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Li J, Wang Z, Li J, Zhao H, Ma Q. HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation. Transl Stroke Res 2025; 16:990-1015. [PMID: 38740617 PMCID: PMC12045843 DOI: 10.1007/s12975-024-01258-5] [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: 02/29/2024] [Revised: 04/27/2024] [Accepted: 05/01/2024] [Indexed: 05/16/2024]
Abstract
Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration of rtPA is essential for restoring perfusion in acute ischemic stroke, though it concurrently elevates the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player in neuroinflammation after brain ischemia and ischemia-reperfusion. Released passively by necrotic cells and actively secreted, including direct secretion of HMGB1 into the extracellular space and packaging of HMGB1 into intracellular vesicles by immune cells, glial cells, platelets, and endothelial cells, HMGB1 represents a prototypical damage-associated molecular pattern (DAMP). It is intricately involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Moreover, HMGB1 significantly contributes to neurovascular remodeling and functional recovery in later stages. Significantly, HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the integrity of the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells. This includes mediating excitotoxicity due to excitatory amino acids, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. In this review, we summarize the structure and redox properties, secretion and pathways, regulation of immune cell activity, the role of pathophysiological mechanisms in stroke, and hemorrhage transformation for HMGB1, which will pave the way for developing new neuroprotective drugs, reduction of post-stroke neuroinflammation, and expansion of thrombolysis time window.
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Affiliation(s)
- Jiamin Li
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Zixin Wang
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Jiameng Li
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Haiping Zhao
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China.
| | - Qingfeng Ma
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China.
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Lambaren K, Trac N, Fehrenbach D, Madhur M, Chung EJ. T Cell-Targeting Nanotherapies for Atherosclerosis. Bioconjug Chem 2025; 36:332-346. [PMID: 39979082 DOI: 10.1021/acs.bioconjchem.4c00590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Cardiovascular diseases remain the leading cause of mortality worldwide. Specifically, atherosclerosis is a primary cause of acute cardiac events. However, current therapies mainly focus on lipid-lowering versus addressing the underlying inflammatory response that leads to its development and progression. Nanoparticle-mediated drug delivery offers a promising approach for targeting and regulating these inflammatory responses. In atherosclerotic lesions, inflammatory cascades result in increased T helper (Th) 1 and Th17 activity and reduced T regulatory activation. The regulation of T cell responses is critical in preventing the inflammatory imbalance in atherosclerosis, making them a key therapeutic target for nanotherapy to achieve precise atherosclerosis treatment. By functionalizing nanoparticles with targeting modalities, therapeutic agents can be delivered specifically to immune cells in atherosclerotic lesions. In this Review, we outline the role of T cells in atherosclerosis, examine current nanotherapeutic strategies for targeting T cells and modulating their differentiation, and provide perspectives for the development of nanoparticles specifically tailored to target T cells for the treatment of atherosclerosis.
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Affiliation(s)
- Karla Lambaren
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Noah Trac
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Daniel Fehrenbach
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Meena Madhur
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Eun Ji Chung
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
- Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California 90089, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089, United States
- Bridge Institute, University of Southern California, Los Angeles, California 90089, United States
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Cheng X, Li YL, Wang H, Zhang RJ, Fan KY, Qi XT, Zheng GP, Dong HL. Mesenchymal stem cell therapy in atherosclerosis: A bibliometric and visual analysis. World J Stem Cells 2024; 16:1062-1085. [PMID: 39734478 PMCID: PMC11669984 DOI: 10.4252/wjsc.v16.i12.1062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation, and extensive studies have demonstrated their therapeutic potential in atherosclerosis (AS). AIM To conduct a bibliometric analysis of studies on the use of MSC therapy for AS over the past two decades, assess key trends and provide insights for future research directions. METHODS We systematically searched the Web of Science Core Collection database for articles published between 1999 and 2023, yielding a total of 556 articles. Visual representation and bibliometric analysis of information and trends were facilitated using CiteSpace, the R package 'bibliometrix' and VOSviewer. RESULTS The analyzed articles were predominantly from 52 countries/regions, with prominent contributions from China and the United States. A cohort of 3057 authors contributed to these publications, with the works of Libby P distinguished by their influence and citation count. Int J Mol Sci has emerged as the journal with the highest publication volume, prominently disseminating influential papers and identifying citation outbreaks. Furthermore, our analysis identified current research hotspots within the field, focusing on vascular progenitor cells, inflammatory mechanisms, and extracellular vesicles. Emerging research frontiers, such as extracellular vesicles and oxidative stress, have been highlighted as areas of burgeoning interest. Finally, we offer perspectives on the status of research and future directions of MSC therapy in AS. CONCLUSION This comprehensive analysis provides valuable insights for advancing scientific research on MSC therapy for AS. By elucidating pivotal trends and research directions, this study aimed to foster innovation and promote the progress of disciplines in this field, thereby contributing to advancing scientific knowledge and clinical practice.
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Affiliation(s)
- Xing Cheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ya-Ling Li
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Heng Wang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Rui-Jing Zhang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ke-Yi Fan
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Xiao-Tong Qi
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Guo-Ping Zheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Hong-Lin Dong
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China.
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Ruggieri E, Di Domenico E, Locatelli AG, Isopo F, Damanti S, De Lorenzo R, Milan E, Musco G, Rovere-Querini P, Cenci S, Vénéreau E. HMGB1, an evolving pleiotropic protein critical for cellular and tissue homeostasis: Role in aging and age-related diseases. Ageing Res Rev 2024; 102:102550. [PMID: 39427887 DOI: 10.1016/j.arr.2024.102550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/05/2024] [Accepted: 10/13/2024] [Indexed: 10/22/2024]
Abstract
Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity.
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Affiliation(s)
- Elena Ruggieri
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Erika Di Domenico
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | | | - Flavio Isopo
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Sarah Damanti
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Rebecca De Lorenzo
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Enrico Milan
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | | | - Patrizia Rovere-Querini
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Simone Cenci
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
| | - Emilie Vénéreau
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
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Kiełbowski K, Skórka P, Plewa P, Bakinowska E, Pawlik A. The Role of Alarmins in the Pathogenesis of Atherosclerosis and Myocardial Infarction. Curr Issues Mol Biol 2024; 46:8995-9015. [PMID: 39194749 DOI: 10.3390/cimb46080532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/30/2024] [Accepted: 08/15/2024] [Indexed: 08/29/2024] Open
Abstract
Atherosclerosis is a condition that is associated with lipid accumulation in the arterial intima. Consequently, the enlarging lesion, which is also known as an atherosclerotic plaque, may close the blood vessel lumen, thus leading to organ ischaemia. Furthermore, the plaque may rupture and initiate the formation of a thrombus, which can cause acute ischaemia. Atherosclerosis is a background pathological condition that can eventually lead to major cardiovascular diseases such as acute coronary syndrome or ischaemic stroke. The disorder is associated with an altered profile of alarmins, stress response molecules that are secreted due to cell injury or death and that induce inflammatory responses. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33, and heat shock proteins (HSPs) also affect the behaviour of endothelial cells and vascular smooth muscle cells (VSMCs). Thus, alarmins control the inflammatory responses of endothelial cells and proliferation of VSMCs, two important processes implicated in the pathogenesis of atherosclerosis. In this review, we will discuss the role of alarmins in the pathophysiology of atherosclerosis and myocardial infarction.
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Affiliation(s)
- Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Patryk Skórka
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Paulina Plewa
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
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Ogiji ED, Aboheimed N, Ross K, Voller C, Siner R, Jensen RL, Jolly CE, Carr DF. Greater mechanistic understanding of the cutaneous pathogenesis of Stevens-Johnson syndrome/toxic epidermal necrolysis can shed light on novel therapeutic strategies: a comprehensive review. Curr Opin Allergy Clin Immunol 2024; 24:218-227. [PMID: 38753537 PMCID: PMC11213502 DOI: 10.1097/aci.0000000000000993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
PURPOSE OF REVIEW Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (SCARs) characterized by widespread epithelial detachment and blistering, which affects the skin and mucocutaneous membranes. To date, therapeutic interventions for SJS/TEN have focused on systematic suppression of the inflammatory response using high-dose corticosteroids or intravenous immunoglobulin G (IgG), for example. No targeted therapies for SJS/TEN currently exist. RECENT FINDINGS Though our understanding of the pathogenesis of SJS/TEN has advanced from both an immunological and dermatological perspective, this knowledge is yet to translate into the development of new targeted therapies. SUMMARY Greater mechanistic insight into SJS/TEN would potentially unlock new opportunities for identifying or repurposing targeted therapies to limit or even prevent epidermal injury and blistering.
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Affiliation(s)
- Emeka D. Ogiji
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Department of Pharmacology and Therapeutics, Ebonyi State University, Abakaliki, Nigeria
| | - Nourah Aboheimed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Department of Pharmacy Practice, Princess Nourah bint Abdulrahman University, Saudi Arabia
| | - Kehinde Ross
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University
| | - Calum Voller
- School of Medicine, University of Liverpool, Liverpool, UK
| | - Ryan Siner
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Rebecca L. Jensen
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Carol E. Jolly
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Daniel F. Carr
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
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Liang W, Wei R, Zhu X, Li J, Lin A, Chen J, Wu W, Jie Q. Downregulation of HMGB1 carried by macrophage-derived extracellular vesicles delays atherosclerotic plaque formation through Caspase-11-dependent macrophage pyroptosis. Mol Med 2024; 30:38. [PMID: 38493291 PMCID: PMC10943908 DOI: 10.1186/s10020-023-00753-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 11/02/2023] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1). ApoE-/- mice were used to construct an AS mouse model by a high-fat diet, followed by injection of macrophage-EV/siHMGB1 to assess the in vivo effect of macrophage-EV/siHMGB1 on AS mice. RAW264.7 cells were subjected to ox-LDL, LPS or macrophage-EV/siHMGB1 for analyzing the in vitro effect of macrophage-EV/siHMGB1 on macrophage pyrophosis and inflammation. RESULTS In silico analysis found that HMGB1 was closely related to the development of AS. Macrophage-EV/siHMGB could inhibit the release of HMGB1 from macrophages to outside cells, and the reduced HMGB1 release could inhibit foam cell formation. Besides, macrophage-EV/siHMGB also inhibited the LPS-induced Caspase-11 activation, thus inhibiting macrophage pyroptosis and preventing atherosclerotic plaque formation. CONCLUSION Our results proved that macrophage-EV/siHMGB could inhibit foam cell formation and suppress macrophage pyroptosis, finally preventing atherosclerotic plaque formation in AS mice.
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Affiliation(s)
- Weijie Liang
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Ruibin Wei
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Xingxing Zhu
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Jinliang Li
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Aiwen Lin
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Jun Chen
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Wen Wu
- Department of Endocrinology, Guangdong Geriatrics Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, No. 106, Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China.
| | - Qiang Jie
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China.
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Domingo E, Marques P, Francisco V, Piqueras L, Sanz MJ. Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases? Pharmacol Res 2024; 200:107058. [PMID: 38218355 DOI: 10.1016/j.phrs.2024.107058] [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: 07/26/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.
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Affiliation(s)
- Elena Domingo
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Patrice Marques
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Vera Francisco
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain
| | - Laura Piqueras
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
| | - Maria-Jesus Sanz
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
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Tamber SS, Bansal P, Sharma S, Singh RB, Sharma R. Biomarkers of liver diseases. Mol Biol Rep 2023; 50:7815-7823. [PMID: 37482588 DOI: 10.1007/s11033-023-08666-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/05/2023] [Indexed: 07/25/2023]
Abstract
The liver is one of the pivotal organs in the human body and is fundamentally responsible for detoxification and metabolism. Various disorders such as non-alcoholic fatty liver disease, fibrosis, cirrhosis, hepatocellular carcinoma, and hepatitis are associated with improper functions of the liver. Hence, biomarkers are needed to determine the severity. Further, many liver enzymes, including the cascade of aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBIL), are conventional liver biomarkers. They are not, however, unique to the liver; hence, efforts are being made to identify the precise biomarkers for liver illness that can target liver diseases. HMGB1, cytokeratin 18 (K18), glutathione-S-transferase-α (GST-α), glutamate dehydrogenase (GLDH), malate dehydrogenase (MDH), and microRNAs (miRNA) are a few examples of developing biomarkers used to detect many liver diseases. Hence, the review has highlighted various novel biomarkers of the liver so that various pathophysiological pathways and treatments can be made easier.
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Affiliation(s)
- Sukhbir Singh Tamber
- University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab, 140103, India
| | - Palak Bansal
- University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab, 140103, India
| | - Suraj Sharma
- University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab, 140103, India
| | - Rai Barinder Singh
- University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab, 140103, India
| | - Ramica Sharma
- University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab, 140103, India.
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10
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Fan Z, Huang Y, Wu J, Yang C, Guo X, Du L, Yang J. Negative Correlation between Serum NLRP3 and the Ratio of Treg/Th17 in Patients with Obstructive Coronary Artery Disease. Rev Cardiovasc Med 2022; 23:403. [PMID: 39076663 PMCID: PMC11270388 DOI: 10.31083/j.rcm2312403] [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: 05/04/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Regulatory T (Treg) cells are a class of anti-inflammatory lymphocyte subpopulations with a potential protective effect against atherosclerosis, whereas T helper 17 (Th17) cells have been reported to possess proatherogenic activity. It was believed that disturbed circulating Treg/Th17 balance was associated with the onset and progression of atherosclerosis. This study is designed to probe the regulative action of serum Nod-like receptor protein 3 (NLRP3) on the Treg/Th17 balance in patients with atherosclerosis. METHODS Fifty-two patients with coronary atherosclerosis and stenosis degrees of more than 50% were assigned to the coronary artery disease (CAD) group, and an equal number of people without coronary atherosclerosis were assigned to the control group (assessed by coronary angiography). Peripheral blood mononuclear cells (PBMCs) from two group patients were extracted and cultivated. The calculation of the Treg/Th17 ratio and quantitative analysis of the Treg and Th17 cell frequencies were performed through flow cytometry. Real-time fluorescence quantitative polymerase chain reaction (RT-PCR) was executed for the quantitative mRNA detection of the fork head-winged helix transcription factor (Foxp3) and the retinoic acid-related orphan nuclear receptor C (RORC) in PBMCs. Enzyme-linked immunosorbent assays were applied to measure the serum level of NLRP3, interleukin (IL)-10, IL-1 β , IL-17A, IL-23, and transforming growth factor (TGF)- β 1. Additionally, the connection between serum Treg/Th17 ratio and NLRP3 levels was analyzed using the Pearson correlation coefficient. RESULTS The baseline parameters, including sex, age, or blood biochemical indices had no difference in both groups (p > 0.05). The CAD group showed higher Th17 cell frequency, lower Treg cell frequency, and a lower Treg/Th17 ratio when compared to the control (p < 0.05). Consistent with the variation in the T-cell subset ratio, in patients with atherosclerosis, the Th17-cell-related transcription factor RORC showed a markedly higher mRNA level (p < 0.05), conversely, the mRNA expression of the Treg cell-related transcription factor Foxp3 was notably reduced (p < 0.05). Similarly, the serum levels of NLRP3, IL-17A, IL-1, and IL-23 were significantly enhanced in CAD group but IL-10 and TGF- β 1 were reduced (p < 0.05). Additionally, a negative correlation was found between NLRP3 and the Treg/Th17 ratio (r = -0.69, p < 0.001). CONCLUSIONS Due to the potential impact on the serum Treg/Th17 ratio, NLRP3 may act as an aggravator in the onset and progression of atherosclerotic disease.
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Affiliation(s)
- ZhiXing Fan
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, 443000 Yichang, Hubei, China
- Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei, China
| | - YiFan Huang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, 443000 Yichang, Hubei, China
- Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei, China
| | - JinChun Wu
- Department of Cardiology, Qinghai Provincial People's Hospital, 810007 Xining, Qinghai, China
| | - ChaoJun Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, 443000 Yichang, Hubei, China
- Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei, China
| | - Xin Guo
- Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China
| | - Linghui Du
- Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China
| | - Jian Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, 443000 Yichang, Hubei, China
- Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei, China
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11
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Zhang G, Yang P, Liu X, Liu H, Wang J, Wang J, Xiao J, Nie D, Ma L. HMGB1 is increased in patients with immune thrombocytopenia and negatively associates with Tregs. Thromb Res 2022; 213:128-136. [DOI: 10.1016/j.thromres.2022.02.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022]
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12
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Yan W, Wang L, Chen Z, Gu C, Chen C, Liu X, Ye Q. Knockdown of lncRNA HAGLR promotes Treg cell differentiation through increasing the RUNX3 level in dermatomyositis. J Mol Histol 2022; 53:413-421. [DOI: 10.1007/s10735-021-10051-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/07/2021] [Indexed: 01/14/2023]
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13
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Zhu D, Zou H, Liu J, Wang J, Ma C, Yin J, Peng X, Li D, Yang Y, Ren Y, Zhang Z, Zhou P, Wang X, Cao Y, Xu X. Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation. Front Immunol 2022; 12:782792. [PMID: 35003098 PMCID: PMC8732860 DOI: 10.3389/fimmu.2021.782792] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/06/2021] [Indexed: 11/21/2022] Open
Abstract
Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.
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Affiliation(s)
- Damin Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of Obstetrics and Gynecology, Chaohu Hospital of Anhui Medical University, Chaohu, China.,National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China
| | - Huijuan Zou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China
| | - Jinxian Liu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Jing Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Cong Ma
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Jiaqian Yin
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Xiaoqing Peng
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Danyang Li
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Yulu Yang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Yu Ren
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Zhiguo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Ping Zhou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics (Anhui Medical University), Hefei, China.,Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, China.,Anhui Provincial Institute of Translational Medicine(Anhui Medical University), Hefei, China
| | - Xiangyan Wang
- Department of Obstetrics and Gynecology, Chaohu Hospital of Anhui Medical University, Chaohu, China
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China
| | - Xiaofeng Xu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, China
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14
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Collado A, Domingo E, Piqueras L, Sanz MJ. Primary hypercholesterolemia and development of cardiovascular disorders: Cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction. Int J Biochem Cell Biol 2021; 139:106066. [PMID: 34438057 DOI: 10.1016/j.biocel.2021.106066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/28/2022]
Abstract
Primary hypercholesterolemia, a metabolic disorder characterized by elevated circulating levels of cholesterol products, mainly low-density lipoproteins, is associated with arteriosclerosis development. Cardiovascular disease, predominantly myocardial infarction and stroke, remains the main cause of death worldwide, with atherosclerosis considered to be the most common underlying pathology. In addition to elevated plasma levels of low-density lipoproteins, low-grade systemic inflammation and endothelial dysfunction seem to be the main drivers of premature atherosclerosis. Here we review current knowledge related to cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction associated with primary hypercholesterolemia. We also discuss the contribution of different inflammatory mediators, immune players and signaling pathways implicated in leukocyte adhesion to the dysfunctional endothelium, a key feature of atherogenesis development. A better understanding of these processes linked to primary hypercholesterolemia should shed new light on cardiovascular disease development and might guide novel and effective therapeutic strategies to impair its progression.
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Affiliation(s)
- Aida Collado
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain.
| | - Elena Domingo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain
| | - Laura Piqueras
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; CIBERDEM-Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute, Spanish Ministry of Health, Madrid, Spain
| | - Maria-Jesus Sanz
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; CIBERDEM-Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute, Spanish Ministry of Health, Madrid, Spain.
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15
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High-mobility group box 1 serves as an inflammation driver of cardiovascular disease. Biomed Pharmacother 2021; 139:111555. [PMID: 33865014 DOI: 10.1016/j.biopha.2021.111555] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/15/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is the most deadly disease, which can cause sudden death, in which inflammation is a key factor in its occurrence and development. High-mobility group box 1 (HMGB1) is a novel nuclear DNA-binding protein that activates innate immunity to induce inflammation in CVD. HMGB1 exists in the cytoplasm and nucleus of different cell types, including those in the heart. By binding to its receptors, HMGB1 triggers a variety of signaling cascades, leading to inflammation and CVD. To help develop HMGB1-targeted therapies, here we discuss HMGB1 and its biological functions, receptors, signaling pathways, and pathophysiology related to inflammation and CVD, including cardiac remodeling, cardiac hypertrophy, myocardial infarction, heart failure, pulmonary hypertension, atherosclerosis, and cardiomyopathy.
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16
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Ni YA, Chen H, Nie H, Zheng B, Gong Q. HMGB1: An overview of its roles in the pathogenesis of liver disease. J Leukoc Biol 2021; 110:987-998. [PMID: 33784425 DOI: 10.1002/jlb.3mr0121-277r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 01/06/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is an abundant architectural chromosomal protein that has multiple biologic functions: gene transcription, DNA replication, DNA-damage repair, and cell signaling for inflammation. HMGB1 can be released passively by necrotic cells or secreted actively by activated immune cells into the extracellular milieu after injury. Extracellular HMGB1 acts as a damage-associated molecular pattern to initiate the innate inflammatory response to infection and injury by communicating with neighboring cells through binding to specific cell-surface receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). Numerous studies have suggested HMGB1 to act as a key protein mediating the pathogenesis of chronic and acute liver diseases, including nonalcoholic fatty liver disease, hepatocellular carcinoma, and hepatic ischemia/reperfusion injury. Here, we provide a detailed review that focuses on the role of HMGB1 and HMGB1-mediated inflammatory signaling pathways in the pathogenesis of liver diseases.
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Affiliation(s)
- Yuan-Ao Ni
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
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17
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Testa C, DI Lorenzo A, Parlato A, D'Ambrosio G, Merolla A, Pacileo M, Iannuzzo G, Gentile M, Nugara C, Sarullo FM, DE Gregorio C, D'Andrea A, Vigorito C, Venturini E, Giallauria F. Exercise for slowing the progression of atherosclerotic process: effects on inflammatory markers. Panminerva Med 2021; 63:122-132. [PMID: 33565757 DOI: 10.23736/s0031-0808.21.04266-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Atherosclerosis is a dynamic process driven by all cardiovascular risk factors that can be briefly divided into an early and a late phase. Inflammation is one of the fundamental substrates that initiates the atherosclerotic process in the early stages and promotes and maintains it in the final stages. In the last decades, clinical and experimental data have shown that inflammation is supported by mediators that respond to physical activity. The present review aimed at investigating the effect of physical exercise on inflammatory mediators, both the positive ones that have a proinflammatory effect (interleukin 6, c-reactive protein and tumor necrosis factor α, interferon γ, high-mobility group box-1), and the negative ones which have an anti-inflammatory effect (interleukin 10). Pooled data support the evidence that physical exercise can directly modulate the activity of inflammatory cytokines slowing down or preventing the formation of the atherosclerotic stage.
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Affiliation(s)
- Crescenzo Testa
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Anna DI Lorenzo
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Alessandro Parlato
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Giuseppe D'Ambrosio
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Aurora Merolla
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Mario Pacileo
- Unit of Cardiology and Intensive Care, "Umberto I" Hospital, Nocera Inferiore, Salerno, Italy
| | - Gabriella Iannuzzo
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Marco Gentile
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Cinzia Nugara
- Unit of Cardiovascular Rehabilitation, Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy
| | - Filippo M Sarullo
- Unit of Cardiovascular Rehabilitation, Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy
| | - Cesare DE Gregorio
- Unit of Cardiology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy.,Post-graduate Residency School in Cardiovascular Diseases, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
| | - Antonello D'Andrea
- Unit of Cardiology and Intensive Care, "Umberto I" Hospital, Nocera Inferiore, Salerno, Italy
| | - Carlo Vigorito
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Elio Venturini
- Cardiac Rehabilitation Unit, AUSL Toscana Nord-Ovest, Cecina Civil Hospital, Cecina, Livorno, Italy
| | - Francesco Giallauria
- Department of Translational Medical Sciences, Federico II University, Naples, Italy - .,Faculty of Sciences and Technology, University of New England, Armidale, Australia
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18
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Rapoport BL, Steel HC, Theron AJ, Heyman L, Smit T, Ramdas Y, Anderson R. High Mobility Group Box 1 in Human Cancer. Cells 2020; 9:E1664. [PMID: 32664328 PMCID: PMC7407638 DOI: 10.3390/cells9071664] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review.
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Affiliation(s)
- Bernardo L. Rapoport
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Helen C. Steel
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
| | - Annette J. Theron
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
| | - Liezl Heyman
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Teresa Smit
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa; (L.H.); (T.S.)
| | - Yastira Ramdas
- The Breast Care Centre, Netcare Milpark, 9 Guild Road, Parktown, Johannesburg 2193, South Africa;
| | - Ronald Anderson
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (A.J.T.); (R.A.)
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19
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López P, Rodríguez-Carrio J, Martínez-Zapico A, Pérez-Álvarez ÁI, Benavente L, Caminal-Montero L, Suárez A. IgM anti-phosphorylcholine antibodies associate with senescent and IL-17+ T cells in SLE patients with a pro-inflammatory lipid profile. Rheumatology (Oxford) 2020; 59:407-417. [PMID: 31302689 DOI: 10.1093/rheumatology/kez264] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/04/2019] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE. METHODS Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls. RESULTS IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (β= -0.252; P = 0.002), high-density lipoprotein (HDL; β = 0.271; P = 0.001), low-density lipoprotein (LDL; β= -0.192; P = 0.017) and glucocorticoid treatment (β= -0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (β = 0.194; P = 0.028) and SLEDAI (β = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: β = -0.455, P = 0.001; Th17: β= -0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines. CONCLUSION The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role.
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Affiliation(s)
- Patricia López
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo.,Group of Basic and Translational Research in Inflammatory Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
| | - Javier Rodríguez-Carrio
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo.,Group of Basic and Translational Research in Inflammatory Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
| | - Aleida Martínez-Zapico
- Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Lorena Benavente
- Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Luis Caminal-Montero
- Group of Basic and Translational Research in Inflammatory Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).,Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana Suárez
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo.,Group of Basic and Translational Research in Inflammatory Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
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20
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Zhang J, Chen L, Wang F, Zou Y, Li J, Luo J, Khan F, Sun F, Li Y, Liu J, Chen Z, Zhang S, Xiong F, Yu Q, Li J, Huang K, Adam BL, Zhou Z, Eizirik DL, Yang P, Wang CY. Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability. Diabetologia 2020; 63:987-1001. [PMID: 32072192 PMCID: PMC7145789 DOI: 10.1007/s00125-020-05105-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/15/2020] [Indexed: 01/07/2023]
Abstract
AIMS/HYPOTHESIS High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a 'danger signal' (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. METHODS In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULTS Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. CONCLUSIONS/INTERPRETATION The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes.
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Affiliation(s)
- Jing Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Longmin Chen
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Faxi Wang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zou
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingyi Li
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Jiahui Luo
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Faheem Khan
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Fei Sun
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Li
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Liu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhishui Chen
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China
| | - Shu Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Xiong
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qilin Yu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China
| | - Jinxiu Li
- Shenzhen Third People's Hospital, Shenzhen, Guangdong, China
| | - Kun Huang
- Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bao-Ling Adam
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Zhiguang Zhou
- Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and Endocrinology, Central South University, Changsha, China
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Ping Yang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China.
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Cong-Yi Wang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China.
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China.
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Chen Z, Pan X, Sheng Z, Yan G, Chen L, Ma G. Baicalin Suppresses the Proliferation and Migration of Ox-LDL-VSMCs in Atherosclerosis through Upregulating miR-126-5p. Biol Pharm Bull 2019; 42:1517-1523. [DOI: 10.1248/bpb.b19-00196] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Zhongpu Chen
- The Department of Cardiology, Zhongda Hospital, Southeast University
| | - Xiaodong Pan
- The Department of Cardiology, Zhongda Hospital, Southeast University
| | - Zulong Sheng
- The Department of Cardiology, Zhongda Hospital, Southeast University
| | - Gaoliang Yan
- The Department of Cardiology, Zhongda Hospital, Southeast University
| | - Long Chen
- The Department of Cardiology, Zhongda Hospital, Southeast University
| | - Genshan Ma
- The Department of Cardiology, Zhongda Hospital, Southeast University
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Gorgulho CM, Romagnoli GG, Bharthi R, Lotze MT. Johnny on the Spot-Chronic Inflammation Is Driven by HMGB1. Front Immunol 2019; 10:1561. [PMID: 31379812 PMCID: PMC6660267 DOI: 10.3389/fimmu.2019.01561] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Although much has been made of the role of HMGB1 acting as an acute damage associated molecular pattern (DAMP) molecule, prompting the response to tissue damage or injury, it is also released at sites of chronic inflammation including sites of infection, autoimmunity, and cancer. As such, the biology is distinguished from homeostasis and acute inflammation by the recruitment and persistence of myeloid derived suppressor cells, T regulatory cells, fibrosis and/or exuberant angiogenesis depending on the antecedents and the other individual inflammatory partners that HMGB1 binds and focuses, including IL-1β, CXCL12/SDF1, LPS, DNA, RNA, and sRAGE. High levels of HMGB1 released into the extracellular milieu and its persistence in the microenvironment can contribute to the pathogenesis of many if not all autoimmune disorders and is a key factor that drives inflammation further and worsens symptoms. HMGB1 is also pivotal in the maintenance of chronic inflammation and a “wound healing” type of immune response that ultimately contributes to the onset of carcinogenesis and tumor progression. Exosomes carrying HMGB1 and other instructive molecules are released and shape the response of various cells in the chronic inflammatory environment. Understanding the defining roles of REDOX, DAMPs and PAMPs, and the host response in chronic inflammation requires an alternative means for positing HMGB1's central role in limiting and focusing inflammation, distinguishing chronic from acute inflammation.
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Affiliation(s)
- Carolina M Gorgulho
- Tumor Immunology Laboratory, Department of Microbiology and Immunology, Botucatu Institute of Biosciences, São Paulo State University, Botucatu, Brazil.,DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Graziela G Romagnoli
- Tumor Immunology Laboratory, Department of Microbiology and Immunology, Botucatu Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Rosh Bharthi
- DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Michael T Lotze
- DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
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Strohbuecker L, Koenen H, van Rijssen E, van Cranenbroek B, Fasse E, Joosten I, Körber A, Bergmann C. Increased dermal expression of chromatin-associated protein HMGB1 and concomitant T-cell expression of the DNA RAGE in patients with psoriasis vulgaris. PSORIASIS (AUCKLAND, N.Z.) 2019; 9:7-17. [PMID: 30859087 PMCID: PMC6385765 DOI: 10.2147/ptt.s190507] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease of the skin, with both vascular and metabolic effects. Aggravating factors have been identified that initiate and maintain inflammation, including expression of Th1-, Th17-, and Th22-cell derived cytokines. Recently, we showed that the evolutionarily ancient and highly conserved damage-associated molecular pattern molecule "high mobility group box 1 (HMGB1)" is significantly increased in the serum of PV patients with disease progression and is decreased under standard therapies. MATERIALS AND METHODS To better understand the role of HMGB1 in the pathogenesis of PV, we recruited 22 untreated psoriatic patients with either mild or severe disease, defined by the Psoriasis Area Severity Index. We assessed HMGB1 and receptor for advanced glycation end products (RAGE) expression in the skin by immunohistochemistry and analyzed the immune-phenotype of Treg and Th17 cells by flow cytometry. RESULTS We found increased staining for HMGB1 in the dermis of psoriatic plaques in comparison to uninvolved skin of patients with PV. In addition, the major histocompatibility complex class III-encoded DNA and HMGB1 RAGE, induced by HMGB1, were highly expressed on psoriatic CD8+ T cells and CD4+ Treg. High expression of HMGB1 in the lesional skin was associated with even higher expression of its receptor, RAGE, on the cell surface of keratino-cytes in patients with severe PV. CONCLUSION The presence of HMGB1 and RAGE signaling may impact orchestration of chronic inflammation in PV which might have implications for Treg and Th17 cells.
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Affiliation(s)
- Lisa Strohbuecker
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
| | - Hans Koenen
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Esther van Rijssen
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bram van Cranenbroek
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Esther Fasse
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Irma Joosten
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Andreas Körber
- Department of Dermatology, University Hospital Essen, 45147 Essen, Germany
| | - Christoph Bergmann
- Department of Otorhinolaryngology, University Hospital Essen, 45147 Essen, Germany,
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Ding JW, Luo CY, Wang XA, Zhou T, Zheng XX, Zhang ZQ, Yu B, Zhang J, Tong XH. Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice. J Vasc Res 2019; 55:365-377. [DOI: 10.1159/000495310] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 11/09/2018] [Indexed: 11/19/2022] Open
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Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation. J Clin Med 2018; 8:jcm8010018. [PMID: 30583563 PMCID: PMC6352074 DOI: 10.3390/jcm8010018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/14/2018] [Accepted: 12/19/2018] [Indexed: 12/27/2022] Open
Abstract
Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX3CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH.
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Zhou J, Li X, Wu X, Zhang T, Zhu Q, Wang X, Wang H, Wang K, Lin Y, Wang X. Exosomes Released from Tumor-Associated Macrophages Transfer miRNAs That Induce a Treg/Th17 Cell Imbalance in Epithelial Ovarian Cancer. Cancer Immunol Res 2018; 6:1578-1592. [PMID: 30396909 DOI: 10.1158/2326-6066.cir-17-0479] [Citation(s) in RCA: 292] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 02/22/2018] [Accepted: 10/29/2018] [Indexed: 12/22/2022]
Abstract
The immune microenvironment is crucial for epithelial ovarian cancer (EOC) progression and consists of tumor-associated macrophages (TAM) and T lymphocytes, such as regulatory T cells (Treg) and T helper 17 (Th17) cells. In this study, the Treg/Th17 ratio was significantly higher in EOC in situ and in metastatic peritoneal tissues than in benign ovarian tumors and benign peritoneum. The Treg/Th17 ratio was associated with histologic grade and was an independent prognostic factor for overall survival of EOC patients. On the basis of microarray analysis of exosomes derived from TAMs, we identified miRNAs enriched in the exosomes, including miR-29a-3p and miR-21-5p. When the two miRNA mimics were transfected into CD4+ T cells, they directly suppressed STAT3 and regulated Treg/Th17 cells, inducing an imbalance, and they had a synergistic effect on STAT3 inhibition. Taken together, these results indicate that exosomes mediate the interaction between TAMs and T cells, generating an immune-suppressive microenvironment that facilitates EOC progression and metastasis. These findings suggest that targeting these exosomes or their associated miRNAs might pave the way for the development of novel treatments for EOC.
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Affiliation(s)
- Jieru Zhou
- Department of Obstetrics and Gynaecology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoduan Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoli Wu
- Department of Obstetrics and Gynaecology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Zhang
- Center for Reproductive Medicine, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China
| | - Qinyi Zhu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinjing Wang
- Department of Obstetrics and Gynaecology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Husheng Wang
- Department of Obstetrics and Gynaecology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Wang
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yingying Lin
- Department of Neurosurgery, RenJi Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Xipeng Wang
- Department of Obstetrics and Gynaecology, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Ding JW, Zhou T, Zheng XX, Wang XA, Tong XH, Luo CY, Zhang ZQ, Yu B. The Effects of High Mobility Group Box-1 Protein on Peripheral Treg/Th17 Balance in Patients with Atherosclerosis. ACTA CARDIOLOGICA SINICA 2018; 34:399-408. [PMID: 30271090 PMCID: PMC6160517 DOI: 10.6515/acs.201809_34(5).20180419a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 04/19/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Atherosclerosis (AS) is defined as chronic inflammation of the vessel wall. The major objective of the this study was to explore the mechanism of Treg/Th17 imbalance and the role of high mobility group box-1 protein (HMGB1) on the balance in AS. METHODS We detected the apoptotic ratios of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects with AS and normal coronary arteries (NCA) by flow cytometry. The effects of recombinant HMGB1 (rHMGB1) on the proportion, apoptosis and differentiation of Treg and Th17 cells were analyzed using flow cytometry, qRT-PCR and ELISA. RESULTS The frequencies of apoptotic Treg cells in the PBMCs from the subjects with AS were significantly higher than in those with NCA (p < 0.01). Stimulation of rHMGB1 obviously increased the level of Th17 cells and acid- related orphan receptor C (RORC) mRNA, and markedly decreased Treg cell frequency and the mRNA expression of factor forkhead family protein 3 (Foxp3) in the PBMCs. rHMGB1 played an obvious role in elevating Treg cell apoptosis ratio (p < 0.01). rHMGB1 treatment significantly decreased Treg cell ratio and IL-10 level, and increased Th17 cell ratio and IL-17A level induced from naïve CD4+ T cells. CONCLUSIONS HMGB1 may modulate Treg/Th17 balance in patients with AS through inducing Treg cell apoptosis and promoting cell differentiation of Th17.
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Affiliation(s)
- Jia-Wang Ding
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Tian Zhou
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xia-Xia Zheng
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xin-An Wang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Xiao-Hong Tong
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Cai-Yun Luo
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Zai-Qiang Zhang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
| | - Bin Yu
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei Province, China
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Allam G, Abdel-Moneim A, Gaber AM. The pleiotropic role of interleukin-17 in atherosclerosis. Biomed Pharmacother 2018; 106:1412-1418. [PMID: 30119214 DOI: 10.1016/j.biopha.2018.07.110] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 07/16/2018] [Accepted: 07/18/2018] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis is the main cause of cardiovascular diseases (CVDs), which considers the leading cause of mortality worldwide. Atherosclerosis is a chronic inflammatory condition of arterials' wall in which the development and the destabilization of plaque occur. Both innate and adaptive immunity play a significant role in modifying lipoproteins in arterials' wall. Recent investigations have demonstrated the opposing roles of CD4+ T cells subtypes in atherosclerosis. T helper-1 (Th1) response and pro-inflammatory cytokines possess proatherogenic effects, whereas T regulatory (Treg) cells have an atheroprotective role. Th17 cells have emerged as a new CD4+ T-cell subtype, which produce IL-17 that plays a crucial role in numerous inflammatory and autoimmune diseases. Recently, several studies have investigated the potential role of IL-17 in atherosclerosis. Some investigations have suggested a proatherogenic effect, however the others proposed an atheroprotective role. Hence, the exact role of IL-17 in the disease development and plaque stability is still debatable. In this review, we summarize the current knowledge on both atherogenesis and atheroprotective roles of IL-17. In addition, the synergistic and antagonistic effects of IL-17 with other cytokines in atherosclerosis will be discussed. On the basis of the current understanding of these roles, the possibility of developing novel therapeutic strategies against atherosclerosis may be evolved.
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Affiliation(s)
- Gamal Allam
- Immunology Section, Department of Microbiology, College of Medicine, Taif University, Taif, Saudi Arabia; Immunology Section, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
| | - Adel Abdel-Moneim
- Physiology Section, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Asmaa M Gaber
- Physiology Section, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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Zhao J, Yu J, Xu Y, Chen L, Zhou F, Zhai Q, Wu J, Shu B, Qi S. Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration. J Invest Dermatol 2018; 138:2322-2332. [PMID: 29787749 DOI: 10.1016/j.jid.2018.04.036] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 04/12/2018] [Accepted: 04/16/2018] [Indexed: 01/01/2023]
Abstract
HMGB1 protein is a multifunctional cytokine involved in inflammatory reactions and is known to play a key role in tissue repair and fibrosis. However, the function of HMGB1 in fibrotic skin diseases, such as hypertrophic scar formation, remains unclear. In this study, HMGB1 was detected in the nuclei of epidermal cells in normal skin and had accumulated in the cytoplasm in hypertrophic scars. By establishing a keratinocyte-fibroblast co-culture and conditional medium treatment models, we found that a reduced hydration condition increased the expression and secretion of HMGB1 in keratinocytes, subsequently activating dermal fibroblasts. HMGB1 secreted from keratinocytes activated fibroblasts by promoting the nuclear import of MRTF-A, increased the nuclear accumulation of MRTF-A/SRF complexes and consequently enhanced α-smooth muscle actin promoter activation. Moreover, blockade of advanced glycation end products or Toll-like receptor 2/4 inhibited the fibroblast activation induced by HMGB1. Finally, local delivery of HMGB1 resulted in marked hypertrophic scar formation in rabbit hypertrophic scar models, while HMGB1 blockade exerted a clear anti-scarring effect. Our results indicate that high HMGB1 levels induced by a reduced hydration status play an important role in hypertrophic scar formation, strongly suggesting that HMGB1 is a novel target for preventing scarring.
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Affiliation(s)
- Jingling Zhao
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jianxing Yu
- Department of Laser Cosmetology Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yingbin Xu
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lei Chen
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fei Zhou
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiyi Zhai
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Wu
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Shu
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Shaohai Qi
- Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Li R, Wang J, Zhu F, Li R, Liu B, Xu W, He G, Cao H, Wang Y, Yang J. HMGB1 regulates T helper 2 and T helper17 cell differentiation both directly and indirectly in asthmatic mice. Mol Immunol 2018; 97:45-55. [PMID: 29567318 DOI: 10.1016/j.molimm.2018.02.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/12/2018] [Accepted: 02/19/2018] [Indexed: 12/15/2022]
Abstract
The Th (T helper) 2 response is characteristic of allergic asthma, and Th17 cells are involved in more severe asthma. Recent studies demonstrated that HMGB1 (High mobility group box 1 protein) regulates airway inflammation and the Th2, Th17 inflammatory response in asthma. HMGB1 can interact with Toll-like receptors (TLR) 2 and 4, and the receptor for advanced glycation end products (RAGE), activating the NF-κB (nuclear factor kappa B) signaling pathway and inducing the release of downstream inflammatory mediators. Both Th cells and dendritic cells express TLR2, TLR4, and RAGE receptors. Therefore, we speculate that HMGB1 could regulate the differentiation of Th2, Th17 cells in asthma through direct and indirect mechanisms. An ovalbumin (OVA)-induced mouse asthmatic model was established. Anti-HMGB1 antibody or rHMGB1 was administered to OVA-sensitized mice 30 min prior to each challenge. For in vitro studies, magnetically separated CD4+ naive T cells were stimulated with or without rHMGB1 and/or anti-HMGB1 antibody. BMDCs (bone marrow-derived dendritic cells)-stimulated with or without rHMGB1 and/or anti-HMGB1 antibody were cocultured with CD4+ naive T cells. Our study showed that administration of rHMGB1 aggravated airway inflammation and mucus production, and induced Th2, Th17 polarization in asthmatic mice, and that anti-HMGB1 antibody weakened characteristic features of asthma and blocked the Th2, Th17 inflammatory responses. HMGB1 could directly act on naive T cells to induce differentiation of Th2, Th17 cells in vitro through activating the TLR2, TLR4, RAGE-NF-κB signal pathway in CD4+ naive T cells. HMGB1 could also indirectly promote Th2, Th17 differentiation via activating the TLR2, TLR4, RAGE-NF-κB signal pathway in DCs to mediate their maturation and antigen-presenting ability in vitro.
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Affiliation(s)
- Ruiting Li
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Jing Wang
- Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Fangfang Zhu
- Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Ruifang Li
- Department of Neurology, Hubei Third People's Hospital, Wuhan, Hubei 430033, PR China
| | - Bing Liu
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Wenjuan Xu
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Guangzhen He
- Department of Respiratory Medicine, Taihe Hospital of Hubei University of Medicine, Shiyan, 442000, PR China
| | - Huan Cao
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Yimin Wang
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
| | - Jiong Yang
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China.
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VanPatten S, Al-Abed Y. High Mobility Group Box-1 (HMGb1): Current Wisdom and Advancement as a Potential Drug Target. J Med Chem 2018; 61:5093-5107. [PMID: 29268019 DOI: 10.1021/acs.jmedchem.7b01136] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
High mobility group box-1 (HMGb1) protein, a nuclear non-histone protein that is released or secreted from the cell in response to damage or stress, is a sentinel for the immune system that plays a critical role in cell survival/death pathways. This review highlights key features of the endogenous danger-associated molecular pattern (DAMP) protein, HMGb1 in the innate inflammatory response along with various cofactors and receptors that regulate its downstream effects. The evidence demonstrating increased levels of HMGb1 in human inflammatory diseases and conditions is presented, along with a summary of current small molecule or peptide-like antagonists proven to specifically target HMGb1. Additionally, we delineate the measures needed toward validating this protein as a clinically relevant biomarker or bioindicator and as a relevant drug target.
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Affiliation(s)
- Sonya VanPatten
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
| | - Yousef Al-Abed
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
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32
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Update on the Protective Role of Regulatory T Cells in Myocardial Infarction: A Promising Therapy to Repair the Heart. J Cardiovasc Pharmacol 2017; 68:401-413. [PMID: 27941502 DOI: 10.1097/fjc.0000000000000436] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myocardial infarction (MI) remains one of the leading causes of heart failure development and death worldwide. To date, interventional and pharmacological therapies are effective in reducing the onset of heart failure and promoting survival. However, progressive maladaptive remodeling post-MI persists in a large fraction of patients resulting in poor prognosis. Immune cell responses and an inflammatory environment largely contribute to adverse cardiac remodeling post-MI. CD4FOXP3 regulatory T cells (Tregs) are known for their immunosuppressive capacity and have been successfully implemented in multiple preclinical studies of permanent and ischemia-reperfusion MI. In this review, we highlight the important cardioprotective role of Tregs at the cardiac tissue, cellular, and molecular level, as well as the most prominent pharmacological venues that could be used to exploit Tregs as a novel therapeutic intervention to lessen myocardial injury post-MI.
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Caveolin-1 Promotes the Imbalance of Th17/Treg in Patients with Chronic Obstructive Pulmonary Disease. Inflammation 2017; 39:2008-2015. [PMID: 27613621 DOI: 10.1007/s10753-016-0436-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The imbalance of Th17/Treg cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Caveolin-1 (Cav-1) has been regarded as a potential critical regulatory protein in pathological mechanisms of chronic inflammatory respiratory diseases. Therefore, we investigated whether the loss of Cav-1 is involved in the homeostasis of Th17/Treg cells in COPD. We examined the expressions of plasma Cav-1 and circulating Th17, Treg cells, and the related cytokines in patients with COPD. Enzyme-linked immunosorbent assay (ELISA) analyses showed a significant reduction of plasma Cav-1 levels in patients with stable COPD (SCOPD) and acutely exacerbated COPD (AECOPD) compared to smokers without COPD. This loss was associated with an increase in frequency of Treg and decreased in frequency of Th17 cells. To further identify the role of Cav-1, we studied the effects of Cav-1 overexpression or downregulation on frequencies of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects. Interestingly, small interfering RNA (siRNA) downregulation of Cav-1 was accompanied by an augmentation of Treg and reduction of Th17 expression. Together, our study demonstrated that the loss of Cav-1 contributed to the imbalance of Th17/Treg cells in patients with COPD.
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Braun M, Vaibhav K, Saad N, Fatima S, Brann DW, Vender JR, Wang LP, Hoda MN, Baban B, Dhandapani KM. Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury. THE JOURNAL OF IMMUNOLOGY 2017; 198:3615-3626. [PMID: 28341672 DOI: 10.4049/jimmunol.1601948] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 02/21/2017] [Indexed: 12/15/2022]
Abstract
Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (TH1/TH17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and TH1/TH17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.
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Affiliation(s)
- Molly Braun
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Kumar Vaibhav
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912.,Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912
| | - Nancy Saad
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912
| | - Sumbul Fatima
- Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912.,Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Darrell W Brann
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912.,Charlie Norwood VA Medical Center, Augusta, GA 30912
| | - John R Vender
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Lei P Wang
- Department of Psychiatry, Medical College of Georgia, Augusta University, Augusta, GA 30912; and
| | - Md Nasrul Hoda
- Department of Medical Laboratory, Imaging, and Radiological Sciences, College of Allied Health Sciences, Augusta University, Augusta, GA 30912.,Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912.,Charlie Norwood VA Medical Center, Augusta, GA 30912
| | - Babak Baban
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912.,Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912.,Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Krishnan M Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912; .,Charlie Norwood VA Medical Center, Augusta, GA 30912
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Zhang W, Guo S, Li B, Liu L, Ge R, Cao T, Wang H, Gao T, Wang G, Li C. Proinflammatory effect of high-mobility group protein B1 on keratinocytes: an autocrine mechanism underlying psoriasis development. J Pathol 2016; 241:392-404. [PMID: 27859256 DOI: 10.1002/path.4848] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 10/13/2016] [Accepted: 11/05/2016] [Indexed: 12/16/2022]
Abstract
Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High-mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signalling pathways were examined. Furthermore, the imiquimod-induced psoriasis-like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of 11 inflammatory factors were shown to be upregulated by HMGB1 in keratinocytes, among which interleukin (IL)-18 showed the greatest change. We then found that activation of the nuclear factor-κB signalling pathway and inflammasomes accounted for HMGB1-induced IL-18 expression and secretion. Moreover, HMGB1 and downstream IL-18 contributed to the development of psoriasiform dermatitis in the imiquimod-treated mice. In addition, T-helper 17 immune response in the psoriasis-like mouse model could be inhibited by both HMGB1 and IL-18 blockade. Our findings indicate that HMGB1 secreted from keratinocytes can facilitate the production and secretion of inflammatory factors such as IL-18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1-IL-18 axis may be useful for psoriasis treatment in the future. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Weigang Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Sen Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Bing Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Lin Liu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Rui Ge
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Tianyu Cao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Huina Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Tianwen Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, PR China
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Zhang X, Huang F, Chen Y, Qian X, Zheng SG. Progress and prospect of mesenchymal stem cell-based therapy in atherosclerosis. Am J Transl Res 2016; 8:4017-4024. [PMID: 27829989 PMCID: PMC5095298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 09/15/2016] [Indexed: 06/06/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial intima, occurring usually in the aged populations who are suffering from hypertension, dyslipidemia and diabetes for a long time. Research on atherosclerosis has shown that macrophage foam cell formation, inflammation, dyslipidemia and immune cells infiltration are all involved in regulating the onset and progression of atherosclerosis. Mesenchymal stem cells (MSCs) originated from different kinds of tissue are a group of cells possessing well-established self-renewal and multipotent differentiation properties as well as immunomodulatory and anti-inflammatory roles. Recent studies have displayed their dyslipidemia regulation functions. Transplantation of MSCs to atherosclerotic patients might be a new multifactorial therapeutic strategy to improve atherosclerosis. This review updates the advancement on MSCs and atherosclerosis.
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Affiliation(s)
- Ximei Zhang
- Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
| | - Feng Huang
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
| | - Yanming Chen
- Division of Endocrinology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
| | - Xiaoxian Qian
- Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
- Institute Integrated Traditional Chinese and Western Medicine, Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
| | - Song Guo Zheng
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
- Division of Rheumatology, Penn State Milton S. Hershey Medical CenterHershey, PA 17033, USA
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