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Xin X, Koenen RR. Assessing platelet-derived extracellular vesicles for potential as therapeutic targets in cardiovascular diseases. Expert Opin Ther Targets 2025; 29:17-28. [PMID: 39817690 DOI: 10.1080/14728222.2025.2454617] [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: 11/04/2024] [Revised: 12/17/2024] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Abstract
INTRODUCTION Cardiovascular disease (CVD) is the leading cause of death worldwide. Platelet-derived extracellular vesicles (PEV) have attracted extensive attention in cardiovascular disease research in recent years because their cargo is involved in a variety of pathophysiological processes, such as thrombosis, immune response, promotion or inhibition of inflammatory response, promotion of angiogenesis as well as cell proliferation and migration. AREAS COVERED This review explores the role of PEV in various cardiovascular diseases (such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, and heart failure), with relation to its molecular cargo (nucleic acids, bioactive lipids, proteins) and aims to provide new insights in the pathophysiologic role of PEV, and methods for preventing and treating cardiovascular diseases based on PEV. EXPERT OPINION Studies have shown that the cargo of PEV may be dysregulated during cardiovascular disease and delivery to tissues can result in detrimental pathophysiologic effects. Counteracting this process might have the potential to inhibit inflammation, promote angiogenesis, and inhibit cardiomyocyte death. In addition, PEV have potential as biocompatible and autologous drug carriers. Therefore, better research on the mechanisms how PEV act during cardiovascular disease and could be implemented as a therapeutic will provide new perspectives for the treatment of cardiovascular disease.
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Affiliation(s)
- Xin Xin
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
| | - Rory R Koenen
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
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Zhang Z, Zou Y, Song C, Cao K, Cai K, Chen S, Wu Y, Geng D, Sun G, Zhang N, Zhang X, Zhang Y, Sun Y, Zhang Y. Advances in the study of exosomes in cardiovascular diseases. J Adv Res 2024; 66:133-153. [PMID: 38123019 PMCID: PMC11674797 DOI: 10.1016/j.jare.2023.12.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/15/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis. AIM OF REVIEW This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.
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Affiliation(s)
- Zhaobo Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yuanming Zou
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Chunyu Song
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cao
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Kexin Cai
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Shuxian Chen
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Yanjiao Wu
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Danxi Geng
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Guozhe Sun
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Naijin Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China; Key Laboratory of Reproductive and Genetic Medicine, China Medical University, National Health Commission, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
| | - Xingang Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Yixiao Zhang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, People's Republic of China.
| | - Yingxian Sun
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
| | - Ying Zhang
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110122, Liaoning Province, People's Republic of China.
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Soriano-Cruz M, Vázquez-González WG, Molina-Vargas P, Faustino-Trejo A, Chávez-Rueda AK, Legorreta-Haquet MV, Aguilar-Ruíz SR, Chávez-Sánchez L. Exosomes as Regulators of Macrophages in Cardiovascular Diseases. Biomedicines 2024; 12:2683. [PMID: 39767590 PMCID: PMC11726971 DOI: 10.3390/biomedicines12122683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/17/2024] [Accepted: 11/18/2024] [Indexed: 01/16/2025] Open
Abstract
Macrophages in atherosclerosis and myocardial infarction have diverse functions, such as foam cell formation and the induction of an inflammatory response that promotes ventricular dysfunction in the heart. Exosomes are small vesicles released by many different types of cells, such as macrophages, dendritic cells, platelets and other immunoregulatory cells, that facilitate communication with other cells, modulating the biological functions of recipient cells. Exosomes offer a novel therapeutic approach for the polarization of macrophages involved in cardiovascular diseases. In this review, we provide an overview of the biological role of macrophages in atherosclerosis and myocardial infarction and the effects of exosomes on these cells as therapeutic agents in the disease.
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Affiliation(s)
- Marina Soriano-Cruz
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
- Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca 68020, Mexico
| | - Wendy Guadalupe Vázquez-González
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
| | - Paula Molina-Vargas
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
- Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Alejandro Faustino-Trejo
- Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Adriana Karina Chávez-Rueda
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
| | - María Victoria Legorreta-Haquet
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
| | | | - Luis Chávez-Sánchez
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (M.S.-C.); (W.G.V.-G.)
- Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
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Tam S, Wear D, Morrone CD, Yu WH. The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology. J Neurochem 2024; 168:2391-2422. [PMID: 38650384 DOI: 10.1111/jnc.16108] [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: 01/14/2024] [Revised: 03/12/2024] [Accepted: 03/31/2024] [Indexed: 04/25/2024]
Abstract
Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease.
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Affiliation(s)
- Stephanie Tam
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Darcy Wear
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Christopher D Morrone
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
| | - Wai Haung Yu
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
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5
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Zisser L, Binder CJ. Extracellular Vesicles as Mediators in Atherosclerotic Cardiovascular Disease. J Lipid Atheroscler 2024; 13:232-261. [PMID: 39355407 PMCID: PMC11439751 DOI: 10.12997/jla.2024.13.3.232] [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: 03/29/2024] [Revised: 07/12/2024] [Accepted: 07/26/2024] [Indexed: 10/03/2024] Open
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial intima, characterized by accumulation of lipoproteins and accompanying inflammation, leading to the formation of plaques that eventually trigger occlusive thrombotic events, such as myocardial infarction and ischemic stroke. Although many aspects of plaque development have been elucidated, the role of extracellular vesicles (EVs), which are lipid bilayer-delimited vesicles released by cells as mediators of intercellular communication, has only recently come into focus of atherosclerosis research. EVs comprise several subtypes that may be differentiated by their size, mode of biogenesis, or surface marker expression and cargo. The functional effects of EVs in atherosclerosis depend on their cellular origin and the specific pathophysiological context. EVs have been suggested to play a role in all stages of plaque formation. In this review, we highlight the known mechanisms by which EVs modulate atherogenesis and outline current limitations and challenges in the field.
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Affiliation(s)
- Lucia Zisser
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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Jan N, Bostanudin MF, Moutraji SA, Kremesh S, Kamal Z, Hanif MF. Unleashing the biomimetic targeting potential of platelet-derived nanocarriers on atherosclerosis. Colloids Surf B Biointerfaces 2024; 240:113979. [PMID: 38823339 DOI: 10.1016/j.colsurfb.2024.113979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/26/2024] [Accepted: 05/17/2024] [Indexed: 06/03/2024]
Abstract
Atherosclerosis, the primary mechanism underlying the development of many cardiovascular illnesses, continues to be one of the leading causes of mortality worldwide. Platelet (PLT), which are essential for maintaining body homeostasis, have been strongly linked to the onset of atherosclerosis at various stages due to their inherent tendency to bind to atherosclerotic lesions and show an affinity for plaques. Therefore, mimicking PLT's innate adhesive features may be necessary to effectively target plaques. PLT-derived nanocarriers have emerged as a promising biomimetic targeting strategy for treating atherosclerosis due to their numerous advantages. These advantages include excellent biocompatibility, minimal macrophage phagocytosis, prolonged circulation time, targeting capability for impaired vascular sites, and suitability as carriers for anti-atherosclerotic drugs. Herein, we discuss the role of PLT in atherogenesis and propose the design of nanocarriers based on PLT-membrane coating and PLT-derived vesicles. These nanocarriers can target multiple biological elements relevant to plaque development. The review also emphasizes the current challenges and future research directions for the effective utilization of PLT-derived nanocarriers in treating atherosclerosis.
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Affiliation(s)
- Nasrullah Jan
- Department of Pharmacy, The University of Chenab, Gujrat 50700, Punjab, Pakistan.
| | - Mohammad F Bostanudin
- College of Pharmacy, Al Ain University, Abu Dhabi 112612, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates
| | - Sedq A Moutraji
- College of Pharmacy, Al Ain University, Abu Dhabi 112612, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates
| | - Sedra Kremesh
- College of Pharmacy, Al Ain University, Abu Dhabi 112612, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi 112612, United Arab Emirates
| | - Zul Kamal
- Department of Pharmacy, Shaheed Benazir Bhutto University, Dir Upper 18000, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Farhan Hanif
- Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Punjab, Pakistan; Bahawalpur College of Pharmacy, BMDC Complex Bahawalpur 63100, Punjab, Pakistan
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Das D, Jothimani G, Banerjee A, Dey A, Duttaroy AK, Pathak S. A brief review on recent advances in diagnostic and therapeutic applications of extracellular vesicles in cardiovascular disease. Int J Biochem Cell Biol 2024; 173:106616. [PMID: 38992790 DOI: 10.1016/j.biocel.2024.106616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024]
Abstract
Extracellular vesicles (EVs) are important mediators of intercellular communication within the cardiovascular system, playing essential roles in physiological homeostasis and contributing to the pathogenesis of various cardiovascular diseases (CVDs). However, their potential as diagnostic biomarkers and therapeutic agents in rare cardiovascular diseases, such as valvular heart disease (VHD) and cardiomyopathies, remains largely unexplored. This review comprehensively emphasizes recent advancements in extracellular vesicle research, explicitly highlighting their growing significance in diagnosing and potentially treating rare cardiovascular diseases, with a particular focus on valvular heart disease and cardiomyopathies. We highlight the potential of extracellular vesicle-based liquid biopsies as non-invasive tools for early disease detection and risk stratification, showcasing specific extracellular vesicle-associated biomarkers (proteins, microRNAs, lipids) with diagnostic and prognostic value. Furthermore, we discussed the therapeutic promise of extracellular vesicles derived from various sources, including stem cells and engineered extracellular vesicles, for cardiac repair and regeneration through their ability to modulate inflammation, promote angiogenesis, and reduce fibrosis. By integrating the findings and addressing critical knowledge gaps, this review aims to stimulate further research and innovation in extracellular vesicle-based diagnostics and therapeutics of cardiovascular disease.
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Affiliation(s)
- Diptimayee Das
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu 603103, India
| | - Ganesan Jothimani
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu 603103, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu 603103, India
| | - Amit Dey
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu 603103, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Tamil Nadu 603103, India.
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Kang Y, Wu W, Yang Y, Luo J, Lu Y, Yin L, Cui X. Progress in extracellular vesicle homeostasis as it relates to cardiovascular diseases. J Physiol Biochem 2024; 80:511-522. [PMID: 38687443 DOI: 10.1007/s13105-024-01027-w] [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: 09/19/2023] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
Extracellular vesicles (EVs) are involved in both physiological and pathological processes in many organ systems and are essential in mediating intercellular communication and maintaining organismal homeostasis. It is helpful to propose new strategies for disease treatment by elucidating the mechanisms of EV release and sorting. An increasing number of studies have shown that there is specific homeostasis in EVs, which is helpful for the human body to carry out physiological activities. In contrast, an EV homeostasis im-balance promotes or accelerates disease onset and development. Alternatively, regulating the quality of EVs can maintain homeostasis and even achieve the purpose of treating conditions. An analysis of the role of EV homeostasis in the onset and development of cardiovascular disease is presented in this review. This article also summarizes the methods that regulate EV homeostasis and their application in cardiovascular diseases. In particular, this study focuses on the connection between EV steady states and the cardiovascular system and the potential value of EVs in treating cardiovascular diseases.
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Affiliation(s)
- Yunan Kang
- College of Anesthesiology, Affiliated Hospital of Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
| | - Wenqian Wu
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
| | - Yi Yang
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
| | - Jinxi Luo
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
| | - Yajie Lu
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China
| | - Luchang Yin
- Clinical Medical School, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China.
- Internal Medicine-Cardiovascular Department, Affiliated Hospital of Shandong Second Medical University, Weifang, P.R. China.
| | - Xiaodong Cui
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, 261053, Shandong, P.R. China.
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Cui Z, Zhang L, Hu G, Zhang F. Extracellular Vesicles in Cardiovascular Pathophysiology: Communications, Biomarkers, and Therapeutic Potential. Cardiovasc Toxicol 2024; 24:711-726. [PMID: 38844744 DOI: 10.1007/s12012-024-09875-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/25/2024] [Indexed: 08/07/2024]
Abstract
Extracellular vesicles (EVs) are diverse, membrane-bound vesicles released from cells into the extracellular environment. They originate from either endosomes or the cell membrane and typically include exosomes and microvesicles. These EVs serve as crucial mediators of intercellular communication, carrying a variety of contents such as nucleic acids, proteins, and lipids, which regulate the physiological and pathological processes of target cells. Moreover, the molecular cargo of EVs can reflect critical information about the originating cells, making them potential biomarkers for the diagnosis and prognosis of diseases. Over the past decade, the role of EVs as key communicators between cell types in cardiovascular physiology and pathology has gained increasing recognition. EVs from different cellular sources, or from the same source under different cellular conditions, can have distinct impacts on the management, diagnosis, and prognosis of cardiovascular diseases. Furthermore, it is essential to consider the influence of cardiovascular-derived EVs on the metabolism of peripheral organs. This review aims to summarize recent advancements in the field of cardiovascular research with respect to the roles and implications of EVs. Our goal is to provide new insights and directions for the early prevention and treatment of cardiovascular diseases, with an emphasis on the therapeutic potential and diagnostic value of EVs.
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Affiliation(s)
- Zhe Cui
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Ling Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Guangyu Hu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Fuyang Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
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Zhu H, Zhao T, Zhao S, Yang S, Jiang K, Li S, Kang Y, Yang Z, Shen J, Shen S, Tao H, Xuan J, Yang M, Xu B, Wang F, Jiang M. O-GlcNAcylation promotes the progression of nonalcoholic fatty liver disease by upregulating the expression and function of CD36. Metabolism 2024; 156:155914. [PMID: 38642829 DOI: 10.1016/j.metabol.2024.155914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood. METHODS O-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT-qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function. RESULTS O-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH. CONCLUSIONS O-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.
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Affiliation(s)
- Hanlong Zhu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Tianming Zhao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China.
| | - Si Zhao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Suzhen Yang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Kang Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Shupei Li
- Department of Gastroenterology, Nanjing University of Chinese Medicine, Jinling School of Clinical Medicine, Nanjing, Jiangsu, China.
| | - Ying Kang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Zhuoxin Yang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Jiajia Shen
- Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Si Shen
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Hui Tao
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Ji Xuan
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Miaofang Yang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Bing Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Fangyu Wang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Mingzuo Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
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11
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Liu J, Du C, Chen H, Huang W, Lei Y. Nano-Micron Combined Hydrogel Microspheres: Novel Answer for Minimal Invasive Biomedical Applications. Macromol Rapid Commun 2024; 45:e2300670. [PMID: 38400695 DOI: 10.1002/marc.202300670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/05/2024] [Indexed: 02/25/2024]
Abstract
Hydrogels, key in biomedical research for their hydrophilicity and versatility, have evolved with hydrogel microspheres (HMs) of micron-scale dimensions, enhancing their role in minimally invasive therapeutic delivery, tissue repair, and regeneration. The recent emergence of nanomaterials has ushered in a revolutionary transformation in the biomedical field, which demonstrates tremendous potential in targeted therapies, biological imaging, and disease diagnostics. Consequently, the integration of advanced nanotechnology promises to trigger a new revolution in the realm of hydrogels. HMs loaded with nanomaterials combine the advantages of both hydrogels and nanomaterials, which enables multifaceted functionalities such as efficient drug delivery, sustained release, targeted therapy, biological lubrication, biochemical detection, medical imaging, biosensing monitoring, and micro-robotics. Here, this review comprehensively expounds upon commonly used nanomaterials and their classifications. Then, it provides comprehensive insights into the raw materials and preparation methods of HMs. Besides, the common strategies employed to achieve nano-micron combinations are summarized, and the latest applications of these advanced nano-micron combined HMs in the biomedical field are elucidated. Finally, valuable insights into the future design and development of nano-micron combined HMs are provided.
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Affiliation(s)
- Jiacheng Liu
- Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chengcheng Du
- Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hong Chen
- Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Wei Huang
- Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yiting Lei
- Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
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12
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Li OQ, Yue H, DeHart AR, Roytenberg R, Aguilar R, Olanipekun O, Bai F, Liu J, Fedorova O, Kennedy D, Thompson E, Pierre SV, Li W. Sodium/Potassium ATPase Alpha 1 Subunit Fine-tunes Platelet GPCR Signaling Function and is Essential for Thrombosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593923. [PMID: 38798556 PMCID: PMC11118499 DOI: 10.1101/2024.05.13.593923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Background Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining intracellular sodium and potassium gradients. However, the role of NKA in platelet function and thrombosis remains unclear. Methods We utilized wild-type (WT, α1+/+) and NKA α1 heterozygous (α1+/-) mice, aged 8 to 16 weeks, of both sexes. An intravital microscopy-based, FeCl3-induced carotid artery injury thrombosis model was employed for in vivo thrombosis assessment. Platelet transfusion assays were used to evaluate platelet NKA α1 function on thrombosis. Human platelets isolated from healthy donors and heart failure patients treated with/without digoxin were used for platelet function and signaling assay. Complementary molecular approaches were used for mechanistic studies. Results NKA α1 haplodeficiency significantly reduced its expression on platelets without affecting sodium homeostasis. It significantly inhibited 7.5% FeCl3-induced thrombosis in male but not female mice without disturbing hemostasis. Transfusion of α1+/-, but not α1+/+, platelets to thrombocytopenic WT mice substantially prolonged thrombosis. Treating WT mice with low-dose ouabain or marinobufagenin, both binding NKA α1 and inhibiting its ion-transporting function, markedly inhibited thrombosis in vivo. NKA α1 formed complexes with leucine-glycine-leucine (LGL)-containing platelet receptors, including P2Y12, PAR4, and thromboxane A2 receptor. This binding was significantly attenuated by LGL>SFT mutation or LGL peptide. Haplodeficiency of NKA α1 in mice or ouabain treatment of human platelets notably inhibited ADP-induced platelet aggregation. While not affecting 10% FeCl3-induced thrombosis, NKA α1 haplodeficiency significantly prolonged thrombosis time in mice treated with an ineffective dose of clopidogrel. Conclusion NKA α1 plays an essential role in enhancing platelet activation through binding to LGL-containing platelet GPCRs. NKA α1 haplodeficiency or inhibition with low-dose ouabain and marinobufagenin significantly inhibited thrombosis and sensitized clopidogrel's anti-thrombotic effect. Targeting NKA α1 emerges as a promising antiplatelet and antithrombotic therapeutic strategy.
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Affiliation(s)
- Oliver Q. Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA
| | - Hong Yue
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Autumn R. DeHart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Renat Roytenberg
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Rodrigo Aguilar
- Department of Medicine, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Olalekan Olanipekun
- Department of Medicine, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Fang Bai
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Jiang Liu
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Olga Fedorova
- National Institute on Aging, Laboratory of Cardiovascular Science of Biomedical Research Center Baltimore, MD, USA
| | - David Kennedy
- Department of Medicine, University of Toledo, Toledo, OH, USA
| | - Ellen Thompson
- Department of Medicine, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
| | - Sandrine V. Pierre
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
- Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA
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13
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Huang J, Zhu Z, Schlüter D, Lambertsen KL, Song W, Wang X. Ubiquitous regulation of cerebrovascular diseases by ubiquitin-modifying enzymes. Clin Transl Med 2024; 14:e1719. [PMID: 38778460 PMCID: PMC11111633 DOI: 10.1002/ctm2.1719] [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: 03/01/2024] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin-modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post-translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis-targeting chimera and deubiquitinase-targeting chimera, may also revolutionize the therapy of CVDs in the future.
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Affiliation(s)
- Jingyong Huang
- Department of Vascular SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Zhenhu Zhu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouChina
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical SchoolHannoverGermany
| | - Kate Lykke Lambertsen
- Department of Neurobiology ResearchInstitute of Molecular MedicineUniversity of Southern DenmarkOdense CDenmark
- BRIGDE—Brain Research—Inter‐Disciplinary Guided Excellence, Department of Clinical ResearchUniversity of Southern DenmarkOdense CDenmark
- Department of NeurologyOdense University HospitalOdense CDenmark
| | - Weihong Song
- Oujiang LaboratoryKey Laboratory of Alzheimer's Disease of Zhejiang ProvinceZhejiang Provincial Clinical Research Center for Mental DisordersInstitute of AgingSchool of Mental HealthAffiliated Kangning HospitalThe Second Affiliated HospitalYuying Children's HospitalWenzhou Medical UniversityWenzhouChina
| | - Xu Wang
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouChina
- Oujiang LaboratoryKey Laboratory of Alzheimer's Disease of Zhejiang ProvinceZhejiang Provincial Clinical Research Center for Mental DisordersInstitute of AgingSchool of Mental HealthAffiliated Kangning HospitalThe Second Affiliated HospitalYuying Children's HospitalWenzhou Medical UniversityWenzhouChina
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14
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Zhao X, Kong X, Cui Z, Zhang Z, Wang M, Liu G, Gao H, Zhang J, Qin W. Communication between nonalcoholic fatty liver disease and atherosclerosis: Focusing on exosomes. Eur J Pharm Sci 2024; 193:106690. [PMID: 38181871 DOI: 10.1016/j.ejps.2024.106690] [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: 10/11/2023] [Revised: 12/13/2023] [Accepted: 01/02/2024] [Indexed: 01/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder on a global scale. Atherosclerosis (AS), a leading cause of cardiovascular diseases, stands as the primary contributor to mortality among patients diagnosed with NAFLD. However, the precise etiology by which NAFLD causes AS remains unclear. Exosomes are nanoscale extracellular vesicles secreted by cells, and are considered to participate in complex biological processes by promoting cell-to-cell and organ-to-organ communications. As vesicles containing protein, mRNA, non-coding RNA and other bioactive molecules, exosomes can participate in the development of NAFLD and AS respectively. Recently, studies have shown that NAFLD can also promote the development of AS via secreting exosomes. Herein, we summarized the recent advantages of exosomes in the pathogenesis of NAFLD and AS, and highlighted the role of exosomes in mediating the information exchange between NAFLD and AS. Further, we discussed how exosomes play a prominent role in enabling information exchange among diverse organs, delving into a novel avenue for investigating the link between diseases and their associated complications. The future directions and emerging challenges are also listed regarding the exosome-based therapeutic strategies for AS under NAFLD conditions.
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Affiliation(s)
- Xiaona Zhao
- School of Pharmacy, Weifang Medical University, Weifang, China; School of Pharmacy, Jining Medical University, Rizhao, China
| | - Xinxin Kong
- School of Pharmacy, Weifang Medical University, Weifang, China; School of Pharmacy, Jining Medical University, Rizhao, China
| | - Zhoujun Cui
- Department of General Surgery, People's Hospital of Rizhao, Rizhao, China
| | - Zejin Zhang
- School of Pharmacy, Jining Medical University, Rizhao, China; School of Pharmacy, Binzhou Medical University, Yantai, China
| | - Minghui Wang
- School of Pharmacy, Jining Medical University, Rizhao, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guoqing Liu
- School of Pharmacy, Jining Medical University, Rizhao, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Honggang Gao
- School of Pharmacy, Jining Medical University, Rizhao, China
| | - Jing Zhang
- School of Pharmacy, Jining Medical University, Rizhao, China
| | - Wei Qin
- School of Pharmacy, Jining Medical University, Rizhao, China.
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15
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Wen SY, Zhi X, Liu HX, Wang X, Chen YY, Wang L. Is the suppression of CD36 a promising way for atherosclerosis therapy? Biochem Pharmacol 2024; 219:115965. [PMID: 38043719 DOI: 10.1016/j.bcp.2023.115965] [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: 10/07/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/05/2023]
Abstract
Atherosclerosis is the main underlying pathology of many cardiovascular diseases and is marked by plaque formation in the artery wall. It has posed a serious threat to the health of people all over the world. CD36 acts as a significant regulator of lipid homeostasis, which is closely associated with the onset and progression of atherosclerosis and may be a new therapeutic target. The abnormal overexpression of CD36 facilitates lipid accumulation, foam cell formation, inflammation, endothelial apoptosis, and thrombosis. Numerous natural products and lipid-lowering agents are found to target the suppression of CD36 or inhibit the upregulation of CD36 to prevent and treat atherosclerosis. Here, the structure, expression regulation and function of CD36 in atherosclerosis and its related pharmacological therapies are reviewed. This review highlights the importance of drugs targeting CD36 suppression in the treatment and prevention of atherosclerosis, in order to develop new therapeutic strategies and potential anti-atherosclerotic drugs both preclinically and clinically.
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Affiliation(s)
- Shi-Yuan Wen
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Xiaoyan Zhi
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Hai-Xin Liu
- School of Traditional Chinese Materia Medica, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Xiaohui Wang
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Yan-Yan Chen
- School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Li Wang
- College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China.
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16
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Hu M, Liu L. Choline regulation of triglycerides synthesis through ubiquintination pathway in MAC-T cells. PeerJ 2023; 11:e16611. [PMID: 38144203 PMCID: PMC10740596 DOI: 10.7717/peerj.16611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/15/2023] [Indexed: 12/26/2023] Open
Abstract
This study aims to investigate the regulatory mechanism of choline (CH) on triglyceride (TG) synthesis in cows, with a specific focus on its potential association with high milk fat percentage in the gut of the Zhongdian yak. By employing combined metagenomics and metabolomics analysis, we establish a correlation between CH and milk fat production in yaks. Bovine mammary epithelial cells (MAC-T) were exposed to varying CH concentrations, and after 24 h, we analyzed the expression levels of key proteins (membrane glycoprotein CD36 (CD36); adipose differentiation-related protein (ADFP); and ubiquintin (UB)), cellular TG content, lipid droplets, and cell vitality. Additionally, we evaluated the genes potentially related to the CH-mediated regulation of TG synthesis using real-time qPCR. CH at 200 μM significantly up-regulated CD36, ADFP, UB, and TG content. Pathway analysis reveals the involvement of the ubiquitination pathway in CH-mediated regulation of TG synthesis. These findings shed light on the role of CH in controlling TG synthesis in MAC-T cells and suggest its potential as a feed additive for cattle, offering possibilities to enhance milk fat production efficiency and economic outcomes in the dairy industry.
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Affiliation(s)
- Mengxue Hu
- College of Life Science, Southwest Forestry University, Kunming, Yunnan Province, China
| | - Lily Liu
- College of Life Science, Southwest Forestry University, Kunming, Yunnan Province, China
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17
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Luo J, He Z, Li Q, Lv M, Cai Y, Ke W, Niu X, Zhang Z. Adipokines in atherosclerosis: unraveling complex roles. Front Cardiovasc Med 2023; 10:1235953. [PMID: 37645520 PMCID: PMC10461402 DOI: 10.3389/fcvm.2023.1235953] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
Adipokines are biologically active factors secreted by adipose tissue that act on local and distant tissues through autocrine, paracrine, and endocrine mechanisms. However, adipokines are believed to be involved in an increased risk of atherosclerosis. Classical adipokines include leptin, adiponectin, and ceramide, while newly identified adipokines include visceral adipose tissue-derived serpin, omentin, and asprosin. New evidence suggests that adipokines can play an essential role in atherosclerosis progression and regression. Here, we summarize the complex roles of various adipokines in atherosclerosis lesions. Representative protective adipokines include adiponectin and neuregulin 4; deteriorating adipokines include leptin, resistin, thrombospondin-1, and C1q/tumor necrosis factor-related protein 5; and adipokines with dual protective and deteriorating effects include C1q/tumor necrosis factor-related protein 1 and C1q/tumor necrosis factor-related protein 3; and adipose tissue-derived bioactive materials include sphingosine-1-phosphate, ceramide, and adipose tissue-derived exosomes. However, the role of a newly discovered adipokine, asprosin, in atherosclerosis remains unclear. This article reviews progress in the research on the effects of adipokines in atherosclerosis and how they may be regulated to halt its progression.
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Affiliation(s)
- Jiaying Luo
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei He
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingwen Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengna Lv
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuli Cai
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Ke
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuan Niu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
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18
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Ma C, Lu T, He Y, Guo D, Duan L, Jia R, Cai D, Gao T, Chen Z, Xue B, Li T, He Y. Comprehensive analysis of autophagy-related gene expression profiles identified five gene biomarkers associated with immune infiltration and advanced plaques in carotid atherosclerosis. Orphanet J Rare Dis 2023; 18:66. [PMID: 36959587 PMCID: PMC10037854 DOI: 10.1186/s13023-023-02660-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/11/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Autophagy plays an important role in the progression of carotid atherosclerosis (CAS). This study aimed to identify hub autophagy-related genes (ATGs) associated with CAS. METHODS GSE43292 and GSE28829 datasets of early and advanced CAS plaques were enrolled from the Gene Expression Omnibus (GEO) database. A comprehensive analysis of differentially expressed ATGs (DE-ATGs) was conducted. Functional enrichment assay was used to explore biological functions of DE-ATGs. The hub ATGs were identified by protein-protein interaction (PPI) network. Immunohistochemistry (IHC) and Real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to validate hub ATGs at the protein level and mRNA level. Correlation analysis of hub ATGs with immune cells was also conducted. In addition, a competitive endogenous RNA (ceRNA) network was constructed, and diagnostic value of hub ATGs was evaluated. RESULTS A total of 19 DE-ATGs were identified in early and advanced CAS plaques. Functional enrichment analysis of DE-ATGs suggested that they were closely correlated to autophagy, apoptosis, and lipid regulation. Moreover, 5 hub ATGs, including TNFSF10, ITGA6, CTSD, CCL2, and CASP1, were identified and further verified by IHC. The area under the curve (AUC) values of the 5 hub ATGs were 0.818, 0.732, 0.792, 0.814, and 0.812, respectively. Competing endogenous RNA (ceRNA) networks targeting the hub ATGs were also constructed. In addition, the 5 hub ATGs were found to be closely associated with immune cell infiltration in CAS. CONCLUSION In this study, we identified 5 hub ATGs including CASP1, CCL2, CTSD, ITGA6 and TNFSF10, which could serve as candidate diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Chi Ma
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
| | - Taoyuan Lu
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
| | - Yanyan He
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
- Department of Cerebrovascular Disease, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Dehua Guo
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
| | - Lin Duan
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
- Department of Cerebrovascular Disease, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Rufeng Jia
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China
| | - Dongyang Cai
- Department of Neurosurgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Tao Gao
- Department of Neurosurgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Zhongcan Chen
- Department of Neurosurgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Binghua Xue
- Department of Endocrinology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Tianxiao Li
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China.
- Department of Cerebrovascular Disease, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.
| | - Yingkun He
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.
- Henan Provincial NeuroInterventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, and Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, 450003, China.
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19
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Ren Y, Zhang H. Emerging role of exosomes in vascular diseases. Front Cardiovasc Med 2023; 10:1090909. [PMID: 36937921 PMCID: PMC10017462 DOI: 10.3389/fcvm.2023.1090909] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/11/2023] [Indexed: 03/06/2023] Open
Abstract
Exosomes are biological small spherical lipid bilayer vesicles secreted by most cells in the body. Their contents include nucleic acids, proteins, and lipids. Exosomes can transfer material molecules between cells and consequently have a variety of biological functions, participating in disease development while exhibiting potential value as biomarkers and therapeutics. Growing evidence suggests that exosomes are vital mediators of vascular remodeling. Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts (AFs) can communicate through exosomes; such communication is associated with inflammatory responses, cell migration and proliferation, and cell metabolism, leading to changes in vascular function and structure. Essential hypertension (EH), atherosclerosis (AS), and pulmonary arterial hypertension (PAH) are the most common vascular diseases and are associated with significant vascular remodeling. This paper reviews the latest research progress on the involvement of exosomes in vascular remodeling through intercellular information exchange and provides new ideas for understanding related diseases.
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Affiliation(s)
- Yi Ren
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Honggang Zhang
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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20
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Samovski D, Jacome-Sosa M, Abumrad NA. Fatty Acid Transport and Signaling: Mechanisms and Physiological Implications. Annu Rev Physiol 2023; 85:317-337. [PMID: 36347219 DOI: 10.1146/annurev-physiol-032122-030352] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function.
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Affiliation(s)
- Dmitri Samovski
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Miriam Jacome-Sosa
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA; .,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
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21
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Zhan M, Shi S, Zheng X, Chen W, Sun L, Zhang Y, Liu J. Research landscape of exosomes in platelets from 2000 to 2022: A bibliometric analysis. Front Cardiovasc Med 2022; 9:1054816. [PMID: 36606281 PMCID: PMC9810141 DOI: 10.3389/fcvm.2022.1054816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Background Blood-derived exosomes are involved in developing multiple pathological processes, with platelets being the most well-known source. Related studies have become an area of research with significant value and potential. However, no bibliometric studies in this field have yet been identified. We aimed to analyze the hotspots and academic trends of platelet exosome research through bibliometric visualization to actively grasp the research base in this field and track its developmental orientation. Methods From 2000 to 2022, we screened all relevant publications on platelet exosome-related research from the Web of Science database, generated knowledge maps using VOSviewer and CiteSpace software, and analyzed research trends in the field. Results A total of 722 articles were screened for inclusion based on the search strategy. The number of articles on exosome studies in platelets has expanded vastly. The USA and the People's Republic of China contributed substantially among 69 countries or regions. Amsterdam University and Semmelweis University are the research institutions with the most publications. The most studied and co-cited journals were the International Journal of Molecular Sciences and the Journal of Extracellular Vesicles. We identified 4,598 authors, with Nieuwland Rienk having the highest number of articles and Bruno Stefania having the most cited publications. Keywords of great interest include "thrombosis," "anti-inflammatory," "anti-apoptosis," "angiogenesis," "microparticles," "miRNAs," "stem cells," and "biomarkers," which are key research areas for future development. Conclusion We used bibliometric and visualization methods to identify hotspots and trends in platelet exosome research. Platelet exosome research is widely expanding. Future research will most likely focus on "thrombosis," "anti-inflammatory," "anti-apoptosis," "angiogenesis," "microparticles," "miRNAs," "stem cells," and "biomarkers."
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Affiliation(s)
- Min Zhan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shengnan Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaoyu Zheng
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linjuan Sun
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Linjuan Sun,
| | - Yehao Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Yehao Zhang,
| | - Jianxun Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Jianxun Liu,
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22
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Gardin C, Ferroni L, Leo S, Tremoli E, Zavan B. Platelet-Derived Exosomes in Atherosclerosis. Int J Mol Sci 2022; 23:ijms232012546. [PMID: 36293399 PMCID: PMC9604238 DOI: 10.3390/ijms232012546] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/15/2022] [Accepted: 10/17/2022] [Indexed: 11/22/2022] Open
Abstract
Atherosclerosis (AS), the main cause of many cardiovascular diseases (CVDs), is a progressive inflammatory disease characterized by the accumulation of lipids, fibrous elements, and calcification in the innermost layers of arteries. The result is the thickening and clogging of these vessel walls. Several cell types are directly involved in the pathological progression of AS. Among them, platelets represent the link between AS, inflammation, and thrombosis. Indeed, besides their pivotal role in hemostasis and thrombosis, platelets are key mediators of inflammation at injury sites, where they act by regulating the function of other blood and vascular cell types, including endothelial cells (ECs), leukocytes, and vascular smooth muscle cells (VSMCs). In recent years, increasing evidence has pointed to a central role of platelet-derived extracellular vesicles (P-EVs) in the modulation of AS pathogenesis. However, while the role of platelet-derived microparticles (P-MPs) has been significantly investigated in recent years, the same cannot be said for platelet-derived exosomes (P-EXOs). For this reason, this reviews aims at summarizing the isolation methods and biological characteristics of P-EXOs, and at discussing their involvement in intercellular communication in the pathogenesis of AS. Evidence showing how P-EXOs and their cargo can be used as biomarkers for AS is also presented in this review.
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Affiliation(s)
- Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
| | - Sara Leo
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
| | - Elena Tremoli
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
| | - Barbara Zavan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Ferrara, Italy
- Correspondence:
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23
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Tang Q, Xiao X, Li R, He H, Li S, Ma C. Recent Advances in Detection for Breast-Cancer-Derived Exosomes. Molecules 2022; 27:molecules27196673. [PMID: 36235208 PMCID: PMC9571663 DOI: 10.3390/molecules27196673] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/28/2022] Open
Abstract
Breast cancer is the most common malignant tumor in women, its incidence is secret, and more than half of the patients are diagnosed in the middle and advanced stages, so it is necessary to develop simple and efficient detection methods for breast cancer diagnosis to improve the survival rate and quality of life of breast cancer patients. Exosomes are extracellular vesicles secreted by all kinds of living cells, and play an important role in the occurrence and development of breast cancer and the formation of the tumor microenvironment. Exosomes, as biomarkers, are an important part of breast cancer fluid biopsy and have become ideal targets for the early diagnosis, curative effect evaluation, and clinical treatment of breast cancer. In this paper, several traditional exosome detection methods, including differential centrifugation and immunoaffinity capture, were summarized, focusing on the latest research progress in breast cancer exosome detection. It was summarized from the aspects of optics, electrochemistry, electrochemiluminescence and other aspects. This review is expected to provide valuable guidance for exosome detection of clinical breast cancer and the establishment of more reliable, efficient, simple and innovative methods for exosome detection of breast cancer in the future.
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Affiliation(s)
- Qin Tang
- School of Life Sciences, Central South University, Changsha 410013, China
- Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Xinying Xiao
- School of Life Sciences, Central South University, Changsha 410013, China
- Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ranhao Li
- School of Life Sciences, Central South University, Changsha 410013, China
- Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Hailun He
- School of Life Sciences, Central South University, Changsha 410013, China
| | - Shanni Li
- School of Life Sciences, Central South University, Changsha 410013, China
- Correspondence: (S.L.); (C.M.)
| | - Changbei Ma
- School of Life Sciences, Central South University, Changsha 410013, China
- Correspondence: (S.L.); (C.M.)
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24
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Bai X, Zhang H, Li Z, Chen O, He H, Jia X, Zou L. Platelet-derived extracellular vesicles encapsulate microRNA-34c-5p to ameliorate inflammatory response of coronary artery endothelial cells via PODXL-mediated P38 MAPK signaling pathway. Nutr Metab Cardiovasc Dis 2022; 32:2424-2438. [PMID: 36096977 DOI: 10.1016/j.numecd.2022.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 05/30/2022] [Accepted: 06/14/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND AND AIMS Low-grade chronic inflammation was reported to serve as a distinctive pathophysiologic feature of coronary artery disease (CAD), the leading cause of death around the world. Herein, the current study aimed to explore whether and how microRNA-34c-5p (miR-34c-5p), a miRNA enriched in extracellular vesicles (EVs) originated from the activated platelet (PLT-EVs), affects the inflammation of human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS HCAECs were established as an in vitro cell model using oxidized low-density lipoprotein (ox-LDL). miR-34c-5p, an abundant miRNA in PLT-EVs, can be transferred to HCAECs and target PODXL by binding to its 3'UTR. Gain- and loss-of-function experiments of miR-34c-5p and podocalyxin (PODXL) were performed in ox-LDL-induced HCAECs. Subsequently, HCAECs were subjected to co-culture with PLT-EVs, followed by detection of the expression patterns of key pro-inflammatory factors. Either miR-34c-5p mimic or PLT-EVs harboring miR-34c-5p attenuated the ox-LDL-evoked inflammation in HCAECs by suppressing interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). By blocking the P38 MAPK signaling pathway, miR-34c-5p-mediated depletion of PODXL contributed to protection against ox-LDL-induced inflammation. In vitro findings were further validated by findings observed in ApoE knock-out mice. Additionally, miR-34c-5p in PLT-EVs showed an athero-protective role in the murine model. CONCLUSION Altogether, our findings highlighted that miR-34c-5p in PLT-EVs could alleviate inflammation response in HCAECs by targeting PODXL and inactivation of the P38 MAPK signaling pathway.
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Affiliation(s)
- Xuetao Bai
- Department of Anaesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Hao Zhang
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China
| | - Zhiguo Li
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China
| | - Ou Chen
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China
| | - Hengpeng He
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China
| | - Xiukun Jia
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China
| | - Lijuan Zou
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, PR China.
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25
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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26
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Saraswat M, Przybyla B, Joenvaara S, Tohmola T, Strandin T, Puhka M, Jouppila A, Lassila R, Renkonen R. Urinary extracellular vesicles carry multiple activators and regulators of coagulation. Front Cell Dev Biol 2022; 10:967482. [PMID: 36158187 PMCID: PMC9489905 DOI: 10.3389/fcell.2022.967482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/12/2022] [Indexed: 11/25/2022] Open
Abstract
Cells shape their extracellular milieu by secreting intracellular products into the environment including extracellular vesicles which are lipid-bilayer limited membrane particles. These vesicles carry out a range of functions, including regulation of coagulation, via multiple contributor mechanisms. Urinary extracellular vesicles are secreted by various cells, lining the urinary space, including the nephron and bladder. They are known to have procoagulant properties, however, the details of this function, beyond tissue factor are not well known. The aim of the study was to access the role of urinary extracellular vesicles in impacting coagulation upon supplementation to plasma. This could indicate their physiological function upon kidney injury or pathology. Supplementation to standard human plasma and plasmas deficient in various coagulation factors was used for this purpose, and calibrated automated thrombogram (CAT®) was the major technique applied. We found that these vesicles contain multiple coagulation-related factors, and their lipid composition affects coagulation activities of plasma upon supplementation. Remarkably, these vesicles can restore thrombin generation in FVII, FVIII, FIX and FXI -deficient plasmas. This study explores the multiple roles of urinary extracellular vesicles in coagulation in in vitro blood coagulation and implies their importance in its regulation by several mechanisms.
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Affiliation(s)
- Mayank Saraswat
- Transplantation Laboratory, University of Helsinki, Helsinki, Finland
- *Correspondence: Mayank Saraswat,
| | - Beata Przybyla
- Coagulation Unit, Helsinki University Central Hospital, Helsinki, Finland
| | - Sakari Joenvaara
- Transplantation Laboratory, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Tiialotta Tohmola
- Department of Biosciences, University of Helsinki, Helsinki, Finland
| | - Tomas Strandin
- Department of Virology, Medicum, Univeristy of Helsinki, Helsinki, Finland
| | - Maija Puhka
- EV Core and Institute for Molecular Medicine Finland, Helsinki, Finland
| | - Annukka Jouppila
- Helsinki University Hospital Research Institute, Helsinki, Finland
| | - Riitta Lassila
- Research Program Unit in Systems Oncology, Coagulation Disorders Unit, Hematology and Cancer Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Risto Renkonen
- Transplantation Laboratory, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Hospital, Helsinki, Finland
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27
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Al-Koussa H, AlZaim I, El-Sabban ME. Pathophysiology of Coagulation and Emerging Roles for Extracellular Vesicles in Coagulation Cascades and Disorders. J Clin Med 2022; 11:jcm11164932. [PMID: 36013171 PMCID: PMC9410115 DOI: 10.3390/jcm11164932] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 05/20/2022] [Indexed: 11/16/2022] Open
Abstract
The notion of blood coagulation dates back to the ancient Greek civilization. However, the emergence of innovative scientific discoveries that started in the seventeenth century formulated the fundamentals of blood coagulation. Our understanding of key coagulation processes continues to evolve, as novel homeostatic and pathophysiological aspects of hemostasis are revealed. Hemostasis is a dynamic physiological process, which stops bleeding at the site of injury while maintaining normal blood flow within the body. Intrinsic and extrinsic coagulation pathways culminate in the homeostatic cessation of blood loss, through the sequential activation of the coagulation factors. Recently, the cell-based theory, which combines these two pathways, along with newly discovered mechanisms, emerged to holistically describe intricate in vivo coagulation mechanisms. The complexity of these mechanisms becomes evident in coagulation diseases such as hemophilia, Von Willebrand disease, thrombophilia, and vitamin K deficiency, in which excessive bleeding, thrombosis, or unnecessary clotting, drive the development and progression of diseases. Accumulating evidence implicates cell-derived and platelet-derived extracellular vesicles (EVs), which comprise microvesicles (MVs), exosomes, and apoptotic bodies, in the modulation of the coagulation cascade in hemostasis and thrombosis. As these EVs are associated with intercellular communication, molecular recycling, and metastatic niche creation, emerging evidence explores EVs as valuable diagnostic and therapeutic approaches in thrombotic and prothrombotic diseases.
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Affiliation(s)
- Houssam Al-Koussa
- Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
| | - Ibrahim AlZaim
- Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, The American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
| | - Marwan E. El-Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, The American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
- Correspondence: ; Tel.: +961-01-350-000 (ext. 4765)
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28
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Hong Y, Truong AD, Vu TH, Lee S, Heo J, Kang S, Lillehoj HS, Hong YH. Profiling and analysis of exosomal miRNAs derived from highly pathogenic avian influenza virus H5N1-infected White Leghorn chickens. Poult Sci 2022; 101:102123. [PMID: 36087445 PMCID: PMC9468452 DOI: 10.1016/j.psj.2022.102123] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/17/2022] [Accepted: 08/02/2022] [Indexed: 11/17/2022] Open
Abstract
Exosomes are small cell membrane-derived vesicles; they play important roles as mediators of cell-to-cell communication via delivery of their contents, such as proteins and microRNAs (miRNAs). In particular, exosomal miRNAs regulate the gene expression of recipient cells by inhibiting the expression of target mRNAs. In this study, we investigated the miRNA expression profiles of highly pathogenic avian influenza virus (HPAIV) H5N1-infected White Leghorn chickens and analyzed the functions of their target genes. After 3 d of infection with A/chicken/Vietnam/NA-01/2019 (H5N1), exosomes were isolated from the blood serum of White Leghorn chickens for small RNA sequencing. We accordingly identified 10 differentially expressed miRNAs (DE miRNAs; 5 upregulated and 5 downregulated) by comparing the exosomes derived from infected and noninfected chickens. The target genes of DE miRNAs were predicted using miRDB and TargetScan for Gene Ontology and KEGG pathway enrichment analyses. A majority of the target genes was found to be associated with the MAPK signaling pathway; several immune-related genes were identified as being regulated by these DE miRNAs. Moreover, we predicted DE miRNA binding sites in HPAIV RNA segments using the RNAhybrid algorithm. The findings of this study provide a theoretical basis for gaining insights into the regulatory mechanisms of exosomal miRNAs in response to HPAIV H5N1 infection and the identification of novel vaccine candidates.
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Affiliation(s)
- Yeojin Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea
| | - Anh Duc Truong
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Hanoi 100000, Vietnam
| | - Thi Hao Vu
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea
| | - Sooyeon Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea
| | - Jubi Heo
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea
| | - Suyeon Kang
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Agricultural Research Services, United States Department of Agriculture, Beltsville, MD 20705, USA
| | - Yeong Ho Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea.
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29
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Fan WJ, Liu D, Pan LY, Wang WY, Ding YL, Zhang YY, Ye RX, Zhou Y, An SB, Xiao WF. Exosomes in osteoarthritis: Updated insights on pathogenesis, diagnosis, and treatment. Front Cell Dev Biol 2022; 10:949690. [PMID: 35959489 PMCID: PMC9362859 DOI: 10.3389/fcell.2022.949690] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/04/2022] [Indexed: 01/09/2023] Open
Abstract
Osteoarthritis (OA) has remained a prevalent public health problem worldwide over the past decades. OA is a global challenge because its specific pathogenesis is unclear, and no effective disease-modifying drugs are currently available. Exosomes are small and single-membrane vesicles secreted via the formation of endocytic vesicles and multivesicular bodies (MVBs), which are eventually released when MVBs fuse with the plasma membrane. Exosomes contain various integral surface proteins derived from cells, intercellular proteins, DNAs, RNAs, amino acids, and metabolites. By transferring complex constituents and promoting macrophages to generate chemokines and proinflammatory cytokines, exosomes function in pathophysiological processes in OA, including local inflammation, cartilage calcification and degradation of osteoarthritic joints. Exosomes are also detected in synovial fluid and plasma, and their levels continuously change with OA progression. Thus, exosomes, specifically exosomal miRNAs and lncRNAs, potentially represent multicomponent diagnostic biomarkers for OA. Exosomes derived from various types of mesenchymal stem cells and other cell or tissue types affect angiogenesis, inflammation, and bone remodeling. These exosomes exhibit promising capabilities to restore OA cartilage, attenuate inflammation, and balance cartilage matrix formation and degradation, thus demonstrating therapeutic potential in OA. In combination with biocompatible and highly adhesive materials, such as hydrogels and cryogels, exosomes may facilitate cartilage tissue engineering therapies for OA. Based on numerous recent studies, we summarized the latent mechanisms and clinical value of exosomes in OA in this review.
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Affiliation(s)
- Wen-Jin Fan
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Di Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Lin-Yuan Pan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wei-Yang Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi-Lan Ding
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yue-Yao Zhang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Rui-Xi Ye
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yang Zhou
- Department of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
| | - Sen-Bo An
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
| | - Wen-Feng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
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30
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Zhang X, Wu Y, Cheng Q, Bai L, Huang S, Gao J. Extracellular Vesicles in Cardiovascular Diseases: Diagnosis and Therapy. Front Cell Dev Biol 2022; 10:875376. [PMID: 35721498 PMCID: PMC9198246 DOI: 10.3389/fcell.2022.875376] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/13/2022] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of global mortality. Therapy of CVDs is still a great challenge since many advanced therapies have been developed. Multiple cell types produce nano-sized extracellular vesicles (EVs), including cardiovascular system-related cells and stem cells. Compelling evidence reveals that EVs are associated with the pathophysiological processes of CVDs. Recently researches focus on the clinical transformation in EVs-based diagnosis, prognosis, therapies, and drug delivery systems. In this review, we firstly discuss the current knowledge about the biophysical properties and biological components of EVs. Secondly, we will focus on the functions of EVs on CVDs, and outline the latest advances of EVs as prognostic and diagnostic biomarkers, and therapeutic agents. Finally, we will introduce the specific application of EVs as a novel drug delivery system and its application in CVDs therapy. Specific attention will be paid to summarize the perspectives, challenges, and applications on EVs’ clinical and industrial transformation.
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Affiliation(s)
- Xiaojing Zhang
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
- *Correspondence: Xiaojing Zhang, ; Jun Gao,
| | - Yuping Wu
- Department of Scientific Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
| | - Qifa Cheng
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
| | - Liyang Bai
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Shuqiang Huang
- Department of Clinical Medicine, The Sixth Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Jun Gao
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
- *Correspondence: Xiaojing Zhang, ; Jun Gao,
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Li T, Wang B, Ding H, Chen S, Cheng W, Li Y, Wu X, Wang L, Jiang Y, Lu Z, Teng Y, Su S, Han X, Zhao M. Effect of Extracellular Vesicles From Multiple Cells on Vascular Smooth Muscle Cells in Atherosclerosis. Front Pharmacol 2022; 13:857331. [PMID: 35620296 PMCID: PMC9127356 DOI: 10.3389/fphar.2022.857331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/05/2022] [Indexed: 12/20/2022] Open
Abstract
Atherosclerosis (AS)-related diseases are still the main cause of death in clinical patients. The phenotype switching, proliferation, migration, and secretion of vascular smooth muscle cells (VSMCs) have a pivotal role in atherosclerosis. Although numerous research studies have elucidated the role of VSMCs in AS, their potential functional regulations continue to be explored. The formation of AS involves various cells, such as endothelial cells, smooth muscle cells, and macrophages. Therefore, intercellular communication of blood vessels cannot be ignored due to closely connected endothelia, media, and adventitia. Extracellular vesicles (EVs), as the vectors of cell-to-cell communication, can deliver proteins and nucleic acids of parent cells to the recipient cells. EVs have emerged as being central in intercellular communication and play a vital role in the pathophysiologic mechanisms of AS. This review summarizes the effects of extracellular vesicles (EVs) derived from multiple cells (endothelial cells, macrophages, mesenchymal stem cells, etc.) on VSMCs in AS. The key findings of this review are as follows: 1) endothelial cell–derived EVs (EEVs) have anti- or pro-atherogenic effects on VSMCs; 2) macrophage-derived EVs (MEVs) aggravate the proliferation and migration of VSMCs; 3) mesenchymal stem cells can inhibit VSMCs; and 4) the proliferation and migration of VSMCs can be inhibited by the treatment of EVs with atherosclerosis-protective factors and promoted by noxious stimulants. These results suggested that EVs have the same functional properties as treated parent cells, which might provide vital guidance for treating AS.
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Affiliation(s)
- Tong Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Baofu Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hao Ding
- Department of Oncology, Shanxi Traditional Chinese Medical Hospital, Taiyuan, China
| | - Shiqi Chen
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Weiting Cheng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoxiao Wu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yangyang Jiang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ziwen Lu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Teng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Sha Su
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaowan Han
- Department of Cardiac Rehabilitation, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mingjing Zhao
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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32
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Wen C, Li B, Nie L, Mao L, Xia Y. Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis. Front Cell Dev Biol 2022; 10:804247. [PMID: 35445015 PMCID: PMC9014218 DOI: 10.3389/fcell.2022.804247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/09/2022] [Indexed: 01/20/2023] Open
Abstract
Atherosclerosis (AS) is universally defined as chronic vascular inflammation induced by dyslipidaemia, obesity, hypertension, diabetes and other risk factors. Extracellular vesicles as information transmitters regulate intracellular interactions and their important cargo circular RNAs are involved in the pathological process of AS. In this review, we summarize the current data to elucidate the emerging roles of extracellular vesicle-derived circular RNAs (EV-circRNAs) in AS and the mechanism by which EV-circRNAs affect the development of AS. Additionally, we discuss their vital role in the progression from risk factors to AS and highlight their great potential for use as diagnostic biomarkers of and novel therapeutic strategies for AS.
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Affiliation(s)
- Cheng Wen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bowei Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanpeng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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33
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Chen X, Luo Q. Potential clinical applications of exosomes in the diagnosis, treatment, and prognosis of cardiovascular diseases: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:372. [PMID: 35433929 PMCID: PMC9011294 DOI: 10.21037/atm-22-619] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/07/2022] [Indexed: 12/17/2022]
Abstract
Background and Objective Cardiovascular diseases (CVDs) have been one of the most common threats to human health in recent decades. At present, despite many diagnostic, prognostic and therapeutic methods being applied in the clinic, the prevalence of CVDs continues to rise. Therefore, new discovery is needed and exosomes have received extensive attention. Exosomes are extracellular vesicles that enable communication between cells. They are widely distributed in biofluids, suggesting that they may be useful in CVD diagnosis and prognosis. Furthermore, exosomes are ideal drug transporters with relatively high transport efficiency and the capability to target different kinds of tissues. However, the present research concentrates, for the most part, on mechanistic studies with less attention to clinical applications. Methods More than 150 relevant scientific articles from databases like PubMed, Web of Science were screened and analysed for this narrative review. Data of clinical trials are collected from clinicaltrials.gov. Key Content and Findings In this review, we concentrate on different exosomes and CVDs, and we summarize the physiological and pathological roles of CVD-related exosomes. We focused on the role exosomes may have as biomarkers of CVDs, therapeutic opportunities, and possible hurdles to the clinical application of exosomes, aiming to provide a useful reference for its translational use in the CVD field. Conclusions Specific changes in exosome cargos (mainly miRNAs and proteins) are in accordance with the occurrence and development of CVDs including acute myocardial infarction (AMI), arrhythmia, coronary artery disease (CAD), heart failure (HF) and cardiomyopathy, therefore meaningful for diagnosis and prognosis of CVDs. For exosome related therapeutic methods, potential ways consist of direct administration of exosomes, targeting on exosome synthesis, processing and release, and working as adjuvants. All in all, exosomes are expected to serve as meaningful tools in the diagnosis, treatment and prognosis of CVDs.
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Affiliation(s)
- Xuyang Chen
- Joint Program of Nanchang University and Queen Mary University of London, Queen Mary School, Medical Department, Nanchang University, Nanchang, China.,Department of Histology and Embryology, Nanchang University School of Basic Medical Sciences, Nanchang, China
| | - Qi Luo
- Department of Histology and Embryology, Nanchang University School of Basic Medical Sciences, Nanchang, China
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34
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Wei K, Huang H, Liu M, Shi D, Ma X. Platelet-Derived Exosomes and Atherothrombosis. Front Cardiovasc Med 2022; 9:886132. [PMID: 35498048 PMCID: PMC9051247 DOI: 10.3389/fcvm.2022.886132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/25/2022] [Indexed: 11/17/2022] Open
Abstract
Platelet-derived exosomes (PLT-Exos) are the main subtype of extracellular vesicles secreted by platelets, which carry proteins, nucleotides, lipids, and other substances to acceptor cells, playing an important role in intercellular communication. PLT-Exos increase with platelet activation and are involved in the process of atherothrombosis by delivering cargo to acceptor cells. Atherosclerotic plaque rupture, causing thrombosis and arterial occlusion, is the basic pathological change leading to cardiovascular events. PLT-Exos from different donors have different functions. PLT-Exos secreted by healthy volunteer or mice can inhibit platelet activation and inflammation of endothelial cells, thus exerting an antithrombotic effect, while PLT-Exos derived from some patients induce endothelial apoptosis and an inflammatory response to promote atherothrombosis. Furthermore, increased PLT-Exos reflect platelet activation and their cargoes also are derived from platelets; therefore, PLT-Exos can also be used as a biomarkers for the diagnosis and prognosis of cardiovascular disease. This article reviews the characteristics of PLT-Exos and discusses their role in cell-to-cell communication and atherothrombosis.
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Affiliation(s)
- Kangkang Wei
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
- Department of Integrated Chinese and Western Medicine, Peking University Health Science Center, Beijing, China
| | - Hongbo Huang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Min Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Dazhuo Shi
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
- Dazhuo Shi,
| | - Xiaojuan Ma
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Xiaojuan Ma,
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35
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Lazana I, Anagnostopoulos C. A Novel, Cell-Free Therapy to Enter Our Hearts: The Potential Role of Small EVs in Prevention and Treatment of CVD. Int J Mol Sci 2022; 23:ijms23073662. [PMID: 35409022 PMCID: PMC8998514 DOI: 10.3390/ijms23073662] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/22/2022] [Accepted: 03/25/2022] [Indexed: 12/18/2022] Open
Abstract
Heart disease constitutes one of the leading causes of morbidity and mortality worldwide. Current therapeutic techniques, such as interventional revascularization, although lifesaving, come along with myocardial injury related to the reperfusion itself, called ischemia-reperfusion injury, which is an added factor for increased morbidity. For that reason, there is an imperative need for novel therapies to be developed that would either prevent or treat myocardial injury. Extracellular vesicles (EVs), specifically small EVs (sEVs), have proven to be important mediators of intercellular communication. The fact that they carry information reflecting that of the parental cell makes them an ideal candidate for diagnostic purposes. sEVs derived from immunoregulatory cells, such as mesenchymal stem cells or cardiac progenitor cells, could also be used therapeutically to exert the primary immunomodulatory function but without carrying the side effects related to cell therapy. Furthermore, as a natural product, they have the added advantage of low immunogenicity, offering the potential for safe drug delivery. In the field of cardiology, there has been great interest in the therapeutic and diagnostic potential of sEVs with significant translational potential. Here, we review the potential use of sEVs in the context of myocardial ischemia and ischemia-reperfusion injury.
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Affiliation(s)
- Ioanna Lazana
- King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK
- Cell and Gene Therapy Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
- Correspondence:
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36
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Macchi C, Greco MF, Favero C, Dioni L, Cantone L, Hoxha M, Vigna L, Solazzo G, Corsini A, Banach M, Pesatori AC, Bollati V, Ruscica M. Associations Among PCSK9 Levels, Atherosclerosis-Derived Extracellular Vesicles, and Their miRNA Content in Adults With Obesity. Front Cardiovasc Med 2022; 8:785250. [PMID: 35071356 PMCID: PMC8782054 DOI: 10.3389/fcvm.2021.785250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/13/2021] [Indexed: 01/16/2023] Open
Abstract
Background: Extracellular vesicles (EV) concentration is generally increased in patients with cardiovascular diseases, although the protective role of EVs in atherosclerosis has been reported. Among the specific cargo of EVs, miRNAs contribute to different stages of atherosclerosis. Aim of the present report has been to investigate, in individuals with obesity, the interplay among EVs derived from cells relevant for the atherosclerotic process (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils), their miRNA content and proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of low-density lipoprotein receptor (LDLR). Methods and Results: EVs have been isolated from 936 individuals with obesity (body mass index = 33.6 ± 5.6 Kg/m2) and a raised cardiovascular risk (e.g., LDL-C = 131.6 ± 36.4 mg/dL, HOMA-IR = 3.1, and roughly 50% on anti-hypertensive medications). PCSK9 levels were negatively associated with EV count in the range 150–400 nm and with those derived from macrophages (CD14+), endothelium (CD105+), and neutrophils (CD66+). The association between PCSK9 and platelet-derived EVs (CD61+) was modified by platelet counts. PCSK9 was significantly associated with five EV-derived miRNAs (hsa-miRNA−362−5p,−150,−1244,−520b-3p,−638). Toll-like receptor 4 and estrogen receptor 1 were targeted by all five miRNAs and LDLR by four. The effect on LDLR expression is mainly driven by hsa-miR-150. Considering the implication of EV in atherosclerosis onset and progression, our findings show a potential role of PCSK9 to regulate EV-derived miRNAs, especially those involved in inflammation and expression of low-density lipoprotein receptor (LDLR) receptor.
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Affiliation(s)
- Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Maria Francesca Greco
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Chiara Favero
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Laura Dioni
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Laura Cantone
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mirjam Hoxha
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Luisella Vigna
- Occupational Medicine Unit, Fondazione Cà Granda, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Solazzo
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.,Istituto di Ricovero e Cura a Carattere ScientificoI (RCCS) Multimedica, Milan, Italy
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Lodz, Poland.,Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Angela C Pesatori
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Valentina Bollati
- Epidemiology, Epigenetics and Toxicology (EPIGET) Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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37
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Exosomes in cardiovascular diseases: a blessing or a sin for the mankind. Mol Cell Biochem 2022; 477:833-847. [PMID: 35064412 DOI: 10.1007/s11010-021-04328-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases (CVDs) comprises disorders of blood vessels and heart. Multiple cells in the heart suggests that hetero-cellular communication, which is an important aspect in heart functioning and there is a need to elucidate the way in which this inter-cellular communication occurs. Now a days, exosomal research has gained much attention. Exosomes, nano-shuttles, are EVs with diameters ranging from 40 to 160 nm (average 100 nm), secreted by body cells. These vesicles act as cell-to-cell communicators and are carriers of important biomolecules such as RNAs, miRNAs, Proteins and lipids. Exosomes can change the gene expression of the recipient cells, thereby, changes the cellular characteristics. Exosomes have known to play an essential role in protection as well as progression of various cardiovascular diseases. In the present review, role of exosomes in various CVDs have been discussed.
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38
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Coly PM, Loyer X. [Extracellular vesicles and cardiovascular diseases]. Med Sci (Paris) 2021; 37:1119-1124. [PMID: 34928215 DOI: 10.1051/medsci/2021204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Cardiovascular diseases remain the leading cause of death globally. There is therefore a need to develop new approaches for the treatment and early detection of these ailments. In the past decades, extracellular vesicles (EVs) have attracted significant attention as their role in intercellular communication has been brought to light. They have been shown to regulate pathways such as cellular inflammation or angiogenesis, and are therefore involved in key aspects of cardiovascular pathophysiology. Interestingly, EVs appear to have a multifaceted role which depends on their origin and cargo. Though at times deleterious, they have also been proposed as promising diagnostic tools and potential therapeutics. This review highlights recent advances in the role of extracellular vesicles in cardiovascular pathologies.
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Affiliation(s)
- Pierre-Michael Coly
- Université de Paris, Inserm UMR 970, Paris-Centre de recherche cardiovasculaire (Paris-Cardiovascular Research Center), 56 rue Leblanc, F-75015 Paris, France
| | - Xavier Loyer
- Université de Paris, Inserm UMR 970, Paris-Centre de recherche cardiovasculaire (Paris-Cardiovascular Research Center), 56 rue Leblanc, F-75015 Paris, France
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39
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Jadli AS, Parasor A, Gomes KP, Shandilya R, Patel VB. Exosomes in Cardiovascular Diseases: Pathological Potential of Nano-Messenger. Front Cardiovasc Med 2021; 8:767488. [PMID: 34869682 PMCID: PMC8632805 DOI: 10.3389/fcvm.2021.767488] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases (CVDs) represent a major global health problem, due to their continued high incidences and mortality. The last few decades have witnessed new advances in clinical research which led to increased survival and recovery in CVD patients. Nevertheless, elusive and multifactorial pathophysiological mechanisms of CVD development perplexed researchers in identifying efficacious therapeutic interventions. Search for novel and effective strategies for diagnosis, prevention, and intervention for CVD has shifted research focus on extracellular vesicles (EVs) in recent years. By transporting molecular cargo from donor to recipient cells, EVs modulate gene expression and influence the phenotype of recipient cells, thus EVs prove to be an imperative component of intercellular signaling. Elucidation of the role of EVs in intercellular communications under physiological conditions implied the enormous potential of EVs in monitoring and treatment of CVD. The EVs secreted from the myriad of cells in the cardiovascular system such as cardiomyocytes, cardiac fibroblasts, cardiac progenitor cells, endothelial cells, inflammatory cells may facilitate the communication in physiological and pathological conditions. Understanding EVs-mediated cellular communication may delineate the mechanism of origin and progression of cardiovascular diseases. The current review summarizes exosome-mediated paracrine signaling leading to cardiovascular disease. The mechanistic role of exosomes in cardiovascular disease will provide novel avenues in designing diagnosis and therapeutic interventions.
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Affiliation(s)
- Anshul S Jadli
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ananya Parasor
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Karina P Gomes
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ruchita Shandilya
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Vaibhav B Patel
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
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40
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Li L, Huang L, Huang C, Xu J, Huang Y, Luo H, Lu X, He S, Yuan G, Chen L, Han X, Cao X, Jiang A, Liu C, Shi J, Yang H, Jiang Y. The multiomics landscape of serum exosomes during the development of sepsis. J Adv Res 2021; 39:203-223. [PMID: 35777909 PMCID: PMC9263672 DOI: 10.1016/j.jare.2021.11.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/03/2021] [Accepted: 11/11/2021] [Indexed: 02/08/2023] Open
Abstract
The study for the first time describes the profile of molecular dynamics in septic serum exosomes. We provide a new direction into proteasome-mediated protein degradation in septic serum exosomes. IL-10 delivery by septic exosomes may play a vital role in alleviation of AKI of CLP mice. Septic serum exosomes participate in the modulation of sepsis by regulating vitamin metabolism. The molecular mechanisms proposed in the study may provide helpful insights for the therapy of sepsis. Introduction Sepsis is an infection-induced severe inflammatory disorder leading to multiple organ dysfunction. It remains a highly lethal condition for which early diagnosis and therapy achieve unsatisfactory results. Circulating exosomes containing biomarkers and mediators of sepsis have recently received attention, but the progress has been far from optimal. Objectives The present study focuses on the profiles of molecular dynamics in serum exosomes and explores the potential molecular mechanisms on serum exosomes during the process of sepsis. Methods We used high-performance liquid chromatography-tandem mass spectrometry and RNA-seq to detect the dynamic profiles of exosome proteins and RNAs (including mRNAs, lncRNAs and miRNAs) in serum exosomes from 3 healthy individuals and 9 septic patients at the different stages. Then integrative multiomics analyses were performed and the results were validated by qRT-PCR, LiquiChip assay and metabolomics analysis on mice subjected to cecal ligation and puncture (CLP) modeling. Results A total of 354 proteins, 195 mRNAs, 82 lncRNAs and 55 miRNAs were identified as differentially expressed molecules in serum exosomes from septic patients. Integrative multiomics analysis showed that exosome components were associated with cytokine storm, complement and clotting cascades, the endothelial barrier, 20S proteasome-dependent protein degradation and vitamin metabolism. Importantly, pretreatment with serum exosomes derived from mice subjected to CLP significantly restrained proinflammatory cytokine expression and alleviated tissue injury in septic mice. Further metabolomics analysis demonstrated that pretreatment with septic serum exosomes significantly affected the metabolites associated with vitamin digestion and absorption in CLP mice. Conclusion Our study for the first time describes the landscape of the molecular dynamics of serum exosomes during the development of sepsis and proposes some hypothetical molecular mechanisms by integrative multiomics analysis, which may provide helpful diagnostic and therapeutic insights for the ongoing battle against sepsis.
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41
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Lananna BV, Imai S. Friends and foes: Extracellular vesicles in aging and rejuvenation. FASEB Bioadv 2021; 3:787-801. [PMID: 34632314 PMCID: PMC8493967 DOI: 10.1096/fba.2021-00077] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022] Open
Abstract
Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance toward their beneficial effects as an antiaging intervention.
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Affiliation(s)
- Brian V. Lananna
- Department of Developmental BiologyWashington University School of MedicineSt. LouisMOUSA
| | - Shin‐ichiro Imai
- Department of Developmental BiologyWashington University School of MedicineSt. LouisMOUSA
- Department of MedicineWashington University School of MedicineSt. LouisMOUSA
- Department of GerontologyLaboratory of Molecular Life ScienceInstitute of Biomedical Research and InnovationKobeJapan
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42
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Al Subayyil A, Basmaeil YS, Alenzi R, Khatlani T. Human Placental Mesenchymal Stem/Stromal cells (pMSCs) inhibit agonist-induced platelet functions reducing atherosclerosis and thrombosis phenotypes. J Cell Mol Med 2021; 25:9268-9280. [PMID: 34535958 PMCID: PMC8500971 DOI: 10.1111/jcmm.16848] [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: 03/31/2021] [Revised: 07/17/2021] [Accepted: 07/20/2021] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem/stromal cells isolated from human term placenta (pMSCs) have potential to treat clinically manifested inflammatory diseases. Atherosclerosis is a chronic inflammatory disease, and platelets play a contributory role towards its pathogenesis. During transplantation, MSCs interact with platelets and exert influence on their functional outcome. In this study, we investigated the consequences of interaction between pMSCs and platelets, and its impact on platelet-mediated atherosclerosis in vitro. Human platelets were treated with various types of pMSCs either directly or with their secretome, and their effect on agonist-mediated platelet activation and functional characteristics were evaluated. Human umbilical vein endothelial cells (HUVECs) were used as control. The impact of pMSCs treatment on platelets was evaluated by the expression of activation markers and by platelet functional analysis. A subset of pMSCs reduced agonist-induced activation of platelets, both via direct contact and with secretome treatments. Decrease in platelet activation translated into diminished spreading, limited adhesion and minimized aggregation. In addition, pMSCs decreased oxidized LDL (ox-LDL)-inducedCD36-mediated platelet activation, establishing their protective role in atherosclerosis. Gene expression and protein analysis show that pMSCs express pro- and anti-thrombotic proteins, which might be responsible for the modulation of agonist-induced platelet functions. These data suggest the therapeutic benefits of pMSCs in atherosclerosis.
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Affiliation(s)
- Abdullah Al Subayyil
- Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Yasser S Basmaeil
- Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Reem Alenzi
- Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Tanvir Khatlani
- Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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Lin B, Yang J, Song Y, Dang G, Feng J. Exosomes and Atherogenesis. Front Cardiovasc Med 2021; 8:738031. [PMID: 34513963 PMCID: PMC8427277 DOI: 10.3389/fcvm.2021.738031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/04/2021] [Indexed: 01/08/2023] Open
Abstract
Myocardial infarction and ischemic stroke are the leading causes of mortality worldwide. Atherosclerosis is their common pathological foundation. It is known that atherosclerosis is characterized by endothelial activation/injury, accumulation of inflammatory immune cells and lipid-rich foam cells, followed by the development of atherosclerotic plaque. Either from arterial vessel wall or blood circulation, endothelial cells, smooth muscle cells, macrophages, T-lymphocytes, B-lymphocytes, foam cells, and platelets have been considered to contribute to the pathogenesis of atherosclerosis. Exosomes, as natural nano-carriers and intercellular messengers, play a significant role in modulation of cell-to-cell communication. Under physiological or pathological conditions, exosomes can deliver their cargos including donor cell-specific proteins, lipids, and nucleic acids to target cells, which in turn affect the function of the target cells. In this review, we will describe the pathophysiological significance of various exosomes derived from different cell types associated with atherosclerosis, and the potential applications of exosome in clinical diagnosis and treatment.
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Affiliation(s)
- Bingbing Lin
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Juan Yang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yuwei Song
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Guohui Dang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Juan Feng
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
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Abstract
Extracellular vesicles (EVs) are membrane particles released by most cell types in response to different stimuli. They are composed of a lipid bilayer that encloses a wide range of bioactive material, including proteins and nucleic acids. EVs have garnered increasing attention over recent years, as their role in intercellular communication has been brought to light. As such, they have been found to regulate pathophysiologic pathways like inflammation, angiogenesis, or senescence, and are therefore implicated in key aspects atherosclerosis initiation and progression. Interestingly, EVs appear to have a multifaceted role; depending on their cargo, they can either facilitate or hamper the development of atherosclerotic lesions. In this review, we examine how EVs of varying origins may be implicated in the different phases of atherosclerotic lesion development. We also discuss the need to standardize isolation and analysis procedures to fully fulfil their potential as biomarkers and therapeutics for cardiovascular diseases.
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Giró O, Jiménez A, Pané A, Badimon L, Ortega E, Chiva-Blanch G. Extracellular vesicles in atherothrombosis and cardiovascular disease: Friends and foes. Atherosclerosis 2021; 330:61-75. [PMID: 34256307 DOI: 10.1016/j.atherosclerosis.2021.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/21/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
Extracellular vesicles (EV, exosomes and microvesicles -MV-) are 30-1000 nm particles surrounded by a phospholipid bilayer membrane that are released from almost all cell types through several pathways. EV encapsulate bioactive molecules, and the molecular cargo is determined by the trigger stimulating its release, reflecting its cell origin and biological functions. This review is primarily focused on the latest evidence of the roles of EV, released from cells involved in the different stages of atherothrombosis. The potential translation of this information to the clinical arena is also discussed. EV can have both pro- and anti-atherothrombotic effects depending on several factors, such as the type of vesicle (MV/exosome), its molecular cargo, its cell of origin, and the context in which are generated, i.e., the stimulus triggering its release. In fact, EV actively participate in every step of atherosclerosis onset and progression, and also in thrombus formation leading to a major adverse cardiovascular event. Moreover, EV have a determinant role in fibrous cap stability, thus determining the propensity of the plaque to rupture. On the other hand, and again, conditioned by the context and stimulus instigating its secretion, some EV may have protective biological functions, perhaps as a compensatory mechanism or even with reparative or regenerative potential. Therefore, the study of the implication of EV in atherothrombosis might be of relevance to unveil new therapeutic targets, vectors and biomarkers of cardiovascular disease (CVD).
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Affiliation(s)
- Oriol Giró
- Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute - IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Amanda Jiménez
- Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute - IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Adriana Pané
- Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute - IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Lina Badimon
- Cardiovascular Program ICCC; Institut de Recerca Hospital Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Emilio Ortega
- Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute - IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Gemma Chiva-Blanch
- Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute - IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Extracellular Vesicles and Antiphospholipid Syndrome: State-of-the-Art and Future Challenges. Int J Mol Sci 2021; 22:ijms22094689. [PMID: 33925261 PMCID: PMC8125219 DOI: 10.3390/ijms22094689] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/21/2021] [Accepted: 04/24/2021] [Indexed: 01/08/2023] Open
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thromboembolism, obstetric complications, and the presence of antiphospholipid antibodies (aPL). Extracellular vesicles (EVs) play a key role in intercellular communication and connectivity and are known to be involved in endothelial and vascular pathologies. Despite well-characterized in vitro and in vivo models of APS pathology, the field of EVs remains largely unexplored. This review recapitulates recent findings on the role of EVs in APS, focusing on their contribution to endothelial dysfunction. Several studies have found that APS patients with a history of thrombotic events have increased levels of EVs, particularly of endothelial origin. In obstetric APS, research on plasma levels of EVs is limited, but it appears that levels of EVs are increased. In general, there is evidence that EVs activate endothelial cells, exhibit proinflammatory and procoagulant effects, interact directly with cell receptors, and transfer biological material. Future studies on EVs in APS may provide new insights into APS pathology and reveal their potential as biomarkers to identify patients at increased risk.
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Jamalkhah M, Asaadi Y, Azangou-Khyavy M, Khanali J, Soleimani M, Kiani J, Arefian E. MSC-derived exosomes carrying a cocktail of exogenous interfering RNAs an unprecedented therapy in era of COVID-19 outbreak. J Transl Med 2021; 19:164. [PMID: 33888147 PMCID: PMC8061879 DOI: 10.1186/s12967-021-02840-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/16/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The onset of the SARS-CoV-2 pandemic has resulted in ever-increasing casualties worldwide, and after 15 months, standard therapeutic regimens are yet to be discovered. MAIN BODY Due to the regenerative and immunomodulatory function of MSCs, they can serve as a suitable therapeutic option in alleviating major COVID-19 complications like acute respiratory distress syndrome. However, the superior properties of their cognate exosomes as a cell-free product make them preferable in the clinic. Herein, we discuss the current clinical status of these novel therapeutic strategies in COVID-19 treatment. We then delve into the potential of interfering RNAs incorporation as COVID-19 gene therapy and introduce targets involved in SARS-CoV-2 pathogenesis. Further, we present miRNAs and siRNAs candidates with promising results in targeting the mentioned targets. CONCLUSION Finally, we present a therapeutic platform of mesenchymal stem cell-derived exosomes equipped with exogenous iRNAs, that can be employed as a novel therapeutic modality in COVID-19 management aiming to prevent further viral spread within the lung, hinder the virus life cycle and pathogenesis such as immune suppression, and ultimately, enhance the antiviral immune response.
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Affiliation(s)
- Monire Jamalkhah
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Yasaman Asaadi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | | | - Javad Khanali
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jafar Kiani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
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El-Kadiry AEH, Merhi Y. The Role of the Proteasome in Platelet Function. Int J Mol Sci 2021; 22:3999. [PMID: 33924425 PMCID: PMC8069084 DOI: 10.3390/ijms22083999] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their limited protein synthesis, platelets are equipped with multiple protein degradation mechanisms, such as the proteasome. In nucleated cells, the functions of the proteasome are well established and primarily include proteostasis among a myriad of other signaling processes. However, the role of proteasome-mediated protein degradation in platelets remains elusive. In this review article, we recapitulate the developing literature on the functions of the proteasome in platelets, discussing its emerging regulatory role in platelet viability and function and highlighting how its functional coupling with the transcription factor NF-κB constitutes a novel potential therapeutic target in atherothrombotic diseases.
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Affiliation(s)
- Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Centre, Montreal, QC H1T 1C8, Canada;
- Biomedical Sciences Program, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Yahye Merhi
- Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Centre, Montreal, QC H1T 1C8, Canada;
- Biomedical Sciences Program, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
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Abstract
Extracellular vesicles (EVs) have received considerable attention in biological and clinical research due to their ability to mediate cell-to-cell communication. Based on their size and secretory origin, EVs are categorized as exosomes, microvesicles, and apoptotic bodies. Increasing number of studies highlight the contribution of EVs in the regulation of a wide range of normal cellular physiological processes, including waste scavenging, cellular stress reduction, intercellular communication, immune regulation, and cellular homeostasis modulation. Altered circulating EV level, expression pattern, or content in plasma of patients with cardiovascular disease (CVD) may serve as diagnostic and prognostic biomarkers in diverse cardiovascular pathologies. Due to their inherent characteristics and physiological functions, EVs, in turn, have become potential candidates as therapeutic agents. In this review, we discuss the evolving understanding of the role of EVs in CVD, summarize the current knowledge of EV-mediated regulatory mechanisms, and highlight potential strategies for the diagnosis and therapy of CVD. We also attempt to look into the future that may advance our understanding of the role of EVs in the pathogenesis of CVD and provide novel insights into the field of translational medicine.
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Affiliation(s)
- Jian Yang
- Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
| | - Xue Zou
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Institute of Cardiology and Chongqing Key Laboratory for Hypertension Research, Chongqing, PR China
| | - Pedro A Jose
- Division of Renal Disease & Hypertension, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Institute of Cardiology and Chongqing Key Laboratory for Hypertension Research, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou, PR China.
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Hong Y, Truong AD, Lee J, Vu TH, Lee S, Song KD, Lillehoj HS, Hong YH. Exosomal miRNA profiling from H5N1 avian influenza virus-infected chickens. Vet Res 2021; 52:36. [PMID: 33658079 PMCID: PMC7931527 DOI: 10.1186/s13567-021-00892-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/02/2021] [Indexed: 12/31/2022] Open
Abstract
Exosomes are membrane vesicles containing proteins, lipids, DNA, mRNA, and micro RNA (miRNA). Exosomal miRNA from donor cells can regulate the gene expression of recipient cells. Here, Ri chickens were divided into resistant (Mx/A; BF2/B21) and susceptible (Mx/G; BF2/B13) trait by genotyping of Mx and BF2 genes. Then, Ri chickens were infected with H5N1, a highly pathogenic avian influenza virus (HPAIV). Exosomes were purified from blood serum of resistant chickens for small RNA sequencing. Sequencing data were analysed using FastQCv0.11.7, Cutadapt 1.16, miRBase v21, non-coding RNA database, RNAcentral 10.0, and miRDeep2. Differentially expressed miRNAs were determined using statistical methods, including fold-change, exactTest using edgeR, and hierarchical clustering. Target genes were predicted using miRDB. Gene ontology analysis was performed using gProfiler. Twenty miRNAs showed significantly different expression patterns between resistant control and infected chickens. Nine miRNAs were up-regulated and 11 miRNAs were down-regulated in the infected chickens compared with that in the control chickens. In target gene analysis, various immune-related genes, such as cytokines, chemokines, and signalling molecules, were detected. In particular, mitogen-activated protein kinase (MAPK) pathway molecules were highly controlled by differentially expressed miRNAs. The result of qRT-PCR for miRNAs was identical with sequencing data and miRNA expression level was higher in resistant than susceptible chickens. This study will help to better understand the host immune response, particularly exosomal miRNA expression against HPAIV H5N1 and could help to determine biomarkers for disease resistance.
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Affiliation(s)
- Yeojin Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Anh Duc Truong
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Vietnam
| | - Jiae Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Thi Hao Vu
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Sooyeon Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Ki-Duk Song
- Department of Animal Biotechnology, College of Agricultural and Life Sciences, Jeonbuk National University, Jeonju, 54896, Republic of Korea
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Agricultural Research Services, United States Department of Agriculture, Beltsville, MD, 20705, USA
| | - Yeong Ho Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.
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