1
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Grizzi F, Martin-Perez M, Rai G, Saeed AFUH, Raman A, Bordoloi D. Editorial: Innate immune pathways as targets for developing therapeutic intervention against human cancers. Front Immunol 2025; 16:1595279. [PMID: 40416962 PMCID: PMC12098504 DOI: 10.3389/fimmu.2025.1595279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Accepted: 04/24/2025] [Indexed: 05/27/2025] Open
Affiliation(s)
- Fabio Grizzi
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Miguel Martin-Perez
- Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain
| | - Geeta Rai
- Department of Molecular & Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | | | - Ayush Raman
- National Cancer Institute, NIH, Bethesda, MD, United States
| | - Devivasha Bordoloi
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
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2
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Soliman AM, Soliman M, Shah SSH, Baig HA, Gouda NS, Alenezi BT, Alenezy A, Hegazy AMS, Jan M, Eltom EH. Molecular dynamics of inflammation resolution: therapeutic implications. Front Cell Dev Biol 2025; 13:1600149. [PMID: 40406415 PMCID: PMC12095172 DOI: 10.3389/fcell.2025.1600149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 04/23/2025] [Indexed: 05/26/2025] Open
Abstract
Inflammation is a critical part of innate immune response that is essential for exclusion of harmful stimuli and restoration of tissue homeostasis. Nonetheless, failure to resolve inflammation results in chronic inflammatory conditions, including autoimmune diseases. Conventionally, resolution of inflammation was deemed a passive process; however, evidence indicates that it entails active, highly regulated molecular and cellular events involving efferocytosis-driven macrophage reprogramming, post-transcriptional regulatory mechanisms and the production of specialized pro-resolving mediators (SPMs). These processes collectively restore tissue homeostasis and prevent chronic inflammation. Emerging therapeutic approaches targeting these pathways demonstrate promising results in preclinical studies and clinical trials, enhancing resolution and improving overall disease outcome. This resulted in a paradigm shift from conventional anti-inflammatory strategies to resolution-focused treatment. Yet, challenges remain due to the complexity of resolution mechanisms and tissue-specific differences. This review summarizes current advances in inflammation resolution, emphasizing emerging concepts of resolution pharmacology. By employing endogenous mechanisms facilitating resolution, novel therapeutic applications can effectively manage several chronic inflammatory disorders.
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Affiliation(s)
- Amro M. Soliman
- Department of Biological Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB, Canada
| | - Mohamed Soliman
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Syed Sajid Hussain Shah
- Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Habeeb Ali Baig
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Nawal Salama Gouda
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Bandar Theyab Alenezi
- Department of Pharmacology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Awwad Alenezy
- Department of Family and Community Medicine, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Ahmed M. S. Hegazy
- Department of Anatomy, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Muhammad Jan
- Department of Pharmacology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Elhassan Hussein Eltom
- Department of Pharmacology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
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3
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Zhang M, Liu C, Tu J, Tang M, Ashrafizadeh M, Nabavi N, Sethi G, Zhao P, Liu S. Advances in cancer immunotherapy: historical perspectives, current developments, and future directions. Mol Cancer 2025; 24:136. [PMID: 40336045 PMCID: PMC12057291 DOI: 10.1186/s12943-025-02305-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/15/2025] [Indexed: 05/09/2025] Open
Abstract
Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.
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Affiliation(s)
- Meiyin Zhang
- Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chaojun Liu
- Department of Breast Surgery, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University; People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Jing Tu
- Department of Pulmonary and Critical Care Medicine, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Min Tang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, 401147, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia, V8 V 1P7, Canada
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR) Yong Loo Lin, School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Peiqing Zhao
- Translational Medicine Center, Zibo Central Hospital Affiliated to Binzhou Medical University, No. 54 Communist Youth League Road, Zibo, China.
| | - Shijian Liu
- Department of General Medicine, The 2nd Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, 150081, China.
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4
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Chen JY, Meng QY, Qian W, Qu YF. Effects of Bacterial Infections under Heatwaves on Chinese Soft-Shelled Turtles and Their Single-Cell Transcriptomic Landscapes. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:8357-8367. [PMID: 40274607 DOI: 10.1021/acs.est.4c09111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
The intensification of global warming could precipitate the widespread dissemination of opportunistic pathogens, exerting a bidirectional strain on wildlife populations and potentially hastening the process of species extinction. In this study, we integrated indicators from peripheral blood single-cell transcriptome, behavior, and physiological indices in Chinese soft-shelled turtles (Pelodiscus sinensis) to explore the impact of dual stress caused by bacterial infections and/or heatwaves on the turtles. Turtles were randomly divided into four groups based on constant temperature at 28 °C and heatwave exposure, as well as whether they were infected with bacteria (Bacillus cereus). Principal component analysis-based cell clustering revealed that the 14 cell clusters were classified into seven distinct cell types: erythrocytes, monocytes, thrombocytes, T cells, B cells, basophils, and heterophils. All cell types participated in the host immune response to heatwaves and bacterial infection, but these cells exhibited significant group-specific differences in their gene expression patterns. Bacterial infections and heatwaves altered turtle behavior and physiology indexes. The dual stresses inhibited the expression of antioxidant enzymes and immune genes, potentially jeopardizing turtle survival. Overall, this study provides valuable insights into peripheral blood cell profiles of Chinese soft-shelled turtles under different environmental conditions, enhancing the understanding of their immune responses and potential stressors.
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Affiliation(s)
- Jing-Yi Chen
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Qing-Yan Meng
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Wei Qian
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
| | - Yan-Fu Qu
- Herpetological Research Center, College of Life Sciences, Nanjing Normal University, Nanjing 210023, Jiangsu, China
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5
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Mu L, Li J, Lin Z, Zeng Q, Deng L, Wu S, Li J, Yin X, Ye J. MBL regulates phagocytosis and bactericidal activity of macrophages by triggering AKT/NF-κB/Rab5A axis occurred early in vertebrate evolution. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf028. [PMID: 40280188 DOI: 10.1093/jimmun/vkaf028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/05/2025] [Indexed: 04/29/2025]
Abstract
Mannose-binding lectin (MBL) is a vital and versatile component of innate immunity, which plays an essential role in host defense. In mammals, MBL performs multiple functions, including pattern recognition, complement activation, and phagocytosis. Previous studies revealed that OnMBL can promote the opsonophagocytosis of macrophages through its interaction with calreticulin (CRT) in a complement activation-independent manner in Nile tilapia (Oreochromis niloticus). However, the oligomer structural characteristics of MBL and the pathways involved in immune defense mechanisms remain poorly understood. In this study, we identified different oligomer forms of OnMBL in tilapia serum, with significant increases in trimer and tetramer levels present following immunization with Streptococcus agalactiae. Further investigation demonstrated that a higher degree of OnMBL oligomerization enhanced its ability to bind and phagocytose bacteria. Notably, OnMBL promoted the formation of phagolysosomes, which are responsible for degrading and eliminating ingested bacteria. Additionally, OnMBL knockdown caused a marked downregulation of the CD91a postinfection. Moreover, it is confirmed that OnMBL interacted with OnCRT and OnCD91a, with OnCD91a being essential for the OnMBL/CRT complex to facilitate phagocytosis and bacterial clearance. Mechanistic studies revealed that OnMBL/CRT complex enhanced phagocytosis through collaboration with OnCD91a, triggering a positive feedback loop mediated by the AKT/NF-κB/Rab5A signaling axis, thereby boosting macrophage activities and antibacterial immune responses. Therefore, this study elucidates the antibacterial response mechanism of oligomer OnMBL and its receptor in early vertebrates. These findings add to the knowledge regarding the regulatory mechanisms of C-type lectins in fish and provide valuable insights into the evolution of innate immunity.
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Affiliation(s)
- Liangliang Mu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Jiadong Li
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Zhanyao Lin
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Qingliang Zeng
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Lu Deng
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Siqi Wu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Jun Li
- School of Biological Science, Lake Superior State University, Sault Ste. Marie, MI, United States
| | - Xiaoxue Yin
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
| | - Jianmin Ye
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
- Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, P. R. China
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6
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Xiao Y, Yue X, Zhang X, Yang Y, Zhang Y, Sun L. The role of bacteriophage in inflammatory bowel disease and its therapeutic potential. Crit Rev Microbiol 2025:1-15. [PMID: 40219702 DOI: 10.1080/1040841x.2025.2492154] [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: 08/02/2024] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory disorders impacting the gastrointestinal (GI) tract. It represents a significant public health challenge due to its rising global incidence and substantial impact on patients' quality of life. Emerging research suggests a pivotal role of the human microbiome in IBD pathogenesis. Bacteriophages, integral components of the human microbiome, are indicated to influence the disease onset, progression, and therapeutic strategies. Here, we review the effect of bacteriophages on the pathogenesis of IBD and, more specifically, on the gut bacteria, the systemic immunity, and the susceptibility genes. Additionally, we explore the potential therapeutic use of the bacteriophages to modify gut microbiota and improve the health outcomes of IBD patients. This review highlights the potential of therapeutic bacteriophages in regulating gut microbiota and modulating the immune response to improve health outcomes in IBD patients. Future studies on personalized bacteriophage therapy and its integration into clinical practice could advance treatment strategies for IBD.
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Affiliation(s)
- Yuyang Xiao
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xinyu Yue
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xupeng Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Yifei Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Yibo Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Lang Sun
- Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
- Department of Microbiology, Xiangya School of the Basic Medical Science, Central South University, Changsha, Hunan Province, China
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7
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Akenroye A, Boyce JA, Kita H. Targeting alarmins in asthma: From bench to clinic. J Allergy Clin Immunol 2025; 155:1133-1148. [PMID: 39855362 DOI: 10.1016/j.jaci.2025.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/24/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
Over the past 2 decades, mechanistic studies of allergic and type 2 (T2)-mediated airway inflammation have led to multiple approved therapies for the treatment of moderate-to-severe asthma. The approval and availability of these monoclonal antibodies targeting IgE, a T2 cytokine (IL-5) and/or cytokine receptors (IL-5Rα, IL-4Rα) has been central to the progresses made in the management of moderate-to-severe asthma over this period. However, there are persistent gaps in clinician's ability to provide precise care, given that many patients with T2-high asthma do not respond to IgE- or T2 cytokine-targeting therapies and that patients with T2-low asthma have few therapeutic options. The new frontier of precision medicine in asthma, as well as in other allergic diseases, includes the targeting of epithelium-derived cytokines known as alarmins, including thymic stromal lymphopoietin, IL-25, IL-33, and their receptors. The effects of these alarmins, which can act upstream of immune cells, involve both the innate and adaptive systems and hold potential for the treatment of both T2-high and -low disease. Tezepelumab, an anti-thymic stromal lymphopoietin antibody, has already been approved for the treatment of severe asthma. In this review, we discuss our current understanding of alarmin biology with a primary focus on allergic airway diseases. We link the mechanistic corollaries to the clinical implications and advances in drug development targeting alarmins, with a particular focus on currently approved treatments, those under study, and future potential targets in alarmin signaling pathways.
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Affiliation(s)
- Ayobami Akenroye
- Jeff and Penny Vinik Immunology Center, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass.
| | - Joshua A Boyce
- Jeff and Penny Vinik Immunology Center, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass
| | - Hirohito Kita
- Division of Allergy, Asthma and Clinical Immunology, the Department of Medicine, and the Department of Immunology, Mayo Clinic Arizona, Scottsdale, Ariz; Department of Immunology, Mayo Clinic Rochester, Rochester, Minn
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8
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Dreher L, Kuehl MB, Wenzel UO, Kylies D. Aortic aneurysm and dissection: complement and precision medicine in aortic disease. Am J Physiol Heart Circ Physiol 2025; 328:H814-H829. [PMID: 40019851 DOI: 10.1152/ajpheart.00853.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/08/2025] [Accepted: 02/25/2025] [Indexed: 03/27/2025]
Abstract
Aortic disease encompasses life-threatening conditions such as aortic aneurysm and dissection, which are associated with high prevalence, morbidity, and mortality. The complement system, a key component of innate immunity, not only defends against pathogens but also maintains tissue homeostasis. Recent discoveries have expanded its role beyond immunity, linking complement dysregulation to numerous diseases and positioning it as a target for pharmacotherapy. Complement-based treatments for precision medicine are emerging, with several pharmaceuticals either already approved or under investigation. In aortic disease, complement activation and dysregulation have unveiled novel mechanisms and clinical implications. Human and experimental studies suggest that all three complement pathways contribute to disease pathophysiology. The complement system induces direct cellular damage via the membrane attack complex, as well as matrix-metalloproteinase (MMP)-associated tissue damage by promoting MMP-2 and MMP-9 expression. The anaphylatoxins C3a and C5a exacerbate disease by recruiting immune cells and triggering proinflammatory responses. Examples include neutrophil extracellular trap formation and cytokine release by polymorphonuclear neutrophils. These findings highlight the complement system as a promising novel diagnostic and therapeutic target in aortic disease with potential for individualized treatment. However, gaps remain, emphasizing the need for standardized multisite preclinical studies to improve reproducibility and translation. Biomarker studies must also be validated across diverse patient cohorts for clinical applicability. This review examines current knowledge regarding complement in aortic disease, aiming to evaluate its potential for innovative diagnostic and personalized treatment strategies.
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Affiliation(s)
- Leonie Dreher
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, Hamburg, Germany
| | - Malte B Kuehl
- Department of Clinical Medicine - The Department of Pathology, Aarhus University, Aarhus, Denmark
| | - Ulrich O Wenzel
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, Hamburg, Germany
| | - Dominik Kylies
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, Hamburg, Germany
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9
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Metwally H. STAT Signature Dish: Serving Immunity with a Side of Dietary Control. Biomolecules 2025; 15:487. [PMID: 40305224 PMCID: PMC12024614 DOI: 10.3390/biom15040487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/10/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Immunity is a fundamental aspect of animal biology, defined as the host's ability to detect and defend against harmful pathogens and toxic substances to preserve homeostasis. However, immune defenses are metabolically demanding, requiring the efficient allocation of limited resources to balance immune function with other physiological and developmental needs. To achieve this balance, organisms have evolved sophisticated signaling networks that enable precise, context-specific responses to internal and external cues. These networks are essential for survival and adaptation in multicellular systems. Central to this regulatory architecture is the STAT (signal transducer and activator of Transcription) family, a group of versatile signaling molecules that govern a wide array of biological processes across eukaryotes. STAT signaling demonstrates remarkable plasticity, from orchestrating host defense mechanisms to regulating dietary metabolism. Despite its critical role, the cell-specific and context-dependent nuances of STAT signaling remain incompletely understood, highlighting a significant gap in our understanding. This review delves into emerging perspectives on immunity, presenting dynamic frameworks to explore the complexity and adaptability of STAT signaling and the underlying logic driving cellular decision-making. It emphasizes how STAT pathways integrate diverse physiological processes, from immune responses to dietary regulation, ultimately supporting organismal balance and homeostasis.
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Affiliation(s)
- Hozaifa Metwally
- Laboratory of Immune Regulation, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
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10
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-like receptor response to Zika virus infection: progress toward infection control. NPJ VIRUSES 2025; 3:20. [PMID: 40295746 PMCID: PMC11906774 DOI: 10.1038/s44298-025-00102-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/19/2025] [Indexed: 04/30/2025]
Abstract
Infection with the Zika virus (ZIKV) poses a threat to human health. An improved understanding of the host Toll-like receptor response, disease onset, and viral clearance in vivo and in vitro may lead to the development of therapeutic or prophylactic interventions against viral infections. Currently, no clinically approved ZIKV vaccine is available, highlighting the need for its development. In this study, we discuss the progress in the Zika vaccine, including advances in the use of Toll-like receptor agonists as vaccine adjuvants to enhance vaccine efficacy.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, Bangladesh.
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
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11
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Xue M, Wang S, Li C, Wang Y, Liu M, Huang X, Wang G, Yin Q, Xiao D, Yang S, Yan M, Niu L, Awais M, Shen C, Wang J, Lai R, Ni H, Tang X. Deficiency of neutrophil gelatinase-associated lipocalin elicits a hemophilia-like bleeding and clotting disorder in mice. Blood 2025; 145:975-987. [PMID: 39693621 DOI: 10.1182/blood.2024026476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/15/2024] [Accepted: 11/04/2024] [Indexed: 12/20/2024] Open
Abstract
ABSTRACT Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the cross talk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.
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Affiliation(s)
- Min Xue
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Shaoying Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Changjiang Li
- Department of Emergency, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Center Medical Group), Qingdao, China
| | - Yuewei Wang
- Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ming Liu
- Department of Pharmacology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Xiaoshan Huang
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Gan Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Qikai Yin
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Dandan Xiao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Shuo Yang
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Musan Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Liyuan Niu
- Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Muhammad Awais
- Department of Pharmacology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Chuanbin Shen
- Department of Pharmacology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Jianxun Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Ren Lai
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Heyu Ni
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital and Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Xiaopeng Tang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao, China
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12
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Gao J, Ding M, Xiyang Y, Qin S, Shukla D, Xu J, Miyagi M, Fujioka H, Liang J, Wang X. Aggregatin is a mitochondrial regulator of MAVS activation to drive innate immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:238-252. [PMID: 40073244 PMCID: PMC11878994 DOI: 10.1093/jimmun/vkae019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/06/2024] [Indexed: 03/14/2025]
Abstract
Mitochondrial antiviral-signaling protein (MAVS) is a key adapter protein required for inducing type I interferons (IFN-Is) and other antiviral effector molecules. The formation of MAVS aggregates on mitochondria is essential for its activation; however, the regulatory mitochondrial factor that mediates the aggregation process is unknown. Our recent work has identified the protein Aggregatin as a critical seeding factor for β-amyloid peptide aggregation. Here we show that Aggregatin serves as a cross-seed for MAVS aggregates on mitochondria to orchestrate innate immune signaling. Aggregatin is primarily localized to mitochondria in the cytosol and has the ability to induce MAVS aggregation and MAVS-dependent IFN-I responses alone in both HEK293 cells and human leukemia monocytic THP-1 cells. Mitochondrial Aggregatin level increases upon viral infection. Also, Aggregatin knockout suppresses viral infection-induced MAVS aggregation and IFN-I signal cascade activation. Nemo-like kinase is further identified as a kinase phosphorylating Aggregatin at Ser59 to regulate its stability and cross-seeding activity. Collectively, our finding reveals an important physiological function of Aggregatin in innate immunity by cross-seeding MAVS aggregation.
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Affiliation(s)
- Ju Gao
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Mao Ding
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Yanbin Xiyang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Siyue Qin
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Devanshi Shukla
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Jiawei Xu
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Masaru Miyagi
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States
| | - Hisashi Fujioka
- Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH, United States
| | - Jingjing Liang
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, United States
| | - Xinglong Wang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
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13
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Hao Q, Gao X, Sun M, Liu Y. Genomic insights into fibrinogen-related proteins and expression analysis in the Pacific white shrimp, Litopenaeusvannamei. FISH & SHELLFISH IMMUNOLOGY 2025; 157:110113. [PMID: 39788463 DOI: 10.1016/j.fsi.2025.110113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/19/2024] [Accepted: 01/07/2025] [Indexed: 01/12/2025]
Abstract
Fibrinogen-related domain (FReD) containing proteins are an evolutionarily conserved immune gene family characterized by the C-terminal fibrinogen (FBG) and diverse N-terminal domains. To understand the complexity of this family in crustaceans, we performed genome screening and identified 43 full-length FReDs encoding genes in Litopenaeus vannamei. Structural classification analysis revealed these putative FReDs could be divided into six types, including two reported types (LvFReDI and II) and four new types (LvFReDIII-VI). Sequence and phylogenetic analysis showed that FBG domains were highly conserved throughout and phylogeny clusters correlated strongly with gene type. We analyzed the temporal and spatial expression patterns of LvFReD genes based on the transcriptomes of developmental stages, adult tissues or pathogen infected tissues of L. vannamei. Most LvFReDs were expressed from larval in membrane stage, and exhibited tissue-specific expression patterns and immune-responsive transcription after challenge with bacteria or virus. Further time-course expression analysis suggested that LvFReDII genes with additional coiled-coil region were more sensitive to pathogens than LvFReDI genes. Our findings provided comprehensive gene sequence resources and expression profiles of FReD genes in shrimp, which give insights into clarifying the diversity and function of these genes in crustaceans.
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Affiliation(s)
- Qiang Hao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China; Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Xiuyan Gao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China; Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Mingzhe Sun
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, 266071, China
| | - Yuan Liu
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, 266071, China.
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14
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Salem PPO, Silva DO, Silva PRS, Costa LPDM, Nicácio KJ, Murgu M, Caldas IS, Leite FB, Paula ACCD, Dias DF, Soares MG, Chagas-Paula DA. Bioguided isolation of anti-inflammatory and anti-urolithiatic active compounds from the decoction of Cissus gongylodes leaves. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118950. [PMID: 39419303 DOI: 10.1016/j.jep.2024.118950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Cissus gongylodes has traditionally been used in the diet of indigenous people in Brazil and in traditional medicine for kidney stone removal and inflammatory diseases. The active compounds responsible for these pharmacological activities are unknown. AIM OF THE STUDY This study aims to isolate, for the first time, the compounds in the decoction of C. gongylodes leaves responsible for their anti-inflammatory and anti-urolithiatic ethnopharmacological properties. MATERIALS AND METHODS The most active fractions of the C. gongylodes leaf decoction were fractionated using SPE-C18 and the compounds were purified through HPLC-UV-DAD. The decoction fractions and isolated compounds were evaluated for their anti-inflammatory and anti-urolithiatic activities. The anti-inflammatory activity was assessed using an ex vivo assay in human blood induced by LPS and calcium ionophore, measuring inflammatory mediators, PGE2 and LTB4. The anti-urolithiatic activity was evaluated using an in vitro experimental model with human urine to determine the dissolution of the most recurrent calcium oxalate (CaOx) crystals. Additionally, the decoction was chemically characterized through metabolomic analysis using UHPLC-ESI-HRMS. RESULTS The isolated compounds from the decoction of C. gongylodes, including rutin, eriodictyol 3'-O-glycoside, and isoquercetin, have demonstrated significant multi-target actions. These components act as anti-inflammatory agents by inhibiting the release of main inflammatory mediators, PGE2 and LTB4. Additionally, they exhibit anti-urolithiatic properties, promoting the dissolution of calcium oxalate (CaOx) crystals. Furthermore, the characterization of the decoction by UHPLC-ESI-HRMS revealed a high content of flavonoids, mainly glycosylated flavonoids. CONCLUSIONS The results support the traditional use of C. gongylodes decoction, identifying the compounds responsible for its anti-inflammatory and anti-urolithiatic effects. The decoction fractions and isolated compounds exhibited dual anti-inflammatory activity, effectively inhibiting key inflammatory pathways and potentially presenting fewer adverse effects while also promoting the dissolution of CaOx crystals associated with urolithiasis. The multi-target action displayed by C. gongylodes is particularly desirable in the treatment of urolithiasis, as inflammation and PGE2 production precede and contribute to the formation of CaOx crystals in the kidneys. Based on these actions, C. gongylodes emerges as a potent source of active compounds for the development of new treatments for urolithiasis.
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Affiliation(s)
- Paula P O Salem
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Daniele O Silva
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Paulo R S Silva
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Lara P D M Costa
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Karen J Nicácio
- Department of Chemistry, Federal University of Mato Grosso, Cuiabá, MT, 78060-900, Brazil
| | | | - Ivo S Caldas
- Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Fernanda B Leite
- Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil
| | - Ana C C de Paula
- Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil
| | - Danielle F Dias
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Marisi G Soares
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil
| | - Daniela A Chagas-Paula
- Laboratory of Phytochemistry, Medicinal Chemistry, and Metabolomics, Chemistry Institute University of Alfenas, Alfenas, MG, 37130-001, Brazil.
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15
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Manik MK, Pan M, Xiao L, Gu W, Kim H, Pospich S, Hedger A, Vajjhala PR, Lee MYL, Qian X, Landsberg MJ, Ve T, Nanson JD, Raunser S, Stacey KJ, Wu H, Kobe B. Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM. Proc Natl Acad Sci U S A 2025; 122:e2418988122. [PMID: 39786929 PMCID: PMC11745336 DOI: 10.1073/pnas.2418988122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/10/2024] [Indexed: 01/30/2025] Open
Abstract
Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 Å and 5.6 Å, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders.
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MESH Headings
- Adaptor Proteins, Vesicular Transport/metabolism
- Adaptor Proteins, Vesicular Transport/chemistry
- Adaptor Proteins, Vesicular Transport/genetics
- Adaptor Proteins, Vesicular Transport/immunology
- Signal Transduction/immunology
- Immunity, Innate
- Humans
- Protein Domains
- Cryoelectron Microscopy
- Receptors, Interleukin-1/metabolism
- Receptors, Interleukin-1/chemistry
- Receptors, Interleukin-1/genetics
- Receptors, Interleukin-1/immunology
- Toll-Like Receptor 4/metabolism
- Toll-Like Receptor 4/chemistry
- Toll-Like Receptor 4/immunology
- Myeloid Differentiation Factor 88/metabolism
- Myeloid Differentiation Factor 88/chemistry
- Myeloid Differentiation Factor 88/genetics
- Toll-Like Receptors/metabolism
- Toll-Like Receptors/immunology
- HEK293 Cells
- Crystallography, X-Ray
- Models, Molecular
- Adaptor Proteins, Signal Transducing
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Affiliation(s)
- Mohammad K. Manik
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA02115
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA02115
| | - Mengqi Pan
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Le Xiao
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA02115
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA02115
| | - Weixi Gu
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Hyoyoung Kim
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
| | - Sabrina Pospich
- Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund44227, Germany
| | - Andrew Hedger
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Parimala R. Vajjhala
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
| | - Morris Y. L. Lee
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
| | - Xiaoqi Qian
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Michael J. Landsberg
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Thomas Ve
- Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD4215, Australia
| | - Jeffrey D. Nanson
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
- Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW2678, Australia
| | - Stefan Raunser
- Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund44227, Germany
| | - Katryn J. Stacey
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA02115
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA02115
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD4072, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD4072, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia
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16
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Wang D, Li K. Emerging Roles of TRIM56 in Antiviral Innate Immunity. Viruses 2025; 17:72. [PMID: 39861861 PMCID: PMC11768893 DOI: 10.3390/v17010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
The tripartite-motif protein 56 (TRIM56) is a RING-type E3 ubiquitin ligase whose functions were recently beginning to be unveiled. While the physiological role(s) of TRIM56 remains unclear, emerging evidence suggests this protein participates in host innate defense mechanisms that guard against viral infections. Interestingly, TRIM56 has been shown to pose a barrier to viruses of distinct families by utilizing its different domains. Apart from exerting direct, restrictive effects on viral propagation, TRIM56 is implicated in regulating innate immune signaling pathways that orchestrate type I interferon response or autophagy, through which it indirectly impacts viral fitness. Remarkably, depending on viral infection settings, TRIM56 either operates in a canonical, E3 ligase-dependent fashion or adopts an enzymatically independent, non-canonical mechanism to bolster innate immune signaling. Moreover, the recent revelation that TRIM56 is an RNA-binding protein sheds new light on its antiviral mechanisms against RNA viruses. This review summarizes recent advances in the emerging roles of TRIM56 in innate antiviral immunity. We focus on its direct virus-restricting effects and its influence on innate immune signaling through two critical pathways: the endolysosome-initiated, double-stranded RNA-sensing TLR3-TRIF pathway and the cytosolic DNA-sensing, cGAS-STING pathway. We discuss the underpinning mechanisms of action and the questions that remain. Further studies understanding the complexity of TRIM56 involvement in innate immunity will add to critical knowledge that could be leveraged for developing antiviral therapeutics.
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Affiliation(s)
| | - Kui Li
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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17
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Chan TCL, Yagound B, Brown GP, Eyck HJF, Shine R, Rollins LA. Infection by the Lungworm Rhabdias pseudosphaerocephala Affects the Expression of Immune-Related microRNAs by Its Co-Evolved Host, the Cane Toad Rhinella marina. Mol Ecol 2025; 34:e17587. [PMID: 39544005 DOI: 10.1111/mec.17587] [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: 06/25/2023] [Revised: 10/09/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
Parasites may suppress the immune function of infected hosts using microRNAs (miRNAs) to prevent protein production. Nonetheless, little is known about the diversity of miRNAs and their mode(s) of action. In this study, we investigated the effects of infection by a parasitic lungworm (Rhabdias pseudosphaerocephala) on miRNA and mRNA expression of its host, the invasive cane toad (Rhinella marina). To investigate the cane toad's innate and adaptive immune response to this parasite, we compared miRNA and mRNA expression in naïve toads that had never been infected by lungworms to toads that were infected with lungworms for the first time in their lives, and toads that were infected the second time in their lives (i.e., had two consecutive infections). In total, we identified 101 known miRNAs and 86 potential novel miRNAs. Compared to uninfected and single-infection toads, multiple-infection animals drastically downregulated three miRNAs. These miRNAs were associated with gene pathways related to the immune response, potentially reflecting the immunosuppression of cane toads by their parasites. Infected hosts did not respond with substantially differential mRNA transcription; only one gene was differentially expressed between control and single-infection hosts. Our study suggests that miRNA may play an important role in mediating host-parasite interactions in a system in which an ongoing range expansion by the host has generated substantial divergence in host-parasite interactions.
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Affiliation(s)
- Tsering C L Chan
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Boris Yagound
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Gregory P Brown
- School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Harrison J F Eyck
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Richard Shine
- School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Lee A Rollins
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
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18
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Zhong Z, Ye Y, Xia L, Na N. Identification of RNA-binding protein genes associated with renal rejection and graft survival. Ren Fail 2024; 46:2360173. [PMID: 38874084 PMCID: PMC11182075 DOI: 10.1080/0886022x.2024.2360173] [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: 12/07/2023] [Accepted: 05/21/2024] [Indexed: 06/15/2024] Open
Abstract
Rejection is one of the major factors affecting the long-term prognosis of kidney transplantation, and timely recognition and aggressive treatment of rejection is essential to prevent disease progression. RBPs are proteins that bind to RNA to form ribonucleoprotein complexes, thereby affecting RNA stability, processing, splicing, localization, transport, and translation, which play a key role in post-transcriptional gene regulation. However, their role in renal transplant rejection and long-term graft survival is unclear. The aim of this study was to comprehensively analyze the expression of RPBs in renal rejection and use it to construct a robust prediction strategy for long-term graft survival. The microarray expression profiles used in this study were obtained from GEO database. In this study, a total of eight hub RBPs were identified, all of which were upregulated in renal rejection samples. Based on these RBPs, the renal rejection samples could be categorized into two different clusters (cluster A and cluster B). Inflammatory activation in cluster B and functional enrichment analysis showed a strong association with rejection-related pathways. The diagnostic prediction model had a high diagnostic accuracy for T cell mediated rejection (TCMR) in renal grafts (area under the curve = 0.86). The prognostic prediction model effectively predicts the prognosis and survival of renal grafts (p < .001) and applies to both rejection and non-rejection situations. Finally, we validated the expression of hub genes, and patient prognosis in clinical samples, respectively, and the results were consistent with the above analysis.
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Affiliation(s)
- Zhaozhong Zhong
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yongrong Ye
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liubing Xia
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ning Na
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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19
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Ahmad F, Ahmad S, Srivastav AK, Upadhyay TK, Husain A, Khubaib M, Kang S, Park MN, Kim B, Sharma R. "β-glucan signalling stimulates NOX-2 dependent autophagy and LC-3 associated autophagy (LAP) pathway". Int J Biol Macromol 2024; 282:136520. [PMID: 39401634 DOI: 10.1016/j.ijbiomac.2024.136520] [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: 08/02/2024] [Revised: 10/02/2024] [Accepted: 10/10/2024] [Indexed: 12/19/2024]
Abstract
β-Glucan, a complex polysaccharide derived from fungal and yeast cell walls, plays a crucial role in modulating immune responses through their interaction with receptors such as Dectin-1 and Complement receptor 3 (CR-3). This review provides an in-depth analysis of the molecular mechanisms by which β-glucans activate receptor-mediated signalling pathways, focusing particularly on the LC3-associated phagocytosis (LAP) and autophagy pathways. Hence, we explore how β-glucan receptor engagement stimulates NADPH oxidase 2 (NOX-2), leading to the intracellular production of significant level of reactive oxygen species (ROS) essential for both conventional autophagy and LAP. While significant progress has been made in elucidation of downstream signaling by glucans, the regulation of phago-lysosomal maturation and antigen presentation during LAP induction still remains less explored. This review aims to provide a comprehensive overview of these pathways and their regulation by β-glucans. By consolidating the current knowledge, we seek to highlight how these mechanisms can be leveraged for therapeutic applications, particularly in the context of tuberculosis (TB) management, where β-glucans could serve as host-directed adjuvant therapies to combat drug-resistant strains. Despite major advancements in this field, currently key research gaps still persist, including detailed molecular interactions between β-glucan receptors and NOX-2 and the translation of these findings to in-vivo models and clinical investigations. This review underscores the need for further research to explore the therapeutic potential of β-glucans in managing not only tuberculosis but also other diseases such as cancer, cardiovascular conditions, and metabolic disorders.
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Affiliation(s)
- Firoz Ahmad
- Department of Biosciences, Integral University, Lucknow 226026, Uttar Pradesh, India; Department of Physiological Sciences, Oklahoma Centre for Respiratory and Infectious Diseases, Oklahoma State University, OK 74074, United States of America
| | - Shad Ahmad
- Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University, Faizabad 224001, Uttar Pradesh, India
| | - Anurag Kumar Srivastav
- Department of Clinical Immunology & Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Tarun Kumar Upadhyay
- Department of Life Sciences, Parul Institute of Applied Sciences & Research and Development Cell, Parul University, Vadodara 391760, Gujarat, India
| | - Adil Husain
- Department of Biosciences, Integral University, Lucknow 226026, Uttar Pradesh, India; Department of Biochemistry, Babu Banarasi Das [BBD] College of Dental Sciences BBD University, Lucknow 226028, Uttar Pradesh, India
| | - Mohd Khubaib
- Department of Biosciences, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Sojin Kang
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea.
| | - Rolee Sharma
- Department of Life Sciences & Biotechnology, CSJM University, Kanpur 228024, Uttar Pradesh, India.
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20
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Beigoli S, Boskabady MH. The molecular basis of the immunomodulatory effects of natural products: A comprehensive review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156028. [PMID: 39276685 DOI: 10.1016/j.phymed.2024.156028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 07/21/2024] [Accepted: 09/02/2024] [Indexed: 09/17/2024]
Abstract
BACKGROUND Natural products (NPs) have long been recognized for their potential to modulate the immune system, offering a natural and holistic approach to enhancing immune function. In recent years, the immunomodulation effects of various natural products have attained significant attention. PURPOSE This article provides an overview of the role of natural products in immunomodulation, exploring their mechanisms of action, common types of NPs with immunomodulation properties, clinical applications, as well as considerations for their safety and efficacy. METHODS Extensive research has been conducted to compile important discoveries on the immunomodulatory properties of NPs through thorough searches of multiple databases such as PubMed, Science Direct, and Scopus up until January 2024. RESULTS By decreasing the levels of Th2 cytokines and pro-inflammatory cytokines, the results suggested that NPs have the ability to modulate the immune system. Therefore, NPs alleviate inflammation in various disorders such as asthma and cancer. Furthermore, the observed increase in CD4 cells and IFN-ɣ/IL4 levels, along with an increased IFN-c/IL4 ratio, indicates a stimulatory effect of NPs on Th1 activity in various inflammatory conditions. Therefore, NPs regulate the immune system by inhibiting T-cells and decreasing the growth of young B-cell lymphoma cells. CONCLUSION Reviewing studies indicated that NPs have the potential to serve as immunomodulatory candidates for treating disorders characterized by immune dysregulation. However, additional experimental and clinical studies are necessary before these agents can be implemented in clinical settings.
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Affiliation(s)
- Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Mun SJ, Cho E, Gil WJ, Kim SJ, Kim HK, Ham YS, Yang CS. Dual alarmin-receptor-specific targeting peptide systems for treatment of sepsis. Acta Pharm Sin B 2024; 14:5451-5463. [PMID: 39807314 PMCID: PMC11725134 DOI: 10.1016/j.apsb.2024.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 01/16/2025] Open
Abstract
The pathophysiology of sepsis is characterized by a systemic inflammatory response to infection; however, the cytokine blockade that targets a specific early inflammatory mediator, such as tumor necrosis factor, has shown disappointing results in clinical trials. During sepsis, excessive endotoxins are internalized into the cytoplasm of immune cells, resulting in dysregulated pyroptotic cell death, which induces the leakage of late mediator alarmins such as HMGB1 and PTX3. As late mediators of lethal sepsis, overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE receptors, thereby amplifying inflammation during early-stage sepsis. In this study, we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide (TMR peptide) derived from the HMGB1/PTX3-receptors interacting motifs. The TMR peptide successfully attenuated HMGB1/PTX3- and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE. Moreover, we developed TMR peptide-conjugated liposomes (TMR-Lipo) to improve the peptide pharmacokinetics. In combination therapy, moderately antibiotic-loaded TMR-Lipo demonstrated a significant therapeutic effect in a mouse model of cecal ligation- and puncture-induced sepsis. The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.
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Affiliation(s)
- Seok-Jun Mun
- Department of Bionano Engineering, Hanyang University, Seoul 04673, Republic of Korea
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
| | - Euni Cho
- Department of Bionano Engineering, Hanyang University, Seoul 04673, Republic of Korea
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
| | - Woo Jin Gil
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea
| | - Seong Jae Kim
- Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea
| | - Hyo Keun Kim
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea
| | - Yu Seong Ham
- Center for Bionano Intelligence Education and Research, Ansan 15588, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea
| | - Chul-Su Yang
- Department of Molecular and Life Science, Hanyang University, Ansan 15588, Republic of Korea
- Department of Medicinal and Life Science, Hanyang University, Ansan 15588, Republic of Korea
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22
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Zhang Z, Yang M, Zhou T, Chen Y, Zhou X, Long K. Emerging trends and hotspots in intestinal microbiota research in sepsis: bibliometric analysis. Front Med (Lausanne) 2024; 11:1510463. [PMID: 39606629 PMCID: PMC11598531 DOI: 10.3389/fmed.2024.1510463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
Background The association between the gut microbiota and sepsis has garnered attention in the field of intestinal research in sepsis. This study utilizes bibliometric methods to visualize and analyze the literature on gut microbiota research in sepsis from 2011 to 2024, providing a scientific foundation for research directions and key issues in this domain. Methods Original articles and reviews of gut microbiota research in sepsis, which published in English between 2011 and 2024, were obtained from the Web of Science Core Collection on June 21, 2024. Python, VOSviewer, and CiteSpace software were used for the visual analysis of the retrieved data. Results A total of 1,031 articles were analyzed, originating from 72 countries or regions, 1,614 research institutions, and 6,541 authors. The articles were published in 434 different journals, covering 89 different research fields. The number of publications and citations in this research area showed a significant growth trend from 2011 to 2024, with China, the United States, and the United Kingdom being the main research forces. Asada Leelahavanichkul from Thailand was identified as the most prolific author, making him the most authoritative expert in this field. "Nutrients" had the highest number of publications, while "Frontiers in Cellular and Infection Microbiology," "Frontiers in Immunology" and "the International Journal of Molecular Sciences" have shown increasing attention to this field in the past 2 years. Author keywords appearing more than 100 times included "gut microbiota (GM)," "sepsis" and "microbiota." Finally, this study identified "lipopolysaccharides (LPS)," "short-chain fatty acids (SCFAs)," "probiotics," "fecal microbiota transplantation (FMT)" and "gut-liver axis" as the research hotspots and potential frontier directions in this field. Conclusion This bibliometric study summarizes current important perspectives and offers comprehensive guidance between sepsis and intestinal microbiota, which may help researchers choose the most appropriate research directions.
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Affiliation(s)
- Zhengyi Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Meijie Yang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tong Zhou
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yingjie Chen
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiujuan Zhou
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kunlan Long
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Jun J, Kim EJ, Jeon D, Yang J, Jeong HG, Jung H, Kim T, Eyun SI. Comparative genomic analysis of copepod humoral immunity genes with sex-biased expression in Labidocera rotunda. J Invertebr Pathol 2024; 207:108198. [PMID: 39313092 DOI: 10.1016/j.jip.2024.108198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 08/31/2024] [Accepted: 09/11/2024] [Indexed: 09/25/2024]
Abstract
Studies of innate immune system function in invertebrates have contributed significantly to our understanding of the mammalian innate immune system. However, in-depth research on innate immunity in marine invertebrates remains sparse. We generated the first de novo genome and transcriptome sequences of copepod Labidocera rotunda using Illumina paired-end data and conducted a comparative genome analysis including five crustaceans (four copepods and one branchiopod species). We cataloged the presence of Toll, Imd, JAK/STAT, and JNK pathway components among them and compared them with 17 previously reported diverse arthropod species representative of insects, myriapods, chelicerates, and malacostracans. Our results indicated that copepod Gram-negative binding proteins may function in direct digestion or pathogen killing. The phylogenetic analysis of arthropod TEP and copepod-specific GCGEQ motif patterns suggested that the evolutionary history of copepod TEPs may have diverged from that of other arthropods. We classified the copepod Toll-like receptors identified in our analysis as either vertebrate or protostome types based on their cysteine motifs and the tree built with their Toll/interleukin-1 receptor domains. LrotCrustin, the first copepod AMP, was identified based on the structure of its WAP domain and deep-learning AMP predictors. Gene expression level analysis of L. rotunda innate immunity-related transcripts in each sex showed higher Toll pathway-related expression in male L. rotunda than in females, which may reflect an inverse correlation between allocation of reproductive investment and elevated immune response in males. Taken together, the results of our study provide insight into copepod innate immunity-related gene families and illuminate the evolutionary potential of copepods relative to other crustaceans.
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Affiliation(s)
- Jimoon Jun
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Eun-Jeong Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Donggu Jeon
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Jihye Yang
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Hyeon Gyeong Jeong
- Department of Taxonomy and Systematics, National Marine Biodiversity Institute of Korea, Seocheon 33662, South Korea
| | - Hyungtaek Jung
- National Centre for Indigenous Genomics, Australian National University, Acton, Australia
| | - Taeho Kim
- Department of Marine Production Management, Chonnam National University, Yeosu 59626, South Korea.
| | - Seong-Il Eyun
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea.
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Narovlyansky A, Pronin A, Poloskov V, Sanin A, Mezentseva M, Fedyakina I, Suetina I, Zubashev I, Ershov F, Filimonova M, Surinova V, Volkova I, Bogdanov E. Expression of Toll-like Receptor Genes and Antiviral Cytokines in Macrophage-like Cells in Response to Indole-3-carboxylic Acid Derivative. Viruses 2024; 16:1718. [PMID: 39599833 PMCID: PMC11598892 DOI: 10.3390/v16111718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/25/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Ongoing outbreaks and often rapid spread of infections caused by coronaviruses, influenza, Nipah, Dengue, Marburg, monkeypox, and other viruses are a concern for health authorities in most countries. Therefore, the search for and study of new antiviral compounds are in great demand today. Since almost all viruses with pandemic potential have immunotoxic properties of various origins, particular attention is paid to the search and development of immunomodulatory drugs. We have synthesised a new compound related to indole-3-carboxylic acid derivatives (hereinafter referred to as the XXV) that has antiviral and interferon-inducing activity. The purpose of this work is to study the effect of the XXV on the stimulation of the expression of toll-like receptor genes, interferons, and immunoregulatory cytokines in a macrophage-like cell model. In this study, real-time PCR methods were used to obtain data on the transcriptional activity of genes in macrophage-like cells. Stimulation of the genes of toll-like receptors TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was detected. A high-fold increase in stimulation (from 6.5 to 16,000) of the expression of the TLR3 and TLR4 genes was detected after 4 h of exposure to the XXV. Increased activity of interferon (IFNA1, IFNA2, IFNB1, IFNK, and IFNλ1) genes with simultaneous stimulation of the expression of interferon receptor (IFNAR1 and IFNAR2) genes and signalling molecule (JAK1 and ISG15) genes was detected. Increased fold stimulation of the expression of the cytokine genes IL6, TNFA, IL12A, and IL12B was also observed. Thus, it is shown that the XXV is an activator of TLR genes of innate immunity, which trigger signalling mechanisms of pathogen "recognition" and lead to stimulation of the expression of genes of proinflammatory cytokines and interferons.
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Affiliation(s)
- Alexander Narovlyansky
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Alexander Pronin
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Vladislav Poloskov
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Alexander Sanin
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Marina Mezentseva
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Irina Fedyakina
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Irina Suetina
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Igor Zubashev
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Felix Ershov
- National Research Centre for Epidemiology and Microbiology Named after the Honorary Academician N.F. Gamaleya, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (V.P.); (A.S.); (M.M.); (I.F.); (I.S.); (I.Z.); (F.E.)
| | - Marina Filimonova
- A. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia; (M.F.); (V.S.); (I.V.)
| | - Valentina Surinova
- A. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia; (M.F.); (V.S.); (I.V.)
| | - Irina Volkova
- A. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk 249036, Russia; (M.F.); (V.S.); (I.V.)
| | - Egor Bogdanov
- Faculty of Biotechnology, Lomonosov Moscow University of Fine Chemical Technology, Moscow 119571, Russia;
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Swaraj S, Tripathi S. Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity. mBio 2024; 15:e0258224. [PMID: 39302126 PMCID: PMC11481898 DOI: 10.1128/mbio.02582-24] [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] [Indexed: 09/22/2024] Open
Abstract
Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.
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Affiliation(s)
- Shachee Swaraj
- Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India
- Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of Science, Bengaluru, India
| | - Shashank Tripathi
- Emerging Viral Pathogens Laboratory, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India
- Microbiology & Cell Biology Department, Biological Sciences Division, Indian Institute of Science, Bengaluru, India
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26
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Sadler RA, Mallard BA, Shandilya UK, Hachemi MA, Karrow NA. The Immunomodulatory Effects of Selenium: A Journey from the Environment to the Human Immune System. Nutrients 2024; 16:3324. [PMID: 39408290 PMCID: PMC11479232 DOI: 10.3390/nu16193324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Selenium (Se) is an essential nutrient that has gained attention for its impact on the human immune system. The purpose of this review is to explore Se's immunomodulatory properties and to make up-to-date information available so novel therapeutic applications may emerge. People acquire Se through dietary ingestion, supplementation, or nanoparticle applications. These forms of Se can beneficially modulate the immune system by enhancing antioxidant activity, optimizing the innate immune response, improving the adaptive immune response, and promoting healthy gut microbiota. Because of these many actions, Se supplementation can help prevent and treat pathogenic diseases, autoimmune diseases, and cancers. This review will discuss Se as a key micronutrient with versatile applications that supports disease management due to its beneficial immunomodulatory effects. Further research is warranted to determine safe dosing guidelines to avoid toxicity and refine the application of Se in medical treatments.
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Affiliation(s)
- Rebecka A. Sadler
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (R.A.S.); (U.K.S.)
| | - Bonnie A. Mallard
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada;
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Umesh K. Shandilya
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (R.A.S.); (U.K.S.)
| | - Mohammed A. Hachemi
- Adisseo France S.A.S., 10, Place du Général de Gaulle, 92160 Antony, France;
| | - Niel A. Karrow
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (R.A.S.); (U.K.S.)
- ImmunoCeutica Inc., Cambridge, ON N1T 1N6, Canada;
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Bonaz B, Sinniger V, Pellissier S. Role of stress and early-life stress in the pathogeny of inflammatory bowel disease. Front Neurosci 2024; 18:1458918. [PMID: 39319312 PMCID: PMC11420137 DOI: 10.3389/fnins.2024.1458918] [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: 07/03/2024] [Accepted: 08/23/2024] [Indexed: 09/26/2024] Open
Abstract
Numerous preclinical and clinical studies have shown that stress is one of the main environmental factor playing a significant role in the pathogeny and life-course of bowel diseases. However, stressful events that occur early in life, even during the fetal life, leave different traces within the central nervous system, in area involved in stress response and autonomic network but also in emotion, cognition and memory regulation. Early-life stress can disrupt the prefrontal-amygdala circuit thus favoring an imbalance of the autonomic nervous system and the hypothalamic-pituitary adrenal axis, resulting in anxiety-like behaviors. The down regulation of vagus nerve and cholinergic anti-inflammatory pathway favors pro-inflammatory conditions. Recent data suggest that emotional abuse at early life are aggravating risk factors in inflammatory bowel disease. This review aims to unravel the mechanisms that explain the consequences of early life events and stress in the pathophysiology of inflammatory bowel disease and their mental co-morbidities. A review of therapeutic potential will also be covered.
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Affiliation(s)
- Bruno Bonaz
- Université Grenoble Alpes, Service d'Hépato-Gastroentérologie, Grenoble Institut Neurosciences, Grenoble, France
| | - Valérie Sinniger
- Université Grenoble Alpes, Service d'Hépato-Gastroentérologie, Grenoble Institut Neurosciences, Grenoble, France
| | - Sonia Pellissier
- Université Savoie Mont Blanc, Université Grenoble Alpes, LIP/PC2S, Chambéry, France
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Soto-Dávila M, Rodríguez-Cornejo T, Benito VW, Rodríguez-Ramos T, Mahoney G, Supinski R, Heath G, Dang X, Valle FM, Hurtado C, Llanco LA, Serrano-Martinez E, Dixon B. Innate and adaptive immune response of Rainbow trout (Oncorhynchus mykiss) naturally infected with Yersinia ruckeri. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109742. [PMID: 38960109 DOI: 10.1016/j.fsi.2024.109742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/05/2024]
Abstract
Rainbow trout is an important fish species for Peruvian artisanal aquaculture, comprising over 60 % of the total aquaculture production. However, their industry has been highly affected by several bacterial agents such as Yersinia ruckeri. This pathogen is the causative agent of Enteric Redmouth Disease, and causes high mortality in fingerlings and chronic infection in adult rainbow trout. To date, the immune response of rainbow trout against Y. ruckeri has been well studied in laboratory-controlled infection studies (i.e. intraperitoneal infection, bath immersion), however, the immune response during natural infection has not been explored. To address this, in this study, 35 clinically healthy O. mykiss without evidence of lesions or changes in behavior and 32 rainbow trout naturally infected by Y. ruckeri, were collected from semi-intensive fish farms located in the Central Highlands of Peru. To evaluate the effect on the immune response, RT-qPCR, western blotting, and ELISA were conducted using head kidney, spleen, and skin tissues to evaluate the relative gene expression and protein levels. Our results show a significant increase in the expression of the pro-inflammatory cytokines il1b, tnfa, and il6, as well as ifng in all three tissues, as well as increases in IL-1β and IFN-γ protein levels. The endogenous pathway of antigen presentation showed to play a key role in defense against Y. ruckeri, due to the upregulation of mhc-I, tapasin, and b2m transcripts, and the significant increase of Tapasin protein levels in infected rainbow trout. None of the genes associated with the exogenous pathway of antigen presentation showed a significant increase in infected fish, suggesting that this pathway is not involved in the response against this intracellular pathogen. Finally, the transcripts of immunoglobulins IgM and IgT did not show a modulation, nor were the protein levels evaluated in this study.
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Affiliation(s)
- Manuel Soto-Dávila
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada; Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, C1A 4P3, Canada
| | - Tania Rodríguez-Cornejo
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada; Faculty of Veterinary Medicine and Zootechnics, Universidad Peruana Cayetano Heredia, Lima, Peru
| | | | | | - Gracen Mahoney
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Rochelle Supinski
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - George Heath
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Xiaoqing Dang
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
| | - Fernando Mesías Valle
- CITEacuícola Pesquero Ahuashiyacu, Instituto Tecnológico de la Producción, La Banda de Shilcayo CP, 22200, San Martín, Peru
| | - Carmen Hurtado
- Faculty of Veterinary Medicine and Zootechnics, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Luis A Llanco
- School of Human Medicine, Universidad Privada San Juan Bautista, Apartado, Chincha, 15067, Peru
| | - Enrique Serrano-Martinez
- Faculty of Veterinary Medicine and Zootechnics, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Brian Dixon
- Department of Biology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.
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Ota Y, Inagaki R, Nagai Y, Hirose Y, Murata M, Yamamoto S. TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation. BMC Immunol 2024; 25:48. [PMID: 39054418 PMCID: PMC11270965 DOI: 10.1186/s12865-024-00643-x] [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: 06/09/2023] [Accepted: 07/15/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND TLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism. RESULT We showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2low, Cd274low, Cd80high, and Il6low were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12. CONCLUSION These data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials.
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Affiliation(s)
- Yosuke Ota
- Cancer Research Unit, Sumitomo Pharma Co Ltd, Osaka, Japan.
| | | | - Yasuhiro Nagai
- Cancer Research Unit, Sumitomo Pharma Co Ltd, Osaka, Japan
| | - Yuko Hirose
- Cancer Research Unit, Sumitomo Pharma Co Ltd, Osaka, Japan
| | - Masashi Murata
- Cancer Research Unit, Sumitomo Pharma Co Ltd, Osaka, Japan
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Akiyama M, Kanayama M, Umezawa Y, Nagao T, Izumi Y, Yamamoto M, Ohteki T. An early regulatory mechanism of hyperinflammation by restricting monocyte contribution. Front Immunol 2024; 15:1398153. [PMID: 39040105 PMCID: PMC11260625 DOI: 10.3389/fimmu.2024.1398153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 06/06/2024] [Indexed: 07/24/2024] Open
Abstract
Innate immune cells play a key role in inflammation as a source of pro-inflammatory cytokines. However, it remains unclear how innate immunity-mediated inflammation is fine-tuned to minimize tissue damage and assure the host's survival at the early phase of systemic inflammation. The results of this study with mouse models demonstrate that the supply of monocytes is restricted depending on the magnitude of inflammation. During the acute phase of severe inflammation, monocytes, but not neutrophils, were substantially reduced by apoptosis and the remaining monocytes were dysfunctional in the bone marrow. Monocyte-specific ablation of Casp3/7 prevented monocyte apoptosis but promoted monocyte necrosis in the bone marrow, leading to elevated levels of pro-inflammatory cytokines and the increased mortality of mice during systemic inflammation. Importantly, the limitation of monocyte supply was dependent on pro-inflammatory cytokines in vivo. Consistently, a reduction of monocytes was observed in the peripheral blood during cytokine-release syndrome (CRS) patients, a pathogen-unrelated systemic inflammation induced by chimeric antigen receptor-T cell (CAR-T cell) therapy. Thus, monocytes act as a safety valve to alleviate tissue damage caused by inflammation and ensure host survival, which may be responsible for a primitive immune-control mechanism that does not require intervention by acquired immunity.
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Affiliation(s)
- Megumi Akiyama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Masashi Kanayama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yoshihiro Umezawa
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Toshikage Nagao
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Yuta Izumi
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Toshiaki Ohteki
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Shirani M, Shariati S, Bazdar M, Sojoudi Ghamnak F, Moradi M, Shams Khozani R, Taki E, Arabsorkhi Z, Heidary M, Eskandari DB. The immunopathogenesis of Helicobacter pylori-induced gastric cancer: a narrative review. Front Microbiol 2024; 15:1395403. [PMID: 39035439 PMCID: PMC11258019 DOI: 10.3389/fmicb.2024.1395403] [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: 03/03/2024] [Accepted: 05/06/2024] [Indexed: 07/23/2024] Open
Abstract
Helicobacter pylori infection is a well-established risk factor for the development of gastric cancer (GC). Understanding the immunopathogenesis underlying this association is crucial for developing effective preventive and therapeutic strategies. This narrative review comprehensively explores the immunopathogenesis of H. pylori-induced GC by delving into several key aspects, emphasizing the pivotal roles played by H. pylori virulence factors, including cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA), blood group antigen-binding adhesin (babA), and sialic acid binding adhesin (sabA). Moreover, the review focuses on the role of toll-like receptors (TLRs) and cytokines in the complex interplay between chronic infection and gastric carcinogenesis. Finally, the study examines the association between H. pylori evasion of the innate and adaptive immune response and development of GC. A comprehensive understanding of the immunopathogenesis of H. pylori-induced GC is essential for designing targeted interventions to prevent and manage this disease. Further research is warranted to elucidate the intricate immune responses involved and identify potential therapeutic targets to improve patient outcomes.
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Affiliation(s)
- Maryam Shirani
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeedeh Shariati
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Monireh Bazdar
- School of Medicine, Razi Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Melika Moradi
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Elahe Taki
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Arabsorkhi
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohsen Heidary
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran
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Jang JH, Lee JE, Kim KT, Ahn DU, Paik HD. Immunostimulatory Effect of Ovomucin Hydrolysates by Pancreatin in RAW 264.7 Macrophages via Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway. Food Sci Anim Resour 2024; 44:885-898. [PMID: 38974730 PMCID: PMC11222692 DOI: 10.5851/kosfa.2024.e25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/26/2024] [Accepted: 03/17/2024] [Indexed: 07/09/2024] Open
Abstract
Ovomucin (OM), which has insoluble fractions is a viscous glycoprotein, found in egg albumin. Enzymatic hydrolysates of OM have water solubility and bioactive properties. This study investigated that the immunostimulatory effects of OM hydrolysates (OMHs) obtained by using various proteolytic enzymes (Alcalase®, bromelain, α-chymotrypsin, Neutrase®, pancreatin, papain, Protamax®, and trypsin) in RAW 264.7 cells. The results showed that OMH prepared with pancreatin (OMPA) produced the highest levels of nitrite oxide in RAW 264.7 cells, through upregulation of inducible nitric oxide synthase mRNA expression. The production of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 were increased with the cytokines mRNA expression. The effect of OMPA on mitogen-activated protein kinase signaling pathway was increased the phosphorylation of p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in a concentration-dependent manner. Therefore, OMPA could be used as a potential immune-stimulating agent in the functional food industry.
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Affiliation(s)
- Jin-Hong Jang
- Department of Food Science and
Biotechnology of Animal Resources, Konkuk University, Seoul
05029, Korea
| | - Ji-Eun Lee
- Department of Food Science and
Biotechnology of Animal Resources, Konkuk University, Seoul
05029, Korea
| | - Kee-Tae Kim
- Research Institute, WithBio
Inc, Seoul 05029, Korea
| | - Dong Uk Ahn
- Department of Animal Science, Iowa State
University, Ames, IA 50011, USA
| | - Hyun-Dong Paik
- Department of Food Science and
Biotechnology of Animal Resources, Konkuk University, Seoul
05029, Korea
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Khan KN, Guo SW, Ogawa K, Fujishita A, Mori T. The role of innate and adaptive immunity in endometriosis. J Reprod Immunol 2024; 163:104242. [PMID: 38503076 DOI: 10.1016/j.jri.2024.104242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/21/2024]
Abstract
The innate and adaptive immune systems are the two key branches that determine host protection at all mucosal surfaces in human body, including the female reproductive tract. The pattern recognition receptors within the host that recognize pathogen-associated molecular patterns are expressed on the cells of the innate immune system. Rapidly reactive, theinnate immune system, responds immediately to the presence of infectious or other non-self agents, thereby launching an inflammatory response to protect the host until the activation of slower adaptive immune system. Macrophages, dendritic cells, and toll-like receptors are integral components of the innate immune system. In contrast, T-helper (Th1/Th2/Th17) cells and regulatory T (Treg) cells are the primary components of adaptive immune system. Studies showed that the growth and progression of endometriosis continue even in unilateral ovariectomized animal suggesting that besides ovarian steroid hormones, the growth of endometriosis could be regulated by innate/adaptive immune systems in pelvic environment. Recent reports demonstrated a potential role of Th1/Th2/Th17/Treg cells either individually or collectively in the initiation, maintenance, and progression of endometriosis. Herewe review the fundamental knowledge of innate and adaptive immunity and elaborate the role of innate and adaptive immunity in endometriosis based on both human and experimental data.
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Affiliation(s)
- Khaleque N Khan
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Sun-Wei Guo
- Shanghai Obstetrics and Gynecology Hospital, Shanghai 200011, China.
| | - Kanae Ogawa
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Akira Fujishita
- Department of Gynecology, Saiseikai Nagasaki Hospital, Nagasaki 850-0003, Japan
| | - Taisuke Mori
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Jin H, Li M, Jeong E, Castro-Martinez F, Zuker CS. A body-brain circuit that regulates body inflammatory responses. Nature 2024; 630:695-703. [PMID: 38692285 PMCID: PMC11186780 DOI: 10.1038/s41586-024-07469-y] [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: 06/14/2023] [Accepted: 04/23/2024] [Indexed: 05/03/2024]
Abstract
The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here we show that a peripheral immune insult strongly activates the body-brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
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Affiliation(s)
- Hao Jin
- Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute, Columbia University, New York, NY, USA.
- Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
- Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
| | - Mengtong Li
- Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute, Columbia University, New York, NY, USA
- Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
| | - Eric Jeong
- Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute, Columbia University, New York, NY, USA
- Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
| | | | - Charles S Zuker
- Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute, Columbia University, New York, NY, USA.
- Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
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35
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Recent Insights into the Molecular Mechanisms of the Toll-like Receptor Response to Influenza Virus Infection. Int J Mol Sci 2024; 25:5909. [PMID: 38892096 PMCID: PMC11172706 DOI: 10.3390/ijms25115909] [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: 04/21/2024] [Revised: 05/23/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
Influenza A viruses (IAVs) pose a significant global threat to human health. A tightly controlled host immune response is critical to avoid any detrimental effects of IAV infection. It is critical to investigate the association between the response of Toll-like receptors (TLRs) and influenza virus. Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host. Consequently, a thorough understanding of the TLR response is essential for targeting TLRs as a novel therapeutic and prophylactic intervention. To date, a limited number of studies have assessed TLR and IAV interactions. Therefore, further research on TLR interactions in IAV infection should be conducted to determine their role in host-virus interactions in disease causation or clearance of the virus. Although influenza virus vaccines are available, they have limited efficacy, which should be enhanced to improve their efficacy. In this study, we discuss the current status of our understanding of the TLR response in IAV infection and the strategies adopted by IAVs to avoid TLR-mediated immune surveillance, which may help in devising new therapeutic or preventive strategies. Furthermore, recent advances in the use of TLR agonists as vaccine adjuvants to enhance influenza vaccine efficacy are discussed.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan
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Purvis GSD, McNeill E, Wright B, Channon KM, Greaves DR. Ly6C hi Monocytes Are Metabolically Reprogrammed in the Blood during Inflammatory Stimulation and Require Intact OxPhos for Chemotaxis and Monocyte to Macrophage Differentiation. Cells 2024; 13:916. [PMID: 38891050 PMCID: PMC11171939 DOI: 10.3390/cells13110916] [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: 04/29/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a coordinated and precise manner. Here, we investigate the origin and transcriptional reprogramming of monocytes using a model of acute inflammation, zymosan-induced peritonitis. Monocyte trafficking and adoptive transfer experiments confirmed that monocytes undergo rapid phenotypic change as they exit the blood and give rise to monocyte-derived macrophages that persist during the resolution of inflammation. Single-cell transcriptomics revealed significant heterogeneity within the surface marker-defined CD11b+Ly6G-Ly6Chi monocyte populations within the blood and at the site of inflammation. We show that two major transcriptional reprogramming events occur during the initial six hours of Ly6Chi monocyte mobilisation, one in the blood priming monocytes for migration and a second at the site of inflammation. Pathway analysis revealed an important role for oxidative phosphorylation (OxPhos) during both these reprogramming events. Experimentally, we demonstrate that OxPhos via the intact mitochondrial electron transport chain is essential for murine and human monocyte chemotaxis. Moreover, OxPhos is needed for monocyte-to-macrophage differentiation and macrophage M(IL-4) polarisation. These new findings from transcriptional profiling open up the possibility that shifting monocyte metabolic capacity towards OxPhos could facilitate enhanced macrophage M2-like polarisation to aid inflammation resolution and tissue repair.
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Affiliation(s)
- Gareth S. D. Purvis
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK;
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (E.M.); (B.W.); (K.M.C.)
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Eileen McNeill
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (E.M.); (B.W.); (K.M.C.)
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Benjamin Wright
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (E.M.); (B.W.); (K.M.C.)
| | - Keith M. Channon
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; (E.M.); (B.W.); (K.M.C.)
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford OX3 9DU, UK
| | - David R. Greaves
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK;
- British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford OX3 9DU, UK
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Hong GH, Lee SY, Kim IA, Suk J, Baeg C, Kim JY, Lee S, Kim KJ, Kim KT, Kim MG, Park KY. Effect of Heat-Treated Lactiplantibacillus plantarum nF1 on the Immune System Including Natural Killer Cell Activity: A Randomized, Placebo-Controlled, Double-Blind Study. Nutrients 2024; 16:1339. [PMID: 38732587 PMCID: PMC11085399 DOI: 10.3390/nu16091339] [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: 04/04/2024] [Revised: 04/26/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
Heat-treated Lactiplantibacillus plantarum nF1 (HT-nF1) increases immune cell activation and the production of various immunomodulators (e.g., interleukin (IL)-12) as well as immunoglobulin (Ig) G, which plays an important role in humoral immunity, and IgA, which activates mucosal immunity. To determine the effect of HT-nF1 intake on improving immune function, a randomized, double-blind, placebo-controlled study was conducted on 100 subjects with normal white blood cell counts. The HT-nF1 group was administered capsules containing 5 × 1011 cells of HT-nF1 once a day for 8 weeks. After 8 weeks of HT-nF1 intake, significant changes in IL-12 were observed in the HT-nF1 group (p = 0.045). In particular, the change in natural killer (NK) cell activity significantly increased in subjects with low secretory (s) IgA (≤49.61 μg/mL) and low NK activity (E:T = 10:1) (≤3.59%). These results suggest that HT-nF1 has no safety issues and improves the innate immune function by regulating T helper (Th)1-related immune factors. Therefore, we confirmed that HT-nF1 not only has a positive effect on regulating the body's immunity, but it is also a safe material for the human body, which confirms its potential as a functional health food ingredient.
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Affiliation(s)
- Geun-Hye Hong
- IMMUNOBIOTECH Corp., Seoul 06628, Republic of Korea; (G.-H.H.); (S.-Y.L.)
| | - So-Young Lee
- IMMUNOBIOTECH Corp., Seoul 06628, Republic of Korea; (G.-H.H.); (S.-Y.L.)
| | - In Ah Kim
- Global Medical Research Center, Seoul 03737, Republic of Korea; (I.A.K.); (J.S.); (C.B.)
| | - Jangmi Suk
- Global Medical Research Center, Seoul 03737, Republic of Korea; (I.A.K.); (J.S.); (C.B.)
| | - Chaemin Baeg
- Global Medical Research Center, Seoul 03737, Republic of Korea; (I.A.K.); (J.S.); (C.B.)
| | - Ji Yeon Kim
- Department of Food Science and Biotechnology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea; (J.Y.K.); (S.L.)
| | - Sehee Lee
- Department of Food Science and Biotechnology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea; (J.Y.K.); (S.L.)
| | - Kyeong Jin Kim
- Department of Nano Bio Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea;
| | - Ki Tae Kim
- IMMUNOBIOTECH Corp., Seoul 06628, Republic of Korea; (G.-H.H.); (S.-Y.L.)
| | - Min Gee Kim
- IMMUNOBIOTECH Corp., Seoul 06628, Republic of Korea; (G.-H.H.); (S.-Y.L.)
| | - Kun-Young Park
- IMMUNOBIOTECH Corp., Seoul 06628, Republic of Korea; (G.-H.H.); (S.-Y.L.)
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Yi JI, Schneider J, Lim ST, Park B, Suh YJ. Interferon-Gamma Secretion Is Significantly Decreased in Stage III Breast Cancer Patients. Int J Mol Sci 2024; 25:4561. [PMID: 38674146 PMCID: PMC11050491 DOI: 10.3390/ijms25084561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. A total of 396 female invasive breast cancer patients who received curative surgical treatment from March 2017 to July 2021 were retrospectively analyzed. NK cell activation-induced interferon-gamma (IFN-γ) secretion measured by enzyme-linked immunosorbent assay was used to measure the activity of peripheral NK cells. Statistical analyses were performed to determine clinical relationships with major clinicopathologic parameters. Quadripartite NK cell activity measured by induced interferon-gamma showed significant relevance with staging and body mass index, and some of the inflammatory serological markers, namely N/L (neutrophil/lymphocyte), P/N (platelet/neutrophil), and P/L (platelet/lymphocyte), showed significantly different NK activity in each interval by univariate analysis. A binary subgroup analysis, setting the IFN-γ secretion cut-off at 100 pg/mL, showed that stage III was significantly increased and axillary lymph node metastasis positivity was increased in the group of IFN-γ < 100 pg/mL, and IFN-γ secretion decreased with an increasing N stage, increased BMI (body mass index), and decreased production of IFN-γ. Following this, the same binary analysis, but with the IFN-γ secretion cut-off at 250 pg/mL, also showed that secretion in stage III was increased in those concentrations with <250 pg/mL, axillary lymph node positivity appeared to be correlated, and BMI ≥ 30 increased in prevalence. Additional ANOVA post hoc tests (Bonferroni) were performed on some serological markers that tended to be somewhat inconsistent. By subgroup analysis with Bonferroni adjustment between the IFN-γ secretion and TNM stage, no significant difference in IFN-γ secretion could be identified at stages I, II, and IV, but at stage III, the IFN-γ secretion < 100 pg/mL was significantly higher than 250 ≤ IFN-γ secretion < 500 pg/mL or IFN-γ secretion ≥ 500 pg/mL. According to this study, stage III was significantly associated with the lowest IFN-γ secretion. Compared to a higher level of IFN-γ secretion, a lower level of IFN-γ secretion seemed to be associated with increased body mass index. Unlike when IFN-γ secretion was analyzed in quartiles, as the IFN-γ secretion fell below 100 pg/mL, the correlation between axillary lymph node positivity and increased N stage, increased BMI, and increased N/L and P/L, which are suggested poor prognostic factors, became more pronounced. We think a peripheral IFN-γ secretion test might be convenient and useful tool for pretreatment risk assessment and selecting probable candidates for further treatment such as immunotherapy in some curable but high-risk invasive breast cancer patients, compared to other costly assaying of tissue NK cell activity at diagnosis.
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Affiliation(s)
- Jung Im Yi
- Department of Surgery, The Catholic University of Korea St. Vincent’s Hospital, Suwon 16247, Republic of Korea; (J.I.Y.); (S.T.L.); (B.P.)
| | - Jean Schneider
- School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Seung Taek Lim
- Department of Surgery, The Catholic University of Korea St. Vincent’s Hospital, Suwon 16247, Republic of Korea; (J.I.Y.); (S.T.L.); (B.P.)
| | - Byeongkwan Park
- Department of Surgery, The Catholic University of Korea St. Vincent’s Hospital, Suwon 16247, Republic of Korea; (J.I.Y.); (S.T.L.); (B.P.)
| | - Young Jin Suh
- Department of Surgery, The Catholic University of Korea St. Vincent’s Hospital, Suwon 16247, Republic of Korea; (J.I.Y.); (S.T.L.); (B.P.)
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Neamțu M, Bild V, Vasincu A, Arcan OD, Bulea D, Ababei DC, Rusu RN, Macadan I, Sciucă AM, Neamțu A. Inflammasome Molecular Insights in Autoimmune Diseases. Curr Issues Mol Biol 2024; 46:3502-3532. [PMID: 38666950 PMCID: PMC11048795 DOI: 10.3390/cimb46040220] [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: 03/18/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Autoimmune diseases (AIDs) emerge due to an irregular immune response towards self- and non-self-antigens. Inflammation commonly accompanies these conditions, with inflammatory factors and inflammasomes playing pivotal roles in their progression. Key concepts in molecular biology, inflammation, and molecular mimicry are crucial to understanding AID development. Exposure to foreign antigens can cause inflammation, potentially leading to AIDs through molecular mimicry triggered by cross-reactive epitopes. Molecular mimicry emerges as a key mechanism by which infectious or chemical agents trigger autoimmunity. In certain susceptible individuals, autoreactive T or B cells may be activated by a foreign antigen due to resemblances between foreign and self-peptides. Chronic inflammation, typically driven by abnormal immune responses, is strongly associated with AID pathogenesis. Inflammasomes, which are vital cytosolic multiprotein complexes assembled in response to infections and stress, are crucial to activating inflammatory processes in macrophages. Chronic inflammation, characterized by prolonged tissue injury and repair cycles, can significantly damage tissues, thereby increasing the risk of AIDs. Inhibiting inflammasomes, particularly in autoinflammatory disorders, has garnered significant interest, with pharmaceutical advancements targeting cytokines and inflammasomes showing promise in AID management.
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Affiliation(s)
- Monica Neamțu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Veronica Bild
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
- Center of Biomedical Research of the Romanian Academy, 8 Carol I Avenue, 700506 Iasi, Romania
| | - Alexandru Vasincu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Oana Dana Arcan
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Delia Bulea
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Daniela-Carmen Ababei
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Răzvan-Nicolae Rusu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Ioana Macadan
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Ana Maria Sciucă
- Department of Oral Medicine, Oral Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Andrei Neamțu
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania;
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Vieira SF, Reis RL, Ferreira H, Neves NM. Plant-derived bioactive compounds as key players in the modulation of immune-related conditions. PHYTOCHEMISTRY REVIEWS 2024. [DOI: 10.1007/s11101-024-09955-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 03/07/2024] [Indexed: 01/03/2025]
Abstract
AbstractThe immune system is a complex and fundamental network for organism protection. A minimal unbalance in the host defense system homeostasis can originate severe repercussions in human health. Fundamentally, immune-related diseases can arise from its compromise (immunodeficiency diseases), overactivation against itself (autoimmune diseases) or harmless substances (allergies), and failure of eliminating the harmful agent (chronic inflammation). The notable advances and achievements in the immune system diseases pathophysiology have been allowing for a dramatic improvement of the available treatments. Nevertheless, they present some drawbacks, including the inappropriate benefit/risk ratio. Therefore, there is a strong and urgent need to develop effective therapeutic strategies. Nature is a valuable source of bioactive compounds that can be explored for the development of new drugs. Particularly, plants produce a broad spectrum of secondary metabolites that can be potential prototypes for innovative therapeutic agents. This review describes the immune system and the inflammatory response and examines the current knowledge of eight plants traditionally used as immunomodulatory medicines (Boswellia serrata, Echinacea purpurea, Laurus nobilis, Lavandula angustifolia, Olea europaea, Salvia officinalis, Salvia rosmarinus, and Taraxacum officinale). Moreover, the issues responsible for possible biologic readout inconsistencies (plant species, age, selected organ, developmental stage, growth conditions, geographical location, drying methods, storage conditions, solvent of extraction, and extraction method) will also be discussed. Furthermore, a detailed list of the chemical composition and the immunomodulatory mechanism of action of the bioactive compounds of the selected plant extracts are presented. This review also includes future perspectives and proposes potential new avenues for further investigation.
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Pradeu T, Thomma BPHJ, Girardin SE, Lemaitre B. The conceptual foundations of innate immunity: Taking stock 30 years later. Immunity 2024; 57:613-631. [PMID: 38599162 DOI: 10.1016/j.immuni.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/23/2024] [Accepted: 03/06/2024] [Indexed: 04/12/2024]
Abstract
While largely neglected over decades during which adaptive immunity captured most of the attention, innate immune mechanisms have now become central to our understanding of immunology. Innate immunity provides the first barrier to infection in vertebrates, and it is the sole mechanism of host defense in invertebrates and plants. Innate immunity also plays a critical role in maintaining homeostasis, shaping the microbiota, and in disease contexts such as cancer, neurodegeneration, metabolic syndromes, and aging. The emergence of the field of innate immunity has led to an expanded view of the immune system, which is no longer restricted to vertebrates and instead concerns all metazoans, plants, and even prokaryotes. The study of innate immunity has given rise to new concepts and language. Here, we review the history and definition of the core concepts of innate immunity, discussing their value and fruitfulness in the long run.
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Affiliation(s)
- Thomas Pradeu
- CNRS UMR 5164 ImmunoConcept, University of Bordeaux, Bordeaux, France; Department of Biological and Medical Sciences, University of Bordeaux, Bordeaux, France; Presidential Fellow, Chapman University, Orange, CA, USA.
| | - Bart P H J Thomma
- Institute for Plant Sciences, University of Cologne, Cologne, Germany
| | - Stephen E Girardin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Bruno Lemaitre
- Global Health Institute, School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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Merk D, Cox FF, Jakobs P, Prömel S, Altschmied J, Haendeler J. Dose-Dependent Effects of Lipopolysaccharide on the Endothelium-Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence. Antioxidants (Basel) 2024; 13:443. [PMID: 38671891 PMCID: PMC11047739 DOI: 10.3390/antiox13040443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
The endothelium, the innermost cell layer of blood vessels, is not only a physical barrier between the bloodstream and the surrounding tissues but has also essential functions in vascular homeostasis. Therefore, it is not surprising that endothelial dysfunction is associated with most cardiovascular diseases. The functionality of the endothelium is compromised by endotoxemia, the presence of bacterial endotoxins in the bloodstream with the main endotoxin lipopolysaccharide (LPS). Therefore, this review will focus on the effects of LPS on the endothelium. Depending on the LPS concentration, the outcomes are either sepsis or, at lower concentrations, so-called low-dose or metabolic endotoxemia. Sepsis, a life-threatening condition evoked by hyperactivation of the immune response, includes breakdown of the endothelial barrier resulting in failure of multiple organs. A deeper understanding of the underlying mechanisms in the endothelium might help pave the way to new therapeutic options in sepsis treatment to prevent endothelial leakage and fatal septic shock. Low-dose endotoxemia or metabolic endotoxemia results in chronic inflammation leading to endothelial cell senescence, which entails endothelial dysfunction and thus plays a critical role in cardiovascular diseases. The identification of compounds counteracting senescence induction in endothelial cells might therefore help in delaying the onset or progression of age-related pathologies. Interestingly, two natural plant-derived substances, caffeine and curcumin, have shown potential in preventing endothelial cell senescence.
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Affiliation(s)
- Dennis Merk
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
| | - Fiona Frederike Cox
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Institute for Translational Pharmacology, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Philipp Jakobs
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
| | - Simone Prömel
- Department of Biology, Institute of Cell Biology, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Joachim Altschmied
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Cardiovascular Research Institute Düsseldorf, CARID, University Hospital and Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Judith Haendeler
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Cardiovascular Research Institute Düsseldorf, CARID, University Hospital and Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
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Parker J, Marten SM, Ó Corcora TC, Rajkov J, Dubin A, Roth O. The effects of primary and secondary bacterial exposure on the seahorse (Hippocampus erectus) immune response. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 153:105136. [PMID: 38185263 DOI: 10.1016/j.dci.2024.105136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024]
Abstract
Evolutionary adaptations in the Syngnathidae teleost family (seahorses, pipefish and seadragons) culminated in an array of spectacular morphologies, key immune gene losses, and the enigmatic male pregnancy. In seahorses, genome modifications associated with immunoglobulins, complement, and major histocompatibility complex (MHC II) pathway components raise questions concerning their immunological efficiency and the evolution of compensatory measures that may act in their place. In this investigation heat-killed bacteria (Vibrio aestuarianus and Tenacibaculum maritimum) were used in a two-phased experiment to assess the immune response dynamics of Hippocampus erectus. Gill transcriptomes from double and single-exposed individuals were analysed in order to determine the differentially expressed genes contributing to immune system responses towards immune priming. Double-exposed individuals exhibited a greater adaptive immune response when compared with single-exposed individuals, while single-exposed individuals, particularly with V. aestuarianus replicates, associated more with the innate branch of the immune system. T. maritimum double-exposed replicates exhibited the strongest immune reaction, likely due to their immunological naivety towards the bacterium, while there are also potential signs of innate trained immunity. MHC II upregulated expression was identified in selected V. aestuarianus-exposed seahorses, in the absence of other pathway constituents suggesting a possible alternative or non-classical MHC II immune function in seahorses. Gene Ontology (GO) enrichment analysis highlighted prominent angiogenesis activity following secondary exposure, which could be linked to an adaptive immune process in seahorses. This investigation highlights the prominent role of T-cell mediated adaptive immune responses in seahorses when exposed to sequential foreign bacteria exposures. If classical MHC II pathway function has been lost, innate trained immunity in syngnathids could be a potential compensatory mechanism.
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Affiliation(s)
- Jamie Parker
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany.
| | - Silke-Mareike Marten
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
| | - Tadhg C Ó Corcora
- Marine Evolutionary Ecology, GEOMAR Helmholtz Centre for Ocean Research Kiel, D-24105, Kiel, Germany
| | - Jelena Rajkov
- Marine Evolutionary Ecology, GEOMAR Helmholtz Centre for Ocean Research Kiel, D-24105, Kiel, Germany
| | - Arseny Dubin
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
| | - Olivia Roth
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
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Vodovotz Y, Arciero J, Verschure PF, Katz DL. A multiscale inflammatory map: linking individual stress to societal dysfunction. FRONTIERS IN SCIENCE 2024; 1:1239462. [PMID: 39398282 PMCID: PMC11469639 DOI: 10.3389/fsci.2023.1239462] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
As populations worldwide show increasing levels of stress, understanding emerging links among stress, inflammation, cognition, and behavior is vital to human and planetary health. We hypothesize that inflammation is a multiscale driver connecting stressors that affect individuals to large-scale societal dysfunction and, ultimately, to planetary-scale environmental impacts. We propose a 'central inflammation map' hypothesis to explain how the brain regulates inflammation and how inflammation impairs cognition, emotion, and action. According to our hypothesis, these interdependent inflammatory and neural processes, and the inter-individual transmission of environmental, infectious, and behavioral stressors - amplified via high-throughput digital global communications - can culminate in a multiscale, runaway, feed-forward process that could detrimentally affect human decision-making and behavior at scale, ultimately impairing the ability to address these same stressors. This perspective could provide non-intuitive explanations for behaviors and relationships among cells, organisms, and communities of organisms, potentially including population-level responses to stressors as diverse as global climate change, conflicts, and the COVID-19 pandemic. To illustrate our hypothesis and elucidate its mechanistic underpinnings, we present a mathematical model applicable to the individual and societal levels to test the links among stress, inflammation, control, and healing, including the implications of transmission, intervention (e.g., via lifestyle modification or medication), and resilience. Future research is needed to validate the model's assumptions, expand the factors/variables employed, and validate it against empirical benchmarks. Our model illustrates the need for multilayered, multiscale stress mitigation interventions, including lifestyle measures, precision therapeutics, and human ecosystem design. Our analysis shows the need for a coordinated, interdisciplinary, international research effort to understand the multiscale nature of stress. Doing so would inform the creation of interventions that improve individuals' lives and communities' resilience to stress and mitigate its adverse effects on the world.
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Affiliation(s)
- Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Immunology, Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Julia Arciero
- Department of Mathematical Sciences, Indiana University - Purdue University Indianapolis, Indianapolis, IN, United States
| | - Paul Fmj Verschure
- Laboratory of Synthetic, Perceptive, Emotive and Cognitive Systems (SPECS), Donders Centre of Neuroscience, Donders Centre for Brain, Cognition and Behaviour, Faculty of Science and Engineering, Radboud University, Netherlands
| | - David L Katz
- Founder, True Health Initiative, The Health Sciences Academy, London, United Kingdom
- Tangelo Services, Auckland, United States
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Fan KQ, Huang T, Yu JS, Li YY, Jin J. The clinical features and potential mechanisms of cognitive disorders in peripheral autoimmune and inflammatory diseases. FUNDAMENTAL RESEARCH 2024; 4:226-236. [PMID: 38933510 PMCID: PMC11197673 DOI: 10.1016/j.fmre.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 10/15/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
According to a study from World Health Organization's Global Burden of Disease, mental and neurological disorders have accounted for 13% of global diseases in recent years and are on the rise. Neuropsychiatric conditions or neuroinflammatory disorders are linked by the presence of an exaggerated immune response both peripherally and in the central nervous system (CNS). Cognitive dysfunction (CD) encompasses a complex group of diseases and has frequently been described in the field of autoimmune diseases, especially in multiple non-CNS-related autoimmune diseases. Recent studies have provided various hypotheses regarding the occurrence of cognitive impairment in autoimmune diseases, including that abnormally activated immune cells can disrupt the integrity of the blood-brain barrier (BBB) to trigger a central neuroinflammatory response. When the BBB is intact, autoantibodies and pro-inflammatory molecules in peripheral circulation can enter the brain to activate microglia, inducing CNS inflammation and CD. However, the mechanisms explaining the association between the immune system and neural function and their contribution to diseases are uncertain. In this review, we used clinical statistics to illustrate the correlation between CD and autoimmune diseases that do not directly affect the CNS, summarized the clinical features and mechanisms by which autoimmune diseases trigger cognitive impairment, and explored existing knowledge regarding the link between CD and autoimmune diseases from the perspective of the field of neuroimmunology.
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Affiliation(s)
- Ke-qi Fan
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Tao Huang
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
| | - Jian-shuai Yu
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yi-yuan Li
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China
| | - Jin Jin
- MOE Laboratory of Biosystem Homeostasis and Protection, and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Gastroenterology, Sir Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou 310016, China
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Gold MS, Loeza-Alcocer E. Experimental colitis-induced visceral hypersensitivity is attenuated by GABA treatment in mice. Am J Physiol Gastrointest Liver Physiol 2024; 326:G252-G263. [PMID: 38193198 PMCID: PMC11211035 DOI: 10.1152/ajpgi.00012.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 01/10/2024]
Abstract
Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis.NEW & NOTEWORTHY GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.
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Affiliation(s)
- Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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Li X, Guo H, Yang J, Liu X, Li H, Yang W, Zhang L, Li Y, Wei W. Enterovirus D68 3C protease antagonizes type I interferon signaling by cleaving signal transducer and activator of transcription 1. J Virol 2024; 98:e0199423. [PMID: 38240591 PMCID: PMC10878094 DOI: 10.1128/jvi.01994-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 02/21/2024] Open
Abstract
Following the successful control of poliovirus, the re-emergence of respiratory enterovirus D68 (EV-D68), a prominent non-polio enterovirus, has become a serious public health concern worldwide. Host innate immune responses are the primary defense against EV-D68 invasion; however, the mechanism underlying viral evasion of the antiviral activity of interferons (IFN) remains unclear. In this study, we found that EV-D68 inhibited type I IFN signaling by cleaving signal transducer and activator of transcription 1 (STAT1), a crucial factor in cellular responses to interferons and other cytokines. We observed that the prototype and circulating EV-D68 strains conserved their ability to induce STAT1 cleavage and attenuate IFN signal transduction. Further investigation revealed that EV-D68 3C protease cleaves STAT1 at the 131Q residue. Interestingly, not all enterovirus-encoded 3C proteases exhibited this ability. EV-D68 and poliovirus 3C proteases efficiently induced STAT1 cleavage; whereas, 3C proteases from EV-A71, coxsackievirus A16, and echoviruses did not. STAT1 cleavage also abolished the nuclear translocation capacity of STAT1 in response to IFN stimulation to activate downstream signaling elements. Overall, these results suggest that STAT1, targeted by viral protease 3C, is utilized by EV-D68 to subvert the host's innate immune response.IMPORTANCEEnterovirus D68 (EV-D68) has significantly transformed over the past decade, evolving from a rare pathogen to a potential pandemic pathogen. The interferon (IFN) signaling pathway is an important defense mechanism and therapeutic target for the host to resist viral invasion. Previous studies have reported that the EV-D68 virus blocks or weakens immune recognition and IFN production in host cells through diverse strategies; however, the mechanisms of EV-D68 resistance to IFN signaling have not been fully elucidated. Our study revealed that EV-D68 relies on its own encoded protease, 3C, to directly cleave signal transducer and activator of transcription 1 (STAT1), a pivotal transduction component in the IFN signaling pathway, disrupting the IFN-mediated antiviral response. Previous studies on human enteroviruses have not documented direct cleavage of the STAT1 protein to evade cellular immune defenses. However, not all enteroviral 3C proteins can cleave STAT1. These findings highlight the diverse evolutionary strategies different human enteroviruses employ to evade host immunity.
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Affiliation(s)
- Xiaohan Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Haoran Guo
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Jiaxin Yang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Xize Liu
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Huili Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Wanying Yang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Lili Zhang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Yan Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Wei Wei
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, First Hospital, Jilin University, Changchun, Jilin, China
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Sun Z, Zhao H, Ma L, Shi Y, Ji M, Sun X, Ma D, Zhou W, Huang T, Zhang D. The quest for nanoparticle-powered vaccines in cancer immunotherapy. J Nanobiotechnology 2024; 22:61. [PMID: 38355548 PMCID: PMC10865557 DOI: 10.1186/s12951-024-02311-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: 10/18/2023] [Accepted: 01/26/2024] [Indexed: 02/16/2024] Open
Abstract
Despite recent advancements in cancer treatment, this disease still poses a serious threat to public health. Vaccines play an important role in preventing illness by preparing the body's adaptive and innate immune responses to combat diseases. As our understanding of malignancies and their connection to the immune system improves, there has been a growing interest in priming the immune system to fight malignancies more effectively and comprehensively. One promising approach involves utilizing nanoparticle systems for antigen delivery, which has been shown to potentiate immune responses as vaccines and/or adjuvants. In this review, we comprehensively summarized the immunological mechanisms of cancer vaccines while focusing specifically on the recent applications of various types of nanoparticles in the field of cancer immunotherapy. By exploring these recent breakthroughs, we hope to identify significant challenges and obstacles in making nanoparticle-based vaccines and adjuvants feasible for clinical application. This review serves to assess recent breakthroughs in nanoparticle-based cancer vaccinations and shed light on their prospects and potential barriers. By doing so, we aim to inspire future immunotherapies for cancer that harness the potential of nanotechnology to deliver more effective and targeted treatments.
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Affiliation(s)
- Zhe Sun
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Hui Zhao
- Department of Endodontics, East Branch of Jinan Stomatological Hospital, Jinan, 250000, Shandong, China
| | - Li Ma
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yanli Shi
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Mei Ji
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Xiaodong Sun
- Department of Endodontics, Gaoxin Branch of Jinan Stomatological Hospital, Jinan, 250000, Shandong, China
| | - Dan Ma
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Wei Zhou
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Tao Huang
- Department of Biomedical Engineering, Graeme Clark Institute, The University of Melbourne, Parkville, VIC, 3010, Australia.
| | - Dongsheng Zhang
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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Zeng J, Li Y, Zou Y, Yang Y, Yang T, Zhou Y. Intestinal toxicity alleviation and efficacy potentiation through therapeutic administration of Lactobacillus paracasei GY-1 in the treatment of gout flares with colchicine. Food Funct 2024; 15:1671-1688. [PMID: 38251779 DOI: 10.1039/d3fo04858f] [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: 01/23/2024]
Abstract
Gout flares have emerged as a significant public health concern. Colchicine (COL) is a first-line and standard drug for treating gout flares. However, its clinical use is limited due to various adverse effects. Besides, COL fails to adequately meet the needs of patients, particularly young patients. In this study, we investigate the therapeutic administration of Lactobacillus paracasei GY-1 (GY-1) to overcome the limitations of COL. Our results demonstrate that GY-1 attenuates COL toxicity in terms of body weight loss, decreased feed intake, mortality, reduced locomotor activity, colon shortening, increased oxidative stress, histological damage, and impaired gut permeability. Meanwhile, we demonstrate that GY-1 enhances the therapeutic effect for gout flares when combined with COL, as evidenced by the reduction in paw swelling, decreased levels of proinflammatory cytokines including IL-1β and TNF-α, and an increase in the anti-inflammatory cytokine IL-10. Additionally, the absolute quantification of the gut microbiota shows that GY-1 restores the gut microbiota imbalance caused by COL. Furthermore, GY-1 reduces the abundance of 4 Alistipes species and 6 Porphyromonadaceae species, which may be responsible for toxicity alleviation. At the same time, GY-1 increases the abundance of Bacteroides sartorii and Enterococcus sp., which may contribute to its therapeutic efficacy. This study demonstrates the feasibility of developing probiotic-based adjuvant therapy or bacteriotherapy for treating gout flares. To our knowledge, GY-1 is the first probiotic that could be used as an alternative synergetic agent with COL for the therapeutic treatment of gout flares.
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Affiliation(s)
- Jiaqi Zeng
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
| | - Yan Li
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
| | - Yizhi Zou
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
| | - Ying Yang
- Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, Guangxi 545005, China
| | - Tingting Yang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
| | - Yizhuang Zhou
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, Guilin, Guangxi 541199, China.
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50
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Mao K, Wang J, Xie Q, Yang YG, Shen S, Sun T, Wang J. Cationic nanoparticles-based approaches for immune tolerance induction in vivo. J Control Release 2024; 366:425-447. [PMID: 38154540 DOI: 10.1016/j.jconrel.2023.12.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/04/2023] [Accepted: 12/25/2023] [Indexed: 12/30/2023]
Abstract
The development of autoimmune diseases and the rejection of transplanted organs are primarily caused by an exaggerated immune response to autoantigens or graft antigens. Achieving immune tolerance is crucial for the effective treatment of these conditions. However, traditional therapies often have limited therapeutic efficacy and can result in systemic toxic effects. The emergence of nanomedicine offers a promising avenue for addressing immune-related diseases. Among the various nanoparticle formulations, cationic nanoparticles have demonstrated significant potential in inducing immune tolerance. In this review, we provide an overview of the underlying mechanism of autoimmune disease and organ transplantation rejection. We then highlight the recent advancements and advantages of utilizing cationic nanoparticles for inducing immune tolerance in the treatment of autoimmune diseases and the prevention of transplant rejection.
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Affiliation(s)
- Kuirong Mao
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China
| | - Jialiang Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China
| | - Qianyue Xie
- Huafu International Department, Affiliated High School of South China Normal University, Guangzhou, Guangdong, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China
| | - Song Shen
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, Guangdong, China
| | - Tianmeng Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; International Center of Future Science, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China; State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin, China.
| | - Jun Wang
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, Guangdong, China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong, China; Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovatiion Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong, China.
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