The structural properties, sensing mechanisms, roles of noncovalent interactions, limits of detection, modeling, advantages, and limitations of MOF sensors have been well-discussed. The study presents an innovative technique to detect the cancer biomarkers by the use of luminescence and electrochemical MOF sensors. In addition, the potential association studies have been opening the way for personalized patient treatments and the development of new cancer-detecting devices.
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Affiliation(s)
- Brij Mohan
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Sandeep Kumar
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Hui Xi
- School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Shixuan Ma
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Zhiyu Tao
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Tiantian Xing
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Hengzhi You
- School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China
| | - Yang Zhang
- School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China.
| | - Peng Ren
- Laboratory of Coordination Chemistry and Functional Materials, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055, China; School of Science, Harbin Institute of Technology (Shezhen), Shenzhen 518055, China.
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26
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Camilli C, Hoeh AE, De Rossi G, Moss SE, Greenwood J. LRG1: an emerging player in disease pathogenesis. J Biomed Sci 2022; 29:6. [PMID: 35062948 PMCID: PMC8781713 DOI: 10.1186/s12929-022-00790-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open
Abstract
The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1-/- mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.
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Affiliation(s)
- Carlotta Camilli
- Institute of Ophthalmology, University College London, London, UK.
| | - Alexandra E Hoeh
- Institute of Ophthalmology, University College London, London, UK
| | - Giulia De Rossi
- Institute of Ophthalmology, University College London, London, UK
| | - Stephen E Moss
- Institute of Ophthalmology, University College London, London, UK
| | - John Greenwood
- Institute of Ophthalmology, University College London, London, UK
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27
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Identification of serum prognostic biomarkers of severe COVID-19 using a quantitative proteomic approach. Sci Rep 2021; 11:20638. [PMID: 34667241 PMCID: PMC8526747 DOI: 10.1038/s41598-021-98253-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 09/06/2021] [Indexed: 12/17/2022] Open
Abstract
The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.
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28
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Yanagimachi M, Fukuda S, Tanaka F, Iwamoto M, Takao C, Oba K, Suzuki N, Kiyohara K, Kuranobu D, Tada N, Nagashima A, Ishii T, Ino Y, Kimura Y, Nawa N, Fujiwara T, Naruto T, Morio T, Doi S, Mori M. Leucine-rich alpha-2-glycoprotein 1 and angiotensinogen as diagnostic biomarkers for Kawasaki disease. PLoS One 2021; 16:e0257138. [PMID: 34499692 PMCID: PMC8428710 DOI: 10.1371/journal.pone.0257138] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 08/24/2021] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Kawasaki disease (KD) is a systemic vasculitis in childhood that can lead to coronary artery lesions (CALs). Although early diagnosis and treatment is important for preventing KD patients from development of CALs, diagnosis depends on the clinical features of KD. We studied the usefulness of leucine-rich alpha-2-glycoprotein 1 (LRG1) and angiotensinogen (AGT), previously reported as KD-related proteins, for KD diagnosis and estimation of intravenous immunoglobulin (IVIG) efficacy. METHODS We undertook a prospective cohort study with patients having two or more KD symptoms in multiple centers in Japan, between July 2017 and February 2019. RESULTS Two hundred forty-two patients were included. In multivariable analysis, one unit increase in LRG1 was associated with higher odds of KD diagnosis (Odds ratio [OR] 1.02 [95% confidence interval (CI) 1.001-1.03]). Double-positivity for AGT (≥ 26 μg/mL) and LRG1 (≥ 123.5 μg/mL) was an independent biomarker for KD diagnosis in both the total cohort and the subgroup of patients with two to four KD symptoms (OR 5.01 [95% CI 1.86-13.50] and 3.71 [95% CI 1.23-11.16], respectively). There was no association between LRG1/AGT and IVIG efficacy. CONCLUSION Double-positivity for LRG1 and AGT is an biomarker for KD diagnosis, especially useful in diagnosing incomplete KD from non-KD. Future studies with larger cohorts should seek to determine whether LRG1 and AGT are valuable as definitive data referred at the diagnosis of KD and for estimating the risk of CALs.
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Affiliation(s)
- Masakatsu Yanagimachi
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hematology/Oncology, Kanagawa Children’s Medical Center, Yokohama, Japan
| | - Sayaka Fukuda
- Department of Pediatrics, Saiseikai Yokohama-shi Tobu Hospital, Yokohama, Japan
| | - Fumiko Tanaka
- Department of Pediatrics, Saiseikai Yokohama-shi Nanbu Hospital, Yokohama, Japan
| | - Mari Iwamoto
- Department of Pediatrics, Saiseikai Yokohama-shi Tobu Hospital, Yokohama, Japan
| | - Chiho Takao
- Department of Pediatrics, Saiseikai Yokohama-shi Nanbu Hospital, Yokohama, Japan
| | - Kunihiro Oba
- Department of Pediatrics, Showa General Hospital, Tokyo, Japan
| | - Natsuko Suzuki
- Department of Pediatrics, Japanese Red Cross Musashino Hospital, Tokyo, Japan
| | - Koji Kiyohara
- Department of Pediatrics, Tokyo-Kita Medical Center, Tokyo, Japan
| | - Dai Kuranobu
- Department of Pediatrics, Kawaguchi Municipal Medical Center, Saitama, Japan
| | - Norimasa Tada
- Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Ayako Nagashima
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Pediatrics, Tokyo-Kita Medical Center, Tokyo, Japan
| | - Taku Ishii
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoko Ino
- Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Yayoi Kimura
- Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Nobutoshi Nawa
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takeo Fujiwara
- Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takuya Naruto
- Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Morio
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shouzaburo Doi
- Department of Community Pediatrics, Perinatal, and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaaki Mori
- Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- * E-mail:
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29
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Prediction Model for Diagnosis of Kawasaki Disease Using iTRAQ-Based Analysis. CHILDREN-BASEL 2021; 8:children8070576. [PMID: 34356555 PMCID: PMC8304649 DOI: 10.3390/children8070576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/28/2021] [Accepted: 07/03/2021] [Indexed: 12/14/2022]
Abstract
A quick prediction method may help confirm the diagnosis of Kawasaki disease (KD), and reduce the risk of coronary artery lesions. The purpose of this study was to evaluate potential candidate diagnostic serum proteins in KD using isobaric tagging for relative and absolute quantification (iTRAQ) gel-free proteomics. Ninety two subjects, including 68 KD patients (1.6 ± 1.2 years, M/F 36/32) and 24 fever controls with evident respiratory tract infection (2.1 ± 1.2 years, M/F 13/11) were enrolled. Medical records were reviewed for demographic and laboratory data. The iTRAQ gel-free proteomics was used to screen serum proteins completely and compare the difference between two groups followed by specific validation with ELISA. The candidate proteins and conventional laboratory items were selected for the prediction model of KD diagnosis by support vector machine. Five selected candidate proteins, including protein S100-A8, protein S100-A9, protein S100-A12, neutrophil defensin 1, and alpha-1-acid glycoprotein 1 were identified for developing the prediction model of KD diagnosis. They were used to develop an efficient KD prediction model with an area under receiver operating characteristic (auROC) value of 0.92 (95% confidence interval: 0.84, 0.98). These protein biomarkers were significantly correlated with the conventional laboratory items as follows: C-reactive protein, glutamic pyruvic transaminase, white blood count, platelet, segment and hemoglobin. These conventional laboratory items were used to develop a prediction model of KD diagnosis with an auROC value of 0.88 (95% confidence interval: 0.80, 0.96). Our result demonstrated that the prediction model with combined five selected candidate protein levels may be a good diagnostic tool of KD. Further prediction model with combined six conventional laboratory data is also an acceptable alternative method for KD diagnosis.
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30
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Suganuma E, Sato S, Honda S, Nakazawa A. All trans retinoic acid alleviates coronary stenosis by regulating smooth muscle cell function in a mouse model of Kawasaki disease. Sci Rep 2021; 11:13856. [PMID: 34226641 PMCID: PMC8257698 DOI: 10.1038/s41598-021-93459-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/22/2021] [Indexed: 12/17/2022] Open
Abstract
Coronary artery (CA) stenosis is a detrimental and often life-threatening sequela in Kawasaki disease (KD) patients with coronary artery aneurysm (CAA). Therapeutic strategies for these patients have not yet been established. All-trans-retinoic acid (atRA) is a modulator of smooth muscle cell functions. The purpose of this study was to investigate the effect of atRA on CA stenosis in a mouse model of KD. Lactobacillus casei cell wall extract (LCWE) was intraperitoneally injected into 5-week-old male C57BL/6 J mice to induce CA stenosis. Two weeks later, the mice were orally administered atRA (30 mg/kg) 5 days per week for 14 weeks (LCWE + atRA group, n = 7). Mice in the untreated group (LCWE group, n = 6) received corn oil alone. Control mice were injected with phosphate-buffered saline (PBS, n = 5). Treatment with atRA significantly suppressed CA inflammation (19.3 ± 2.8 vs 4.4 ± 2.8, p < 0.0001) and reduced the incidence of CA stenosis (100% vs 18.5%, p < 0.05). In addition, atRA suppressed the migration of human coronary artery smooth muscle cells (HCASMCs) induced by platelet-derived growth factor subunit B homodimer (PDGF-BB). In conclusion, atRA dramatically alleviated CA stenosis by suppressing SMC migration. Therefore, it is expected to have clinical applications preventing CA stenosis in KD patients with CAA.
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Affiliation(s)
- Eisuke Suganuma
- Division of Infectious Diseases and Immunology, Allergy, Saitama Children's Medical Center, 1-2 Shintoshin Chuou-ku Saitama-shi, Saitama, 330-8777, Japan.
| | - Satoshi Sato
- Division of Infectious Diseases and Immunology, Allergy, Saitama Children's Medical Center, 1-2 Shintoshin Chuou-ku Saitama-shi, Saitama, 330-8777, Japan
| | - Satoko Honda
- Division of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Atsuko Nakazawa
- Division of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
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Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles. Int J Mol Sci 2021; 22:ijms22115655. [PMID: 34073389 PMCID: PMC8198135 DOI: 10.3390/ijms22115655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023] Open
Abstract
The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host 'omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple 'omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of 'omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both 'omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both 'omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.
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Qian G, Xu L, Qin J, Huang H, Zhu L, Tang Y, Li X, Ma J, Ma Y, Ding Y, Lv H. Leukocyte proteomics coupled with serum metabolomics identifies novel biomarkers and abnormal amino acid metabolism in Kawasaki disease. J Proteomics 2021; 239:104183. [PMID: 33737236 DOI: 10.1016/j.jprot.2021.104183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/01/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022]
Abstract
Kawasaki disease (KD) is a systemic vasculitis that can lead to severe cardiovascular complications, whereas the development and clinical usage of specific biomarkers might help diagnose KD and avoid certain complications. To this end, the molecular profiles of acute KD patients with coronary artery lesions (CAL) were first investigated through leukocyte proteomics and serum metabolomics assays. A total of 269 differentially abundant proteins and 35 differentially abundant metabolites with the top fold-changed levels were identified in acute KD patients compared to those in the healthy controls. Among them, several highly promising candidate marker proteins and metabolites indicative of KD progression were further analysed, such as the increased proteins ALPL, NAMPT, and S100P, as well as the decreased proteins C1QB and apolipoprotein family members. Moreover, metabolites, including succinic acid, dGMP, hyaluronic acid, L-tryptophan, propionylcarnitine, inosine, and phosphorylcholine, were found to be highly accurate at distinguishing between KD patients and healthy controls. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon intravenous immunoglobulin (IVIG) treatment. Overall, this work has revealed novel biomarkers and abnormal amino-acid metabolism as a prominent feature involved in KD patients with CAL. SIGNIFICANCE: KD is frequently concomitant with the development of life-threatening coronary vasculitis. Here, the profiles of leukocyte proteomics and serum metabolomics in acute KD patients with CALs were first investigated, and several hub molecules identified here could be used as supplemental biomarkers for KD diagnosis. Moreover, the metabolomic abnormalities especially the amino acids are particularly prominent in KD patients. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon IVIG treatment. Therefore, these findings might help understand the IVIG activities and also the underlying mechanisms of IVIG-resistant patients, thereby providing a new perspective for the exploration of mechanisms related to KD.
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Affiliation(s)
- Guanghui Qian
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China.
| | - Lei Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China
| | - Jie Qin
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China
| | - Hongbiao Huang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China
| | - Liyan Zhu
- Medical College of Soochow University, Suzhou 215123, China
| | - Yunjia Tang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Xuan Li
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Jin Ma
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Yingying Ma
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu Province 215025, China
| | - Yueyue Ding
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China.
| | - Haitao Lv
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China.
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Yoshimura T, Mitsuyama K, Sakemi R, Takedatsu H, Yoshioka S, Kuwaki K, Mori A, Fukunaga S, Araki T, Morita M, Tsuruta K, Yamasaki H, Torimura T. Evaluation of Serum Leucine-Rich Alpha-2 Glycoprotein as a New Inflammatory Biomarker of Inflammatory Bowel Disease. Mediators Inflamm 2021; 2021:8825374. [PMID: 33623482 PMCID: PMC7874844 DOI: 10.1155/2021/8825374] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Studies on serum leucine-rich alpha-2 glycoprotein (LRG) in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are scarce; the methods for estimating disease activity are less established, particularly for CD. This study is aimed at evaluating the utility of serum LRG as a potential inflammatory marker for IBD and to investigate the LRG gene expression in peripheral blood mononuclear cells (PBMCs) as a possible source of serum LRG. Overall, 98 patients with UC and 96 patients with CD were prospectively enrolled and clinically evaluated; 92 age-matched individuals served as the healthy controls. The blood samples were analyzed for serum LRG levels and routine laboratory parameters. Disease activity was assessed clinically and endoscopically. Finally, LRG gene expression in the PBMCs from a different cohort (41 patients with UC, 34 patients with CD, and 30 healthy controls) was examined. The serum LRG levels were higher during active disease than during inactive disease; additionally, serum LRG levels were positively correlated with clinical disease activity, C-reactive protein (CRP) levels, and other laboratory parameters in patients with UC and CD and with endoscopic disease activity in UC. UC and CD showed comparable areas under the curve (AUC) values for determining clinical remission and differentiating between endoscopic remission associated with LRG and CRP. The levels of LRG mRNA were also increased in PBMCs from patients with UC and CD and reflected disease activity. These data suggest that serum LRG, originated partially from PBMCs, is an inflammatory marker in UC and CD. A large-scale well-designed study should be conducted in the future to more accurately reveal the clinical significance of LRG in patients with IBD.
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Affiliation(s)
- Tetsuhiro Yoshimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Ryosuke Sakemi
- Department of Gastroenterology, Tobata Kyoritsu Hospital, Kitakyushu, Japan
| | - Hidetoshi Takedatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Shinichiro Yoshioka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Kotaro Kuwaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Atsushi Mori
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Shuhei Fukunaga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Toshihiro Araki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Masaru Morita
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Kozo Tsuruta
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
- Inflammatory Bowel Disease Center, Kurume University Hospital, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Hiroshi Yamasaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
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Li SC, Tsai KW, Huang LH, Weng KP, Chien KJ, Lin Y, Tu CY, Lin PH. Serum proteins may facilitate the identification of Kawasaki disease and promote in vitro neutrophil infiltration. Sci Rep 2020; 10:15645. [PMID: 32973234 PMCID: PMC7518260 DOI: 10.1038/s41598-020-72695-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/04/2020] [Indexed: 12/16/2022] Open
Abstract
Kawasaki disease (KD) usually affects the children younger than 5 years of age and subsequently causes coronary artery lesions (CALs) without timely identification and treatment. Developing a robust and fast prediction method may facilitate the timely diagnosis of KD, significantly reducing the risk of CALs in KD patients. The levels of inflammatory serum proteins dramatically vary during the onsets of many immune diseases, including in KD. However, our understanding of their pathogenic roles in KD is behind satisfaction. The purpose of this study was to evaluate candidate diagnostic serum proteins and the potential mechanism in KD using iTRAQ gel-free proteomics. We enrolled subjects and conducted iTRAQ gel-free proteomics to globally screen serum proteins followed by specific validation with ELISA. Further in vitro leukocyte trans-endothelial model was also applied to investigate the pathogenesis roles of inflammatory serum proteins. We identified six KD protein biomarkers, including Protein S100-A8 (S100A8), Protein S100-A9 (S100A9), Protein S100-A12 (S100A12), Peroxiredoxin-2 (PRDX2), Neutrophil defensin 1 (DEFA1) and Alpha-1-acid glycoprotein 1 (ORM1). They enabled us to develop a high-performance KD prediction model with an auROC value of 0.94, facilitating the timely identification of KD. Further assays concluded that recombinant S100A12 protein treatment activated neutrophil surface adhesion molecules responsible for adhesion to endothelial cells. Therefore, S100A12 promoted both freshly clinically isolated neutrophils and neutrophil-like cells to infiltrate through the endothelial layer in vitro. Finally, the antibody against S100A12 may attenuate the infiltration promoted by S100A12. Our result demonstrated that evaluating S100A8, S100A9, S100A12, PRDX2, DEFA1 and ORM1 levels may be a good diagnostic tool of KD. Further in vitro study implied that S100A12 could be a potential therapeutic target for KD.
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Affiliation(s)
- Sung-Chou Li
- Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Lien-Hung Huang
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ken-Pen Weng
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, No.386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung, Taiwan. .,Department of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.
| | - Kuang-Jen Chien
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, No.386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung, Taiwan
| | - Yuyu Lin
- Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chi-Ying Tu
- Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, No.386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung, Taiwan
| | - Pei-Hsien Lin
- Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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35
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Structure equation model and neural network analyses to predict coronary artery lesions in Kawasaki disease: a single-centre retrospective study. Sci Rep 2020; 10:11868. [PMID: 32681105 PMCID: PMC7368009 DOI: 10.1038/s41598-020-68657-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/28/2020] [Indexed: 12/17/2022] Open
Abstract
A new method to predict coronary artery lesions (CALs) in Kawasaki disease (KD) was developed using a mean structure equation model (SEM) and neural networks (Nnet). There were 314 admitted children with KD who met at least four of the six diagnostic criteria for KD. We defined CALs as the presence of a maximum z score of ≥ 3.0. The SEM using age, sex, intravenous immunoglobulin resistance, number of steroid pulse therapy sessions, C-reactive protein level, and urinary β2-microglobulin (u-β2MG/Cr) values revealed a perfect fit based on the root mean square error of approximation with an R2 value of 1.000 and the excellent discrimination of CALs with a sample score (SS) of 2.0 for a latent variable. The Nnet analysis enabled us to predict CALs with a sensitivity, specificity and c-index of 73%, 99% and 0.86, respectively. This good and simple statistical model that uses common parameters in clinical medicine is useful in deciding the appropriate therapy to prevent CALs in Japanese KD patients.
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36
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Correlation of increased serum leucine-rich α2-glycoprotein levels with disease prognosis, progression, and activity of interstitial pneumonia in patients with dermatomyositis: A retrospective study. PLoS One 2020; 15:e0234090. [PMID: 32479560 PMCID: PMC7263588 DOI: 10.1371/journal.pone.0234090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 05/18/2020] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To investigate whether leucine-rich α2-glycoprotein (LRG) can be a biomarker for the disease activity, progression, and prognosis of interstitial pneumonia (IP) in patients with dermatomyositis (DM). METHODS Correlations between the clinical findings and serum LRG levels were investigated in 46 patients with DM-IP (33 with acute/subacute IP [A/SIP] and 13 patients with chronic IP [CIP], including 10 fatal cases of IP). RESULTS The median serum LRG level of 18.4 (14.6-25.2) μg/mL in DM-IP patients was higher than that in healthy control subjects. The median levels of serum LRG at baseline and at 2 and 4 weeks after the initiation of treatment in the patients who died were significantly higher than those in the surviving patients (P = 0.026, 0.029, and 0.008, respectively). The median level of serum LRG in the DM-A/SIP patients was significantly higher than that in the DM-CIP patients (P = 0.0004), and that in the anti-MDA5-Ab-positive group was slightly higher than that in the anti-ARS-Ab-positive group. The serum LRG levels correlated significantly with the serum levels of LDH, C-reactive protein, ferritin, AaDO2, %DLco, and total ground-glass opacity score. The survival rate after 24 weeks in patients with an initial LRG level ≥ 17.6 μg/mL (survival rate: 40%) was significantly lower than that in patients with an initial LRG level < 17.6 μg/mL (100%) (P = 0.0009). CONCLUSION The serum LRG level may be a promising marker of disease activity, progression, and prognosis in patients with DM-IP.
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Hicar MD. Antibodies and Immunity During Kawasaki Disease. Front Cardiovasc Med 2020; 7:94. [PMID: 32671098 PMCID: PMC7326051 DOI: 10.3389/fcvm.2020.00094] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 04/30/2020] [Indexed: 12/14/2022] Open
Abstract
The cause of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology studies support that an infectious disease is involved in at least starting the inflammatory cascade set off during KD. Clues from epidemiology support that humoral immunity can have a protective effect. However, the role of the immune system, particularly of B cells and antibodies, in pathogenesis of KD is still unclear. Intravenous immunoglobulin (IVIG) and other therapies targeted at modulating inflammation can prevent development of coronary aneurysms. A number of autoantibody responses have been reported in children with KD and antibodies have been generated from aneurysmal plasma cell infiltrates. Recent reports show that children with KD have similar plasmablast responses as other children with infectious diseases, further supporting an infectious starting point. As ongoing studies are attempting to identify the etiology of KD through study of antibody responses, we sought to review the role of humoral immunity in KD pathogenesis, treatment, and recovery.
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Affiliation(s)
- Mark Daniel Hicar
- University at Buffalo, Buffalo, NY, United States.,John R. Oishei Children's Hospital, Buffalo, NY, United States.,Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
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38
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Fujimoto M, Matsumoto T, Serada S, Tsujimura Y, Hashimoto S, Yasutomi Y, Naka T. Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis. Sci Rep 2020; 10:3384. [PMID: 32099022 PMCID: PMC7042324 DOI: 10.1038/s41598-020-60450-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 02/12/2020] [Indexed: 12/17/2022] Open
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB.
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Affiliation(s)
- Minoru Fujimoto
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, 783-8505, Japan.
| | - Tomoshige Matsumoto
- Department of Medicine, Osaka Prefectural Hospital Organization Osaka Habikino Medical Center, Habikino, 583-8588, Japan.,Department of Internal Medicine, Osaka Anti-Tuberculosis Association Osaka Hospital, Neyagawa, 572-0854, Japan
| | - Satoshi Serada
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, 783-8505, Japan
| | - Yusuke Tsujimura
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, 305-0843, Japan
| | - Shoji Hashimoto
- Department of Clinical Research Center, Osaka Prefectural Hospital Organization Osaka Habikino Medical Center, Habikino, 583-8588, Japan
| | - Yasuhiro Yasutomi
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, 305-0843, Japan
| | - Tetsuji Naka
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, 783-8505, Japan.,Laboratory of Immune Signal, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 567-0085, Japan
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Ching LL, Nerurkar VR, Lim E, Shohet RV, Melish ME, Bratincsak A. Elevated Levels of Pentraxin 3 Correlate With Neutrophilia and Coronary Artery Dilation During Acute Kawasaki Disease. Front Pediatr 2020; 8:295. [PMID: 32670996 PMCID: PMC7330095 DOI: 10.3389/fped.2020.00295] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022] Open
Abstract
Kawasaki disease (KD) is the leading cause of acquired pediatric heart disease in the developed world as 25-30% of untreated patients and at least 5% of treated patients will develop irreversible coronary artery lesions (CAL). Pentraxin-3 (PTX-3) has been well-studied in inflammatory diseases, particularly in cardiovascular diseases associated with vascular endothelial dysfunction. We hypothesized that PTX-3 plays an important role in the development of KD-associated CAL and investigated the circulating levels of PTX-3 in the serum of KD patients. Children with acute KD were followed from diagnosis through normalization of the clinical parameters of inflammation (convalescent phase). Serum samples were obtained and echocardiograms were conducted at several phases of the illness: acute [prior to intravenous immunoglobulin (IVIG) treatment], sub-acute (5-10 days after IVIG treatment), and convalescent (1-4 months after KD diagnosis). Seventy children were included in the final cohort of the study, of whom 26 (37%) presented with CAL and 18 (26%) developed IVIG resistance. The patients included in this study came from diverse ethnic backgrounds, mostly with mixed ancestry/ ethnicity. Significantly increased PTX-3 levels were observed during the acute phase of KD compared to the sub-acute and the convalescent phases. The PTX-3 levels during acute KD were significantly higher among KD patients with CAL compared to patients with normal coronary arteries (NCA). Also, the PTX-3 levels were significantly higher in patients with IVIG resistance. Furthermore, the PTX-3 levels were significantly higher in IVIG-resistant KD patients with CAL as compared to the NCA group. Moreover, the PTX-3 levels were significantly correlated to coronary artery z-score during acute KD and to neutrophil counts throughout KD progression regardless of coronary artery z-score. Elevated PTX-3 levels correlated to elevated neutrophil counts, a known source of PTX-3 in acute inflammation and an important player in the development of KD vasculitis. We, therefore, suggest PTX-3 as a novel factor in the development of KD-associated CAL and propose neutrophil-derived PTX-3 as contributing to KD vascular dysfunction.
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Affiliation(s)
- Lauren L Ching
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.,Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States
| | - Vivek R Nerurkar
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.,Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States
| | - Eunjung Lim
- Biostatistics Core Facility, Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States
| | - Ralph V Shohet
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States
| | - Marian E Melish
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.,Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.,Department of Pediatrics, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States
| | - Andras Bratincsak
- Department of Pediatrics, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, United States.,Kapi'olani Medical Specialists, Hawai'i Pacific Health, Honolulu, HI, United States
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40
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Cai QY, Jiang JH, Jin RM, Jin GZ, Jia NY. The clinical significance of lipopolysaccharide binding protein in hepatocellular carcinoma. Oncol Lett 2019; 19:159-166. [PMID: 31897126 PMCID: PMC6924111 DOI: 10.3892/ol.2019.11119] [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] [Received: 03/06/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
Lipopolysaccharide binding protein (LBP) has been reported to be associated with prognosis in colorectal carcinoma and renal cell carcinoma; however, the clinical significance of LBP in human primary hepatocellular carcinoma (HCC) is inconclusive. We aimed to investigate the clinical significance and prognostic value of LBP in human primary HCC. In the present study, 346 patients with HCC who underwent curative resection were retrospectively analyzed. LBP protein expression was evaluated using western blot analysis and immunohistochemistry. LBP scores collected from immunohistochemical analysis were obtained by multiplying staining intensity and the percentage of positive cells. An outcome-based best cutoff-point was calculated by X-tile software. Moreover, Kaplan-Meier curves and Cox regressions were used for prognosis evaluation. LBP was frequently overexpressed in HCC compared with that in peritumor tissues (five pairs by western blot analysis, P=0.0533; 77 pairs by immunohistochemistry, P=0.0171), and LBP expression was positively associated with tumor-node-metastasis stage and tumor differentiation. Patients who had high LBP expression had decreased overall survival and time to recurrence compared with patients with low LBP expression. Furthermore, patients who were both serum α-fetoprotein positive and had high LBP expression had poor prognoses. Univariate and multivariate Cox analyses indicated that this combination was an independent prognostic factor [overall survival: Hazard ratio (HR), 1.458; 95% confidence interval (CI), 1.158–1.837; P=0.001; time to recurrence: HR,1.382; 95% Cl, 1.124–1.700; P=0.002]. In conclusion, LBP is highly expressed in HCC, and high LBP expression combined with serum α-fetoprotein may predict poor outcomes in patients with HCC following curative resection.
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Affiliation(s)
- Quan-Yu Cai
- Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
| | - Jing-Hua Jiang
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
| | - Ri-Ming Jin
- Department of Hepatic Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
| | - Guang-Zhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
| | - Ning-Yang Jia
- Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, P.R. China
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Giudice G, Petsalaki E. Proteomics and phosphoproteomics in precision medicine: applications and challenges. Brief Bioinform 2019; 20:767-777. [PMID: 29077858 PMCID: PMC6585152 DOI: 10.1093/bib/bbx141] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 09/21/2017] [Indexed: 12/11/2022] Open
Abstract
Recent advances in proteomics allow the accurate measurement of abundances for thousands of proteins and phosphoproteins from multiple samples in parallel. Therefore, for the first time, we have the opportunity to measure the proteomic profiles of thousands of patient samples or disease model cell lines in a systematic way, to identify the precise underlying molecular mechanism and discover personalized biomarkers, networks and treatments. Here, we review examples of successful use of proteomics and phosphoproteomics data sets in as well as their integration other omics data sets with the aim of precision medicine. We will discuss the bioinformatics challenges posed by the generation, analysis and integration of such large data sets and present potential reasons why proteomics profiling and biomarkers are not currently widely used in the clinical setting. We will finally discuss ways to contribute to the better use of proteomics data in precision medicine and the clinical setting.
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Affiliation(s)
- Girolamo Giudice
- European Molecular Biology Laboratory European Bioinformatics Institute
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Serum Leucine-Rich α2-Glycoprotein as a Biomarker for Monitoring Disease Activity in Patients with Systemic Juvenile Idiopathic Arthritis. J Immunol Res 2019; 2019:3140204. [PMID: 30863782 PMCID: PMC6378769 DOI: 10.1155/2019/3140204] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 12/20/2018] [Accepted: 01/09/2019] [Indexed: 12/17/2022] Open
Abstract
To investigate whether serum leucine-rich α2-glycoprotein (LRG) levels are useful as a marker of disease activity in systemic juvenile idiopathic arthritis (s-JIA), we determined serum LRG levels in fifty-nine s-JIA patients, 15 with other subtypes of JIA, 7 with Kawasaki disease (KD), 7 with influenza A infection (flu), 7 with enterohemorrhagic Escherichia coli (EHEC) infection, and 20 healthy controls (HC). Results were compared with the clinical features of s-JIA and serum cytokine levels including interleukin- (IL-) 6, IL-18, and soluble tumor necrosis factor receptors I and II. Serum LRG levels in active s-JIA were higher compared to those in other subtypes of JIA, EHEC, flu patients, and HC. Serum LRG levels were normalized in the inactive s-JIA phase after treatment. Serum LRG levels were positively correlated with serum C-reactive protein and ferritin levels. Serum LRG levels reflected s-JIA disease activity and thus may be useful for monitoring s-JIA disease activity.
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Wang B, Wang LN, Cheng FF, Lv HT, Sun L, Wei DK, Pu Y, Wu J, Hou YY, Wen B, Xu XP, Yan WH. MiR-222-3p in Platelets Serves as a Distinguishing Marker for Early Recognition of Kawasaki Disease. Front Pediatr 2019; 7:237. [PMID: 31316949 PMCID: PMC6611386 DOI: 10.3389/fped.2019.00237] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 05/24/2019] [Indexed: 12/19/2022] Open
Abstract
Kawasaki disease (KD) is an acute vasculitis, which leads to 20% of sufferers developing coronary artery aneurysm in children if not appropriately treated. Therefore, the early diagnosis of KD is essential for alleviating the risk of developing heart disease. MicroRNAs (miRNAs) are a large class of small non-coding RNAs which post-transcriptionally regulate gene expression and have been shown to play critical roles in numerous biological processes and diseases. In this study, we used high-throughput miRNA sequencing and found dozens of miRNAs are highly expressed in platelets. By comparing the miRNA expression profile of platelets of acute KD patients and other febrile patients, miR-222-3p is validated to be significantly upregulated in platelets of acute KD patients. Furthermore, KEGG pathway analysis shows that targets of miR-222-3p are enriched in immune-related signaling pathways. Our study uncovers the potential of miR-222-3p in platelets as biomarker for early diagnosis of Kawasaki disease.
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Affiliation(s)
- Bo Wang
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
| | - Li-Nong Wang
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
| | - Fang-Fang Cheng
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
| | - Hai-Tao Lv
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
| | - Ling Sun
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
| | - Dong-Kai Wei
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Yu Pu
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Jie Wu
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Yuan-Yuan Hou
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Bin Wen
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Xia-Ping Xu
- QIAGEN (Suzhou) Translational Medicine Co., Ltd., Suzhou, China
| | - Wen-Hua Yan
- Internal Medicine-Cardiovascular Department, Children's Hospital of Soochow University, Suzhou, China
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Abstract
PURPOSE OF REVIEW Kawasaki disease presents many challenges to the diverse group of physicians who care for these patients including infectious disease specialists, rheumatologists, and cardiologists. Here we review some of the progress being made toward improved understanding of disease pathogenesis, treatment, and long-term outcomes. RECENT FINDINGS Epidemiologic studies in different populations documented increasing numbers of cases in countries with high physician awareness of the disease. These data suggest true increases in patient numbers rather than increases because of increased case ascertainment. Adequately powered clinical trials for adjunctive therapies continue to be an unmet need. Long-term consequences of damage to the arterial wall and myocardium are beginning to emerge and systematic, longitudinal observational studies are needed to better define outcomes. SUMMARY The unknown cause, lack of a specific diagnostic test, and uncertain future for patients who develop permanent cardiovascular damage all require further study.
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Leucine-rich alpha-2 glycoprotein in the cerebrospinal fluid is a potential inflammatory biomarker for meningitis. J Neurol Sci 2018; 392:51-55. [PMID: 30097155 DOI: 10.1016/j.jns.2018.07.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/19/2018] [Accepted: 07/08/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Leucine-rich alpha-2 glycoprotein (LRG) is a novel biomarker for inflammatory diseases. We evaluated the levels of LRG, interleukin (IL)-6, and tumor necrosis factor (TNF)-α in the cerebrospinal fluid (CSF) of children with meningitis. METHODS CSF samples from 10 patients with bacterial meningitis (BM) and 10 with aseptic meningitis (AM) were evaluated. Samples from 10 patients with febrile status (FS) were used as controls. LRG levels were measured using a two-site enzyme immunoassay. IL-6 and TNF-α levels were measured using a multiplex bead-based assay. CSF examination of patients with BM at the convalescent stage was also conducted. RESULTS LRG and TNF-α levels in patients with BM, and IL-6 levels in patients with BM and AM showed significant increase compared with those in FS. Patients with BM at the convalescent stage showed significantly diminished LRG and IL-6 levels. LRG and IL-6 levels in CSF were indicated to be effective predictors for BM (LRG, AUC = 0.91; IL-6, AUC = 0.85). Only LRG levels showed a significant difference between patients with BM and AM (AUC = 0.78, P = 0.034). CONCLUSIONS LRG level could be a sensitive inflammatory biomarker for inflammatory diseases of the central nervous system, comparable with IL-6 level.
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Abstract
Kawasaki disease (KD) is a medium vessel vasculitis with predilection for coronary arteries. Due to lack of a reliable confirmatory laboratory test, the diagnosis of KD is based on a constellation of clinical findings that appear in a typical temporal sequence. These diagnostic criteria have been modified from time to time and the most recent guidelines have been proposed by the American Heart Association (AHA) in 2017. However, several children may have incomplete or atypical forms of KD and the diagnosis can often be difficult, especially in infants and young children. In this review, we have detailed the steps involved in arriving at a diagnosis of KD and also highlight the important role of echocardiography in diagnosis and management of children with KD.
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Affiliation(s)
- Surjit Singh
- Allergy Immunology UnitDepartment of PediatricsAdvanced Pediatrics CentrePost‐Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Ankur Kumar Jindal
- Allergy Immunology UnitDepartment of PediatricsAdvanced Pediatrics CentrePost‐Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Rakesh Kumar Pilania
- Allergy Immunology UnitDepartment of PediatricsAdvanced Pediatrics CentrePost‐Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
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