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Afrin MR, Upadhyaya PG, Hashim A, Bhattacharya K, Chanu NR, Das D, Khanal P, Deka S. Advanced biomarkers: Beyond amyloid and tau: Emerging non-traditional biomarkers for alzheimer`s diagnosis and progression. Ageing Res Rev 2025; 108:102736. [PMID: 40122399 DOI: 10.1016/j.arr.2025.102736] [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: 01/07/2025] [Revised: 03/07/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder that leads to progressive cognitive decline and imposes a significant socio-economic burden. Traditional diagnostic methods, primarily based on amyloid-beta (Aβ) and tau biomarkers, often identify the disease at late stages, highlighting the need for more sensitive and accessible early detection tools. This review explores emerging non-traditional biomarkers, including salivary, lipid, urinary, synaptic, blood-based, microRNA (miRNA), cerebrospinal fluid (CSF), fecal, and inflammatory markers, which provide deeper insights into AD pathophysiology. These biomarkers reflect key pathological processes such as neuroinflammation, mitochondrial dysfunction, oxidative stress, synaptic damage, lipid dysregulation, and genetic factors. Non-invasive biomarkers, such as those found in saliva and urine, present promising avenues for large-scale screening, while advanced blood-based markers like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) offer precise monitoring of neurodegeneration and inflammation. Additionally, miRNAs and lipid biomarkers shed light on molecular alterations in neuronal health and signaling. Integrating these biomarkers with imaging techniques, proteomics, and genetic profiling enhances diagnostic accuracy and enables personalized treatment approaches. This shift toward multi-dimensional biomarker assessment not only improves early detection but also aids in tailoring therapeutic strategies to individual disease profiles. By reviewing recent advancements, this article highlights the transformative potential of emerging biomarkers in overcoming the limitations of conventional diagnostics. Standardization and validation across diverse populations will be crucial in expanding their clinical applicability, ultimately improving disease management, reducing societal burden, and enhancing the quality of life for individuals affected by AD.
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Affiliation(s)
- Meher Rijwana Afrin
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India
| | | | - Abdul Hashim
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India
| | - Kunal Bhattacharya
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India; Royal School of Pharmacy, The Assam Royal Global University, Guwahati, Assam 781035, India.
| | - Nongmaithem Randhoni Chanu
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India; Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhinagar, Panikhaiti, Guwahati, Assam PIN - 781026, India
| | - Dibyajyoti Das
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004, India
| | - Pukar Khanal
- KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research. (KAHER), Belagavi 590010, India.
| | - Satyendra Deka
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam 781026, India
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Van Damme J, Struyf S, Proost P, Opdenakker G, Gouwy M. Functional Interactions Between Recombinant Serum Amyloid A1 (SAA1) and Chemokines in Leukocyte Recruitment. Int J Mol Sci 2025; 26:2258. [PMID: 40076881 PMCID: PMC11900440 DOI: 10.3390/ijms26052258] [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: 12/31/2024] [Revised: 02/20/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
The acute phase response is a hallmark of all inflammatory reactions and acute phase reactants, such as C-reactive protein (CRP) and serum amyloid A (SAA) proteins, are among the most useful plasma and serum markers of inflammation in clinical medicine. Although it is well established that inflammatory cytokines, mainly interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) induce SAA in the liver, the biological functions of elicited SAA remain an enigma. By the classical multi-step protein purification studies of chemotactic factors present in plasma or serum, we discovered novel chemokines and SAA1 fragments, which are induced during inflammatory reactions. In contrast to earlier literature, pure SAA1 fails to induce chemokines, an ascribed function that most probably originates from contaminating lipopolysaccharide (LPS). However, intact SAA1 and fragments thereof synergize with CXC and CC chemokines to enhance chemotaxis. Natural SAA1 fragments are generated by inflammatory proteinases such as matrix metalloproteinase-9 (MMP-9). They mediate synergy with chemokines by the interaction with cognate G protein-coupled receptors (GPCRs), formyl peptide receptor 2 (FPR2) and (CC and CXC) chemokine receptors. In conclusion, SAA1 enforces the action of many chemokines and assists in local leukocyte recruitment, in particular, when the concentrations of specifically-induced chemokines are still low.
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Affiliation(s)
| | | | | | | | - Mieke Gouwy
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; (J.V.D.); (S.S.); (P.P.); (G.O.)
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Russo RC, Ryffel B. The Chemokine System as a Key Regulator of Pulmonary Fibrosis: Converging Pathways in Human Idiopathic Pulmonary Fibrosis (IPF) and the Bleomycin-Induced Lung Fibrosis Model in Mice. Cells 2024; 13:2058. [PMID: 39768150 PMCID: PMC11674266 DOI: 10.3390/cells13242058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system.
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Affiliation(s)
- Remo Castro Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais-UFMG, Belo Horizonte 31270-901, MG, Brazil
| | - Bernhard Ryffel
- Laboratory of Immuno-Neuro Modulation (INEM), UMR7355 Centre National de la Recherche Scientifique (CNRS), University of Orleans, 45071 Orleans, France
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Králová M, Kubalová I, Hajný J, Kubiasová K, Vagaská K, Ge Z, Gallei M, Semerádová H, Kuchařová A, Hönig M, Monzer A, Kovačik M, Friml J, Novák O, Benková E, Ikeda Y, Zalabák D. A decoy receptor derived from alternative splicing fine-tunes cytokinin signaling in Arabidopsis. MOLECULAR PLANT 2024; 17:1850-1865. [PMID: 39501563 DOI: 10.1016/j.molp.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 06/27/2024] [Accepted: 11/03/2024] [Indexed: 11/29/2024]
Abstract
Hormone perception and signaling pathways have a fundamental regulatory function in the physiological processes of plants. Cytokinins, a class of plant hormones, regulate cell division and meristem maintenance. The cytokinin signaling pathway is well established in the model plant Arabidopsisthaliana. Several negative feedback mechanisms, tightly controlling cytokinin signaling output, have been described previously. In this study, we identified a new feedback mechanism executed through alternative splicing of the cytokinin receptor AHK4/CRE1. A novel splicing variant named CRE1int7 results from seventh intron retention, introducing a premature termination codon in the transcript. We showed that CRE1int7 is translated in planta into a truncated receptor lacking the C-terminal receiver domain essential for signal transduction. CRE1int7 can bind cytokinin but cannot activate the downstream cascade. We present a novel negative feedback mechanism of the cytokinin signaling pathway, facilitated by a decoy receptor that can inactivate canonical cytokinin receptors via dimerization and compete with them for ligand binding. Ensuring proper plant growth and development requires precise control of the cytokinin signaling pathway at several levels. CRE1int7 represents a so-far unknown mechanism for fine-tuning the cytokinin signaling pathway in Arabidopsis.
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Affiliation(s)
- Michaela Králová
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Ivona Kubalová
- Department of Molecular Biology, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Jakub Hajný
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Karolina Kubiasová
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Karolína Vagaská
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Zengxiang Ge
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Michelle Gallei
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Hana Semerádová
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Anna Kuchařová
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Martin Hönig
- Department of Chemical Biology, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Aline Monzer
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Martin Kovačik
- Institute of Experimental Botany of the Czech Academy of Sciences, Centre of Plant Structural and Functional Genomics, Šlechtitelů 31, 779 00 Olomouc, Czech Republic
| | - Jiří Friml
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Ondřej Novák
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Eva Benková
- Institute of Science and Technology Austria (ISTA), 3400 Klosterneuburg, Austria
| | - Yoshihisa Ikeda
- Department of Molecular Biology, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - David Zalabák
- Laboratory of Growth Regulators, Faculty of Science of Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
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Upadhyay S, Kumar S, Singh VK, Tiwari R, Kumar A, Sundar S, Kumar R. Chemokines Signature and T Cell Dynamics in Leishmaniasis: Molecular insight and therapeutic application. Expert Rev Mol Med 2024; 27:1-55. [PMID: 39587036 PMCID: PMC11707835 DOI: 10.1017/erm.2024.36] [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: 12/05/2023] [Revised: 09/04/2024] [Accepted: 10/28/2024] [Indexed: 11/27/2024]
Abstract
Leishmaniasis, caused by obligate intracellular Leishmania parasites, poses a significant global health burden. The control of Leishmania infection relies on an effective T cell-dependent immune response; however, various factors impede the host’s ability to mount a successful defence. Alterations in the chemokine profile, responsible for cell trafficking to the infection site, can disrupt optimal immune responses and influence the outcome of pathogenesis by facilitating parasite persistence. This review aims to emphasize the significance of the chemokine system in T cell responses and to summarize the current knowledge on the dysregulation of chemokines and their receptors associated with different subsets of T lymphocytes during Leishmaniasis. A comprehensive understanding of the dynamic nature of the chemokine system during Leishmaniasis is crucial for the development of successful immunotherapeutic approaches.
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Affiliation(s)
- Shreya Upadhyay
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Shashi Kumar
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Vishal Kumar Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Rahul Tiwari
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Awnish Kumar
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Shyam Sundar
- Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Rajiv Kumar
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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Hu Y, Wang C, Liang H, Li J, Yang Q. The treatment landscape of triple-negative breast cancer. Med Oncol 2024; 41:236. [PMID: 39210220 DOI: 10.1007/s12032-024-02456-9] [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] [Accepted: 07/18/2024] [Indexed: 09/04/2024]
Abstract
Triple-negative breast cancer (TNBC) tumors are biologically aggressive breast cancer. On the molecular level, TNBC is a highly heterogeneous disease; more biotechnologies are gradually being used to advance the understanding of TNBC subtypes and help establish more targeted therapies. Multiple TNBC target-related agents are already approved by the Food and Drug Administration for clinical use, including PI3K/AKT/mTOR inhibitors, PRAP inhibitors, and antibody-drug conjugates. Some innovative approaches, like peptide strategies, also promise to treat TNBC. Currently, the interplay between TNBC tumors and their tumor microenvironment provides a promising prospect for improving the efficacy of immunotherapy. In this review, we summarize the prevalent TNBC subtype methodologies, discuss the evolving therapeutic strategies, and propose new therapeutic possibilities based on existing foundational theories, with the attempt to serve as a reference to further advance tailoring treatment of TNBC.
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Affiliation(s)
- Yi Hu
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Chen Wang
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Huishi Liang
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Jie Li
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China.
| | - Qiong Yang
- Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China.
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Lv Y, Qi J, Babon JJ, Cao L, Fan G, Lang J, Zhang J, Mi P, Kobe B, Wang F. The JAK-STAT pathway: from structural biology to cytokine engineering. Signal Transduct Target Ther 2024; 9:221. [PMID: 39169031 PMCID: PMC11339341 DOI: 10.1038/s41392-024-01934-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/12/2024] [Accepted: 07/16/2024] [Indexed: 08/23/2024] Open
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway.
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Affiliation(s)
- You Lv
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Jianxun Qi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100080, China
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Longxing Cao
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China
| | - Guohuang Fan
- Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai, 201112, China
| | - Jiajia Lang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jin Zhang
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Pengbing Mi
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, 4072, Australia.
| | - Faming Wang
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China.
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Portes E Silva KR, Nogueira EM, Jesus Mendes ALD, Pena ALB, Simões E Silva AC. The potential role of renin angiotensin system in acute leukemia: a narrative review. Mol Biol Rep 2024; 51:775. [PMID: 38904729 DOI: 10.1007/s11033-024-09659-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 05/21/2024] [Indexed: 06/22/2024]
Abstract
Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.
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Affiliation(s)
- Kacio Roger Portes E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Eugênia Maia Nogueira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - André Luiz de Jesus Mendes
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Ana Luisa Batista Pena
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil.
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Minvielle Moncla LH, Briend M, Sokhna Sylla M, Mathieu S, Rufiange A, Bossé Y, Mathieu P. Mendelian randomization reveals interactions of the blood proteome and immunome in mitral valve prolapse. COMMUNICATIONS MEDICINE 2024; 4:108. [PMID: 38844506 PMCID: PMC11156961 DOI: 10.1038/s43856-024-00530-x] [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: 02/17/2023] [Accepted: 05/21/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Mitral valve prolapse (MVP) is a common heart disorder characterized by an excessive production of proteoglycans and extracellular matrix in mitral valve leaflets. Large-scale genome-wide association study (GWAS) underlined that MVP is heritable. The molecular underpinnings of the disease remain largely unknown. METHODS We interrogated cross-modality data totaling more than 500,000 subjects including GWAS, 4809 molecules of the blood proteome, and genome-wide expression of mitral valves to identify candidate drivers of MVP. Data were investigated through Mendelian randomization, network analysis, ligand-receptor inference and digital cell quantification. RESULTS In this study, Mendelian randomization identify that 33 blood proteins, enriched in networks for immunity, are associated with the risk of MVP. MVP- associated blood proteins are enriched in ligands for which their cognate receptors are differentially expressed in mitral valve leaflets during MVP and enriched in cardiac endothelial cells and macrophages. MVP-associated blood proteins are involved in the renewal-polarization of macrophages and regulation of adaptive immune response. Cytokine activity profiling and digital cell quantification show in MVP a shift toward cytokine signature promoting M2 macrophage polarization. Assessment of druggability identify CSF1R, CX3CR1, CCR6, IL33, MMP8, ENPEP and angiotensin receptors as actionable targets in MVP. CONCLUSIONS Hence, integrative analysis identifies networks of candidate molecules and cells involved in immune control and remodeling of the extracellular matrix, which drive the risk of MVP.
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Affiliation(s)
| | - Mewen Briend
- Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada
| | - Mame Sokhna Sylla
- Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada
| | - Samuel Mathieu
- Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada
| | - Anne Rufiange
- Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada
| | - Yohan Bossé
- Department of Molecular Medicine, Laval University, Quebec City, QC, Canada
| | - Patrick Mathieu
- Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada.
- Department of Surgery, Laval University, Quebec City, QC, Canada.
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Zaid A, Ariel A. Harnessing anti-inflammatory pathways and macrophage nano delivery to treat inflammatory and fibrotic disorders. Adv Drug Deliv Rev 2024; 207:115204. [PMID: 38342241 DOI: 10.1016/j.addr.2024.115204] [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: 07/30/2023] [Revised: 12/08/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
Targeting specific organs and cell types using nanotechnology and sophisticated delivery methods has been at the forefront of applicative biomedical sciences lately. Macrophages are an appealing target for immunomodulation by nanodelivery as they are heavily involved in various aspects of many diseases and are highly plastic in their nature. Their continuum of functional "polarization" states has been a research focus for many years yielding a profound understanding of various aspects of these cells. The ability of monocyte-derived macrophages to metamorphose from pro-inflammatory to reparative and consequently to pro-resolving effectors has raised significant interest in its therapeutic potential. Here, we briefly survey macrophages' ontogeny and various polarization phenotypes, highlighting their function in the inflammation-resolution shift. We review their inducing mediators, signaling pathways, and biological programs with emphasis on the nucleic acid sensing-IFN-I axis. We also portray the polarization spectrum of macrophages and the characteristics of their transition between different subtypes. Finally, we highlighted different current drug delivery methods for targeting macrophages with emphasis on nanotargeting that might lead to breakthroughs in the treatment of wound healing, bone regeneration, autoimmune, and fibrotic diseases.
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Affiliation(s)
- Ahmad Zaid
- Department of Biology and Human Biology, University of Haifa, Haifa, 3498838 Israel
| | - Amiram Ariel
- Department of Biology and Human Biology, University of Haifa, Haifa, 3498838 Israel.
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11
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Preedy MK, White MRH, Tergaonkar V. Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells. Cell Death Dis 2024; 15:202. [PMID: 38467621 PMCID: PMC10928192 DOI: 10.1038/s41419-024-06559-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: 09/29/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/13/2024]
Abstract
Cellular responses to TNF are inherently heterogeneous within an isogenic cell population and across different cell types. TNF promotes cell survival by activating pro-inflammatory NF-κB and MAPK signalling pathways but may also trigger apoptosis and necroptosis. Following TNF stimulation, the fate of individual cells is governed by the balance of pro-survival and pro-apoptotic signalling pathways. To elucidate the molecular mechanisms driving heterogenous responses to TNF, quantifying TNF/TNFR1 signalling at the single-cell level is crucial. Fluorescence live-cell imaging techniques offer real-time, dynamic insights into molecular processes in single cells, allowing for detection of rapid and transient changes, as well as identification of subpopulations, that are likely to be missed with traditional endpoint assays. Whilst fluorescence live-cell imaging has been employed extensively to investigate TNF-induced inflammation and TNF-induced cell death, it has been underutilised in studying the role of TNF/TNFR1 signalling pathway crosstalk in guiding cell-fate decisions in single cells. Here, we outline the various opportunities for pathway crosstalk during TNF/TNFR1 signalling and how these interactions may govern heterogenous responses to TNF. We also advocate for the use of live-cell imaging techniques to elucidate the molecular processes driving cell-to-cell variability in single cells. Understanding and overcoming cellular heterogeneity in response to TNF and modulators of the TNF/TNFR1 signalling pathway could lead to the development of targeted therapies for various diseases associated with aberrant TNF/TNFR1 signalling, such as rheumatoid arthritis, metabolic syndrome, and cancer.
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Affiliation(s)
- Marcus K Preedy
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, D3308, Dover Street, Manchester, M13 9PT, England, UK
| | - Michael R H White
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, D3308, Dover Street, Manchester, M13 9PT, England, UK.
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 8 Medical Drive, MD7, Singapore, 117596, Singapore.
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12
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Pyrillou K, Humphry M, Kitt LA, Rodgers A, Nus M, Bennett MR, Smith KG, Lyons PA, Mallat Z, Clarke MC. Loss of T follicular regulatory cell-derived IL-1R2 augments germinal center reactions via increased IL-1. JCI Insight 2024; 9:e174005. [PMID: 38329807 PMCID: PMC11143922 DOI: 10.1172/jci.insight.174005] [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: 07/18/2023] [Accepted: 01/31/2024] [Indexed: 02/10/2024] Open
Abstract
Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown. We found that IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal center (GC) T follicular regulatory (Tfr) cells increased the GC response after a first, but not booster, immunization, with an increase in T follicular helper (Tfh) cells, GC B cells, and antigen-specific antibodies, which was reversed upon IL-1 blockade. However, IL-1 signaling is not obligate for GC reactions, as WT and Il1r1-/- mice showed equivalent phenotypes, suggesting that GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2-/- mice did not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulated it, implying that compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn's disease had lower serum IL-1R2. All together, we show that IL-1R2 controls important aspects of innate and adaptive immunity and that IL-1R2 level may contribute to human disease propensity and/or progression.
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Affiliation(s)
- Katerina Pyrillou
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Melanie Humphry
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Lauren A. Kitt
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Amanda Rodgers
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Meritxell Nus
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Martin R. Bennett
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Kenneth G.C. Smith
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Paul A. Lyons
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Ziad Mallat
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
| | - Murray C.H. Clarke
- Section of CardioRespiratory Medicine, Heart and Lung Research Institute, and
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13
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Luo J, Tian Z, Song F, Ren C, Liu W. Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses. Exp Cell Res 2024; 434:113869. [PMID: 38049081 DOI: 10.1016/j.yexcr.2023.113869] [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: 09/12/2023] [Revised: 11/24/2023] [Accepted: 11/28/2023] [Indexed: 12/06/2023]
Abstract
Mycobacterium tuberculosis (Mtb) reprograms FAs metabolism of macrophages during infection and affects inflammatory reaction eventually, however, the mechanism remains poorly understood. Here we show that Mycobacterium bovis (BCG) induces DUSP5 expression through TLR2-MAPKs signaling pathway and promotes fatty acid oxidation (FAO). Silencing DUSP5 by adeno-associated virus vector (AAV) ameliorates lung injury and DUSP5 knockdown reduces the expression of IL-1β, IL-6 and inactivated NF-κB signaling in BCG-infected macrophages. Of note, DUSP5 specific siRNA increases the content of free fatty acids (FFAs) and triglyceride (TG), but represses the expression of FAO associated enzymes such as CPT1A and PPARα, suggesting DUSP5 mediated FAO during BCG infection. Moreover, Inhibiting FAO by pharmacological manner suppresses IL-1β, IL-6, TNF-α expression and relieves lung damage. Taken together, our data indicates DUSP5 mediates FAO reprogramming and promotes inflammatory response to BCG infection.
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Affiliation(s)
- Jia Luo
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China; General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China
| | - Zengjian Tian
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, 750004, China
| | - Fuyang Song
- College of Life Science, Ningxia University, Yinchuan, Ningxia, 750021, China
| | - Chao Ren
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China
| | - Wenmiao Liu
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China; The Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
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14
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Moratal C, Murdaca J, Cruzel C, Zamiti-Smondel A, Heme N, Asarisi F, Neels JG, Ferrari E, Chinetti G. An exploratory human study investigating the influence of type 2 diabetes on macrophage phenotype after myocardial infarction. IJC HEART & VASCULATURE 2023; 49:101309. [PMID: 38020056 PMCID: PMC10679475 DOI: 10.1016/j.ijcha.2023.101309] [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: 08/09/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023]
Abstract
Background Myocardial infarction (MI) is the primary cause of death in subjects with type 2 diabetes (T2D) and their in-hospital mortality after MI is still elevated compared with those without T2D. Therefore, it is of crucial importance to identify possible mechanisms of worse clinical outcomes and mortality in T2D subjects. Monocyte/macrophage-mediated immune response plays an important role in heart remodelling to limit functional deterioration after MI. Indeed, first pro-inflammatory macrophages digest damaged tissue, then anti-inflammatory macrophages become prevalent and promote tissue repair. Here, we hypothesize that the worse clinical outcomes in patients with T2D could be the consequence of a defective or a delayed polarization of macrophages toward an anti-inflammatory phenotype. Methods and results In an exploratory human study, circulating monocytes from male patients with or without T2D at different time-points after MI were in vitro differentiated toward pro- or anti-inflammatory macrophages. The results of this pilot study suggest that the phenotype of circulating monocytes, as well as the pro- and anti-inflammatory macrophage polarization, or the kinetics of the pro- and anti-inflammatory polarization, is not influenced by T2D. Conclusion Further studies will be necessary to understand the real contribution of macrophages after MI in humans.
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Affiliation(s)
| | | | | | | | | | | | | | - Emile Ferrari
- Université Côte d’Azur, CHU, INSERM, C3M, Nice, France
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15
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Ornelas MY, Cournoyer JE, Bram S, Mehta AP. Evolution and synthetic biology. Curr Opin Microbiol 2023; 76:102394. [PMID: 37801925 PMCID: PMC10842511 DOI: 10.1016/j.mib.2023.102394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 08/29/2023] [Accepted: 09/08/2023] [Indexed: 10/08/2023]
Abstract
Evolutionary observations have often served as an inspiration for biological design. Decoding of the central dogma of life at a molecular level and understanding of the cellular biochemistry have been elegantly used to engineer various synthetic biology applications, including building genetic circuits in vitro and in cells, building synthetic translational systems, and metabolic engineering in cells to biosynthesize and even bioproduce complex high-value molecules. Here, we review three broad areas of synthetic biology that are inspired by evolutionary observations: (i) combinatorial approaches toward cell-based biomolecular evolution, (ii) engineering interdependencies to establish microbial consortia, and (iii) synthetic immunology. In each of the areas, we will highlight the evolutionary premise that was central toward designing these platforms. These are only a subset of the examples where evolution and natural phenomena directly or indirectly serve as a powerful source of inspiration in shaping synthetic biology and biotechnology.
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Affiliation(s)
- Marya Y Ornelas
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S Matthews Avenue, Urbana, IL 61801, United States
| | - Jason E Cournoyer
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S Matthews Avenue, Urbana, IL 61801, United States
| | - Stanley Bram
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S Matthews Avenue, Urbana, IL 61801, United States
| | - Angad P Mehta
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S Matthews Avenue, Urbana, IL 61801, United States; Institute for Genomic Biology, University of Illinois at Urbana, Champaign, United States; Cancer Center at Illinois, University of Illinois at Urbana, Champaign, United States.
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16
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Russo RC, Quesniaux VFJ, Ryffel B. Homeostatic chemokines as putative therapeutic targets in idiopathic pulmonary fibrosis. Trends Immunol 2023; 44:1014-1030. [PMID: 37951789 DOI: 10.1016/j.it.2023.10.003] [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: 09/22/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 11/14/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease (ILD) that affects lung mechanical functions and gas exchange. IPF is caused by increased fibroblast activity and collagen deposition that compromise the alveolar-capillary barrier. Identifying an effective therapy for IPF remains a clinical challenge. Chemokines are key proteins in cell communication that have functions in immunity as well as in tissue homeostasis, damage, and repair. Chemokine receptor signaling induces the activation and proliferation of lung-resident cells, including alveolar macrophages (AMs) and fibroblasts. AMs are an important source of chemokines and cytokines during IPF. We highlight the complexity of this system and, based on insights from genetic and transcriptomic studies, propose a new role for homeostatic chemokine imbalance in IPF, with implications for putative therapeutic targets.
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Affiliation(s)
- Remo C Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
| | - Valerie F J Quesniaux
- Experimental and Molecular Immunology and Neurogenetics (INEM), Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7355, University of Orleans, Orleans 45071, France.
| | - Bernhard Ryffel
- Experimental and Molecular Immunology and Neurogenetics (INEM), Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7355, University of Orleans, Orleans 45071, France.
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17
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Frank M, Fechete LI, Tedeschi F, Nadzieja M, Nørgaard MMM, Montiel J, Andersen KR, Schierup MH, Reid D, Andersen SU. Single-cell analysis identifies genes facilitating rhizobium infection in Lotus japonicus. Nat Commun 2023; 14:7171. [PMID: 37935666 PMCID: PMC10630511 DOI: 10.1038/s41467-023-42911-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 10/25/2023] [Indexed: 11/09/2023] Open
Abstract
Legume-rhizobium signaling during establishment of symbiotic nitrogen fixation restricts rhizobium colonization to specific cells. A limited number of root hair cells allow infection threads to form, and only a fraction of the epidermal infection threads progress to cortical layers to establish functional nodules. Here we use single-cell analysis to define the epidermal and cortical cell populations that respond to and facilitate rhizobium infection. We then identify high-confidence nodulation gene candidates based on their specific expression in these populations, pinpointing genes stably associated with infection across genotypes and time points. We show that one of these, which we name SYMRKL1, encodes a protein with an ectodomain predicted to be nearly identical to that of SYMRK and is required for normal infection thread formation. Our work disentangles cellular processes and transcriptional modules that were previously confounded due to lack of cellular resolution, providing a more detailed understanding of symbiotic interactions.
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Affiliation(s)
- Manuel Frank
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | - Lavinia Ioana Fechete
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | - Francesca Tedeschi
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | - Marcin Nadzieja
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | | | - Jesus Montiel
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
- Center for Genomic Sciences, National Autonomous University of Mexico, Cuernavaca, Mexico
| | - Kasper Røjkjær Andersen
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | - Mikkel H Schierup
- Bioinformatics Research Centre, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark
| | - Dugald Reid
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark.
- Department of Animal, Plant and Soil Sciences, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia.
| | - Stig Uggerhøj Andersen
- Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, DK-8000, Aarhus C, Denmark.
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18
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Rahangdale R, Tender T, Balireddy S, Goswami K, Pasupuleti M, Hariharapura RC. A critical review on antiviral peptides derived from viral glycoproteins and host receptors to decoy herpes simplex virus. Microb Biotechnol 2023; 16:2036-2052. [PMID: 37740682 PMCID: PMC10616652 DOI: 10.1111/1751-7915.14342] [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: 07/24/2023] [Revised: 09/09/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023] Open
Abstract
The health of the human population has been continuously challenged by viral infections. Herpes simplex virus (HSV) is one of the common causes of illness and can lead to death in immunocompromised patients. Existing anti-HSV therapies are not completely successful in eliminating the infection due to anti-viral drug resistance, ineffectiveness against the latent virus and high toxicity over prolonged use. There is a need to update our knowledge of the current challenges faced in anti-HSV therapeutics and realize the necessity of developing alternative treatment approaches. Protein therapeutics are now being explored as a novel approach due to their high specificity and low toxicity. This review highlights the significance of HSV viral glycoproteins and host receptors in the pathogenesis of HSV infection. Proteins or peptides derived from HSV glycoproteins gC, gB, gD, gH and host cell receptors (HSPG, nectin and HVEM) that act as decoys to inhibit HSV attachment, entry, or fusion have been discussed. Few researchers have tried to improve the efficacy and stability of the identified peptides by modifying them using a peptidomimetic approach. With these efforts, we think developing an alternative treatment option for immunocompromised patients and drug-resistant organisms is not far off.
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Affiliation(s)
- Rakesh Rahangdale
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Tenzin Tender
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Sridevi Balireddy
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Kamini Goswami
- Microbiology Division, Council of Scientific and Industrial ResearchCentral Drug Research InstituteLucknowUttar PradeshIndia
| | - Mukesh Pasupuleti
- Microbiology Division, Council of Scientific and Industrial ResearchCentral Drug Research InstituteLucknowUttar PradeshIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Raghu Chandrashekar Hariharapura
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalKarnatakaIndia
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19
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Liang M, Wang K, Wei X, Gong X, Tang H, Xue H, Wang J, Yin P, Zhang L, Ma Z, Dou C, Dong S, Xu J, Luo F, Ma Q. Replenishing decoy extracellular vesicles inhibits phenotype remodeling of tissue-resident cells in inflammation-driven arthritis. Cell Rep Med 2023; 4:101228. [PMID: 37852176 PMCID: PMC10591050 DOI: 10.1016/j.xcrm.2023.101228] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 08/10/2023] [Accepted: 09/15/2023] [Indexed: 10/20/2023]
Abstract
The interleukin 6 (IL6) signaling pathway plays pleiotropic roles in regulating the inflammatory milieu that contributes to arthritis development. Here, we show that activation of IL6 trans-signaling induces phenotypic transitions in tissue-resident cells toward an inflammatory state. The establishment of arthritis increases the serum number of extracellular vesicles (EVs), while these EVs express more IL6 signal transducer (IL6ST, also known as gp130) on their surface. Transferring these EVs can block IL6 trans-signaling in vitro by acting as decoys that trap hyper IL6 and prevent inflammatory amplification in recipient arthritic mice. By genetically fusing EV-sorting domains with extracellular domains of receptors, we engineered EVs that harbor a higher quantity of signaling-incompetent decoy receptors. These exogenous decoy EVs exhibit significant potential in eliciting efficient anti-inflammatory effects in vivo. Our findings suggest an inherent resistance of decoy EVs against inflammation, highlighting the therapeutic potential of efficient decoy EVs in treating inflammatory diseases.
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Affiliation(s)
- Mengmeng Liang
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China
| | - Ke Wang
- College of Bioengineering, Chongqing University, Chongqing 400030, China; National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China
| | - Xiaoyu Wei
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiaoshan Gong
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing 400038, China
| | - Hao Tang
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing 400038, China
| | - Hao Xue
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Jing Wang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China
| | - Pengbin Yin
- Department of Orthopedics, The Fourth Medical Center, Chinese PLA General Hospital, Beijing 100853, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Licheng Zhang
- Department of Orthopedics, The Fourth Medical Center, Chinese PLA General Hospital, Beijing 100853, China; National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Zaisong Ma
- Department of Orthopedics, General Hospital of Xinjiang Military Command, Urumqi, Xinjiang 830000, China
| | - Ce Dou
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Shiwu Dong
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Department of Biomedical Materials Science, Third Military Medical University, Chongqing 400038, China
| | - Jianzhong Xu
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Fei Luo
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Qinyu Ma
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse 857000, China.
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20
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Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J 2023; 290:1362-1383. [PMID: 35015337 DOI: 10.1111/febs.16350] [Citation(s) in RCA: 258] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/17/2021] [Accepted: 01/10/2022] [Indexed: 12/15/2022]
Abstract
The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene-induced stress. Many senescent cells (SnCs) develop a senescent-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up-regulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre-clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.
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Affiliation(s)
- Lei Zhang
- Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA
| | - Louise E Pitcher
- Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA
| | - Vaishali Prahalad
- Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA
| | - Laura J Niedernhofer
- Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA
| | - Paul D Robbins
- Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA
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21
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Shroka TM, Kufareva I, Salanga CL, Handel TM. The dual-function chemokine receptor CCR2 drives migration and chemokine scavenging through distinct mechanisms. Sci Signal 2023; 16:eabo4314. [PMID: 36719944 PMCID: PMC10091583 DOI: 10.1126/scisignal.abo4314] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 01/11/2023] [Indexed: 02/02/2023]
Abstract
C-C chemokine receptor 2 (CCR2) is a dual-function receptor. Similar to other G protein-coupled chemokine receptors, it promotes monocyte infiltration into tissues in response to the chemokine CCL2, and, like atypical chemokine receptors (ACKRs), it scavenges chemokine from the extracellular environment. CCR2 therefore mediates CCL2-dependent signaling as a G protein-coupled receptor (GPCR) and also limits CCL2 signaling as a scavenger receptor. We investigated the mechanisms underlying CCR2 scavenging, including the involvement of intracellular proteins typically associated with GPCR signaling and internalization. Using CRISPR knockout cell lines, we showed that CCR2 scavenged by constitutively internalizing to remove CCL2 from the extracellular space and recycling back to the cell surface for further rounds of ligand sequestration. This process occurred independently of G proteins, GPCR kinases (GRKs), β-arrestins, and clathrin, which is distinct from other "professional" chemokine scavenger receptors that couple to GRKs, β-arrestins, or both. These findings set the stage for understanding the molecular regulators that determine CCR2 scavenging and may have implications for drug development targeting this therapeutically important receptor.
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Affiliation(s)
- Thomas M. Shroka
- Biomedical Sciences Program, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Irina Kufareva
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Catherina L. Salanga
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Tracy M. Handel
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
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22
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Dong BQ, Liao ZK, Le Y, Jiang S, Luo LF, Miao F, Le Poole IC, Lei TC. Acceleration of melanocyte senescence by the proinflammatory cytokines IFNγ and TNFα impairs the repigmentation response of vitiligo patients to narrowband ultraviolet B (NBUVB) phototherapy. Mech Ageing Dev 2023; 211:111779. [PMID: 36731753 DOI: 10.1016/j.mad.2023.111779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/14/2022] [Accepted: 01/28/2023] [Indexed: 01/31/2023]
Abstract
Vitiligo is a chronic autoimmune disease characterized by the T helper 1 (Th1) cytokine-driven immune destruction of melanocytes (MCs). Although narrowband ultraviolet B (NBUVB) phototherapy has been proven to be an effective therapeutic option, the repigmentation response to that phototherapy varies greatly in different vitiligo patients. Here, we demonstrate that there is an increase of NBUVB-induced cellular senescence in vitiligo MCs exposed to Th1 cytokine interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) in lesional vitiligo skin from poor responders who had undergone NBUVB phototherapy. Supplementation with exogenous recombinant human stem cell factor (rhSCF) in the culture medium as well as the lentiviral vector-mediated overexpression of cKIT could prevent the MCs from the IFNγ/TNFα-accelerated cellular senescence. Mechanistic studies indicated that the reduced ratio of membrane-bound KIT (mKIT) to the soluble form of KIT (sKIT) is directly related to the cellular senescence of vitiligo MCs following exposure to IFNγ and TNFα. Furthermore, the matrix metalloprotease 9 (MMP9) inhibitor GM6001 attenuates the production of sKIT via the suppression of cKIT ectodomain shedding. Altogether, our study indicates that the presence of Th1 cytokines IFNγ and/or TNFα in the epidermal milieu might impair the repigmentation response of vitiligo patients to NBUVB phototherapy.
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Affiliation(s)
- Bing-Qi Dong
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhi-Kai Liao
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yue Le
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Shan Jiang
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Long-Fei Luo
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Fang Miao
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - I Caroline Le Poole
- Department of Dermatology, Microbiology and Immunology, Northwestern University at Chicago, IL60611, USA
| | - Tie-Chi Lei
- Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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23
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Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov 2023; 22:21-37. [PMID: 36131080 DOI: 10.1038/s41573-022-00557-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 01/10/2023]
Abstract
Cytokines are secreted signalling proteins that play essential roles in the initiation, maintenance and resolution of immune responses. Although the unique ability of cytokines to control immune function has garnered clinical interest in the context of cancer, autoimmunity and infectious disease, the use of cytokine-based therapeutics has been limited. This is due, in part, to the ability of cytokines to act on many cell types and impact diverse biological functions, resulting in dose-limiting toxicity or lack of efficacy. Recent studies combining structural biology, protein engineering and receptor pharmacology have unlocked new insights into the mechanisms of cytokine receptor activation, demonstrating that many aspects of cytokine function are highly tunable. Here, we discuss the pharmacological principles underlying these efforts to overcome cytokine pleiotropy and enhance the therapeutic potential of this important class of signalling molecules.
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24
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Truong AD, Tran HTT, Nguyen HT, Chu NT, Hong YH, Lillehoj HS, Dang HV, Song KD. Molecular and functional characterization of chicken interleukin 1 receptor 2 (chIL-1R2). Poult Sci 2022; 102:102399. [PMID: 36586293 PMCID: PMC9811199 DOI: 10.1016/j.psj.2022.102399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/24/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for exogenous IL-1. However, its functional role in chicken immunity is poorly understood. Herein, chicken IL-1R2 (chIL-1R2) was identified and functionally characterized in vivo and in vitro. The chIL-1R2 coding sequence includes 1,236 nucleotides encoding 412 amino acids, is highly conserved, and has a close relationship with its mammalian counterpart. Its extracellular region has three Ig-like domains but no TIR domain for intracellular signaling. Using ELISA, the recombinant chIL-1R2 protein was demonstrated to specifically bind to the chicken IL-1β. ChIL-1R2 mRNA expression was shown to be higher in the spleen, lung, kidney, small intestine, and liver. The expression of chIL-1R2 and chIL-1R1 was significantly upregulated in DF-1 cells treated with poly (I:C), but significantly downregulated in the presence of NF-κB, JNK, and MEK inhibitors, indicating that the NF-κB, JNK, and MEK signaling pathways are required for the transcriptional regulation of chIL-1R1 and chIL-1R2 expression. It is worth noting that while the p30 MAPK pathway was required for chIL-1R1 expression, it was not required for chIL-1R2 expression. Furthermore, chIL-1R2 expression increased as early as day 1, and then significantly decreased until day 3, while chIL-1R1 was dramatically upregulated in four organs of chickens infected with the highly pathogenic avian influenza virus (HPAIV). These findings indicate that chIL-1R1 and chIL-1R2 may play a crucial in innate and adaptive immune responses toward HPAIV infection. In summary the present study showed that chIL-1R2 binds to chIL-1β antibody. ChIL-1R2 expression can be induced by a viral infection, and may be regulated through NF-κB/JNK/MEK-mediated signaling pathways.
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Affiliation(s)
- Anh Duc Truong
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Ha Noi, 100000, Vietnam
| | - Ha Thi Thanh Tran
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Ha Noi, 100000, Vietnam
| | - Huyen Thi Nguyen
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Ha Noi, 100000, Vietnam
| | - Nhu Thi Chu
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Ha Noi, 100000, Vietnam
| | - Yeong Ho Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Hyun S. Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Agricultural Research Services, United States Department of Agriculture, Beltsville, MD 20705, USA
| | - Hoang Vu Dang
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, Dong Da, Ha Noi, 100000, Vietnam
| | - Ki-Duk Song
- The Animal Molecular Genetics and Breeding Center & Department of Agricultural Convergence Technology, JeonBuk National University, Jeonju, 54896, Republic of Korea,Corresponding author:
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25
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Jinna N, Rida P, Su T, Gong Z, Yao S, LaBarge M, Natarajan R, Jovanovic-Talisman T, Ambrosone C, Seewaldt V. The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations. Cells 2022; 11:cells11233818. [PMID: 36497078 PMCID: PMC9740232 DOI: 10.3390/cells11233818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/09/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
The proclivity of certain pre-malignant and pre-invasive breast lesions to progress while others do not continues to perplex clinicians. Clinicians remain at a crossroads with effectively managing the high-risk patient subpopulation owing to the paucity of biomarkers that can adequately risk-stratify and inform clinical decisions that circumvent unnecessary administration of cytotoxic and invasive treatments. The immune system mounts the most important line of defense against tumorigenesis and progression. Unfortunately, this defense declines or "ages" over time-a phenomenon known as immunosenescence. This results in "inflamm-aging" or the excessive infiltration of pro-inflammatory chemokines, which alters the leukocyte composition of the tissue microenvironment, and concomitant immunoediting of these leukocytes to diminish their antitumor immune functions. Collectively, these effects can foster the sequelae of neoplastic transformation and progression. The erythrocyte cell antigen, Duffy antigen receptor for chemokines(DARC/ACKR1), binds and internalizes chemokines to maintain homeostatic levels and modulate leukocyte trafficking. A negative DARC status is highly prevalent among subpopulations of West African genetic ancestry, who are at higher risk of developing breast cancer and disease progression at a younger age. However, the role of DARC in accelerated inflamm-aging and malignant transformation remains underexplored. Herein, we review compelling evidence suggesting that DARC may be protective against inflamm-aging and, therefore, reduce the risk of a high-risk lesion progressing to malignancy. We also discuss evidence supporting that immunotherapeutic intervention-based on DARC status-among high-risk subpopulations may evade malignant transformation and progression. A closer look into this unique role of DARC could glean deeper insight into the immune response profile of individual high-risk patients and their predisposition to progress as well as guide the administration of more "cyto-friendly" immunotherapeutic intervention to potentially "turn back the clock" on inflamm-aging-mediated oncogenesis and progression.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Padmashree Rida
- Department of Science, Rowland Hall, Salt Lake City, UT 84102, USA
| | - Tianyi Su
- Department of Science, Rowland Hall, Salt Lake City, UT 84102, USA
| | - Zhihong Gong
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Mark LaBarge
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Christine Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Victoria Seewaldt
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
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26
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Pacheco-Hernández LM, Ramírez-Noyola JA, Gómez-García IA, Ignacio-Cortés S, Zúñiga J, Choreño-Parra JA. Comparing the Cytokine Storms of COVID-19 and Pandemic Influenza. J Interferon Cytokine Res 2022; 42:369-392. [PMID: 35674675 PMCID: PMC9422807 DOI: 10.1089/jir.2022.0029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/19/2022] [Indexed: 12/15/2022] Open
Abstract
Emerging respiratory viruses are major health threats due to their potential to cause massive outbreaks. Over the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has caused millions of cases of severe infection and deaths worldwide. Although natural and vaccine-induced protective immune mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been increasingly identified, the factors that determine morbimortality are less clear. Comparing the immune signatures of COVID-19 and other severe respiratory infections such as the pandemic influenza might help dissipate current controversies about the origin of their severe manifestations. As such, identifying homologies in the immunopathology of both diseases could provide targets for immunotherapy directed to block shared pathogenic mechanisms. Meanwhile, finding unique characteristics that differentiate each infection could shed light on specific immune alterations exploitable for diagnostic and individualized therapeutics for each case. In this study, we summarize immunopathological aspects of COVID-19 and pandemic influenza from the perspective of cytokine storms as the driving force underlying morbidity. Thereby, we analyze similarities and differences in the cytokine profiles of both infections, aiming to bring forward those molecules more attractive for translational medicine and drug development.
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Affiliation(s)
- Lynette Miroslava Pacheco-Hernández
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Jazmín Ariadna Ramírez-Noyola
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Programa de Maestría en Ciencias de la Salud, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón and Plan de San Luis, Mexico City, Mexico
| | - Itzel Alejandra Gómez-García
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Sergio Ignacio-Cortés
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Joaquín Zúñiga
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - José Alberto Choreño-Parra
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
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27
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Krut' VG, Chuvpilo SA, Astrakhantseva IV, Kozlovskaya LI, Efimov GA, Kruglov AA, Drutskaya MS, Nedospasov SA. Will Peptides Help to Stop COVID-19? BIOCHEMISTRY (MOSCOW) 2022; 87:590-604. [PMID: 36154880 PMCID: PMC9282900 DOI: 10.1134/s0006297922070021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Peptides are widely used for the diagnostics, prevention, and therapy of certain human diseases. How useful can they be for the disease caused by the SARS-CoV-2 coronavirus? In this review, we discuss the possibility of using synthetic and recombinant peptides and polypeptides for prevention of COVID-19 via blocking the interaction between the virus and its main receptor ACE2, as well as components of antiviral vaccines, in particular, against new emerging virus variants.
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Affiliation(s)
- Viktoriya G Krut'
- Sirius University of Science and Technology, Federal Territory Sirius, Krasnodar Krai, 354340, Russia
| | - Sergei A Chuvpilo
- Sirius University of Science and Technology, Federal Territory Sirius, Krasnodar Krai, 354340, Russia
| | - Irina V Astrakhantseva
- Sirius University of Science and Technology, Federal Territory Sirius, Krasnodar Krai, 354340, Russia
| | - Liubov I Kozlovskaya
- Chumakov Federal Scientific Center for Research and Development of Immunobiological Products, Russian Academy of Sciences, Moscow, 108819, Russia
- Institute of Translational Medicine and Biotechnology, Sechenov Moscow State Medical University, Moscow, 119991, Russia
| | - Grigory A Efimov
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, 125167, Russia
| | - Andrei A Kruglov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- German Rheumatism Research Center (DRFZ), Leibniz Institute, Berlin, 10117, Germany
| | - Marina S Drutskaya
- Sirius University of Science and Technology, Federal Territory Sirius, Krasnodar Krai, 354340, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Sergei A Nedospasov
- Sirius University of Science and Technology, Federal Territory Sirius, Krasnodar Krai, 354340, Russia.
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
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28
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Association of Interleukin-1 Beta and Interleukin-1 Receptor Antagonist Gene Polymorphisms and Plasma Levels with Diabetic Nephropathy. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9661823. [PMID: 35663044 PMCID: PMC9159863 DOI: 10.1155/2022/9661823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/18/2022] [Accepted: 05/07/2022] [Indexed: 12/25/2022]
Abstract
Objective We investigated the relationships between interleukin- (IL-) 1β and IL-1 receptor antagonist (IL-1Ra) gene polymorphism and plasma levels in patients with diabetic nephropathy (DN). Methods The genotype and allele frequency distribution of IL-1β and IL-1Ra in 61 patients with DN and 48 healthy controls (HCs) were determined by kompetitive allele-specific PCR (KASP), and the plasma concentrations of IL-1β and IL-1Ra in DN patients and HCs were measured by enzyme-linked immunosorbent assays (ELISA). Results Significant differences were detected in the distribution of IL-1β (−511C/T) genotype and allele frequencies between the DN and HC groups (P < 0.05), with the T genotype being more frequent in DN patients than HCs (OR = 2.84, 95% CI: 1.489–5.416). The IL-1β (+3953C/T) and IL-1Ra (+8006C/T) genotypes and allele frequencies were not significantly different between the two groups (P > 0.05). The plasma IL-1β level was significantly higher (P < 0.01), while the plasma IL-1Ra concentration was significantly lower in the DN group than the HC group (P < 0.05). Furthermore, the plasma IL-1β level was significantly different between IL-1β (−511C/T) locus variants (P < 0.05). Conclusion The IL-1β (−511C/T) gene polymorphism was significantly associated with DN risk in the population of northern Guangxi, China, and the T allele maybe responsible for genetic susceptibility to DN.
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29
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Hu H, Zhao R, He Q, Cui C, Song J, Guo X, Zang N, Yang M, Zou Y, Yang J, Li J, Wang L, Xia L, Wang L, He F, Hou X, Yan F, Chen L. cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic β-cells induced by metabolic stress. FASEB J 2022; 36:e22266. [PMID: 35357035 DOI: 10.1096/fj.202101988r] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 03/08/2022] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic β cell function and insulin resistance. Recent studies have shown that the accumulation of senescent β cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of β cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic β cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic β cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic β-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176.
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Affiliation(s)
- Huiqing Hu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jinquan Li
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Falian He
- Nuolai Biomedical Technology Co., Ltd., Taian, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China.,Nuolai Biomedical Technology Co., Ltd., Taian, China
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30
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Tuomela K, Ambrose AR, Davis DM. Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity. Front Immunol 2022; 13:867098. [PMID: 35401556 PMCID: PMC8984481 DOI: 10.3389/fimmu.2022.867098] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/04/2022] [Indexed: 12/14/2022] Open
Abstract
Cytotoxic lymphocytes are critical in our immune defence against cancer and infection. Cytotoxic T lymphocytes and Natural Killer cells can directly lyse malignant or infected cells in at least two ways: granule-mediated cytotoxicity, involving perforin and granzyme B, or death receptor-mediated cytotoxicity, involving the death receptor ligands, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). In either case, a multi-step pathway is triggered to facilitate lysis, relying on active pro-death processes and signalling within the target cell. Because of this reliance on an active response from the target cell, each mechanism of cell-mediated killing can be manipulated by malignant and infected cells to evade cytolytic death. Here, we review the mechanisms of cell-mediated cytotoxicity and examine how cells may evade these cytolytic processes. This includes resistance to perforin through degradation or reduced pore formation, resistance to granzyme B through inhibition or autophagy, and resistance to death receptors through inhibition of downstream signalling or changes in protein expression. We also consider the importance of tumour necrosis factor (TNF)-induced cytotoxicity and resistance mechanisms against this pathway. Altogether, it is clear that target cells are not passive bystanders to cell-mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing. Understanding these processes of immune evasion may lead to novel ideas for medical intervention.
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Affiliation(s)
| | | | - Daniel M. Davis
- The Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
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31
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Kefaloyianni E. Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation. FEBS Lett 2022; 596:589-606. [PMID: 35113454 PMCID: PMC11924200 DOI: 10.1002/1873-3468.14305] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/16/2021] [Accepted: 01/12/2022] [Indexed: 11/09/2022]
Abstract
Cytokine and growth factor receptors are usually transmembrane proteins, but they can also exist in soluble forms, either through cleavage and release of their ligand-binding extracellular domain or through the secretion of a soluble isoform. As an extension of this concept, transmembrane receptors on exosomes released into the circulation may act similarly to circulating soluble receptors. These soluble receptors add to the complexity of cytokine and growth factor signalling: they can function as decoy receptor that compete for ligand binding with their respective membrane-bound forms thereby attenuating signalling, or stabilize their ligands, or activate additional signalling events through interactions with other cell-surface proteins. Their soluble nature allows for a functional role away from the production sites, in remote cell types and organs. Accumulating evidence demonstrates that soluble receptors participate in the regulation and orchestration of various key cellular processes, particularly inflammatory responses. In this review, we will discuss release mechanisms of soluble cytokine and growth factor receptors, their mechanisms of action and strategies for targeting their pathways in disease.
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Affiliation(s)
- Eirini Kefaloyianni
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
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Duvvuri VR, Baumgartner A, Molani S, Hernandez PV, Yuan D, Roper RT, Matos WF, Robinson M, Su Y, Subramanian N, Goldman JD, Heath JR, Hadlock JJ. Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping. HEALTH DATA SCIENCE 2022; 2022:0002. [PMID: 36817759 PMCID: PMC9934012 DOI: 10.34133/hds.0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. Methods We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. Results The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Conclusion Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.
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Affiliation(s)
| | | | | | | | - Dan Yuan
- Department of Bioengineering, University of Washington, Seattle, WA, USA
- Washington University, St. Louis, MO, USA
| | | | | | | | - Yapeng Su
- Institute for Systems Biology, Seattle, WA, USA
| | | | - Jason D. Goldman
- Swedish Center for Research and Innovation, Swedish Medical Center, Seattle, WA, USA
- Providence St. Joseph Health, Renton, WA, USA
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA
| | - James R. Heath
- Institute for Systems Biology, Seattle, WA, USA
- Washington University, St. Louis, MO, USA
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Boggio E, Gigliotti CL, Moia R, Scotta A, Crespi I, Boggione P, De Paoli L, Deambrogi C, Garzaro M, Vidali M, Chiocchetti A, Stoppa I, Rolla R, Dianzani C, Monge C, Clemente N, Gaidano G, Dianzani U. Inducible T-cell co-stimulator (ICOS) and ICOS ligand are novel players in the multiple-myeloma microenvironment. Br J Haematol 2021; 196:1369-1380. [PMID: 34954822 DOI: 10.1111/bjh.17968] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/03/2021] [Accepted: 11/09/2021] [Indexed: 12/19/2022]
Abstract
The inducible T-cell co-stimulator (ICOS) is a T-cell receptor that, once bound to ICOS ligand (ICOSL) expressed on several cell types including the B-cell lineage, plays a decisive role in adaptive immunity by regulating the interplay between B and T cells. In addition to its immunomodulatory functions, we have shown that ICOS/ICOSL signalling can inhibit the activity of osteoclasts, unveiling a novel mechanism of lymphocyte-bone cells interactions. ICOS and ICOSL can also be found as soluble forms, namely sICOS and sICOSL. Here we show that: (i) levels of sICOS and sICOSL are increased in multiple myeloma (MM) compared to monoclonal gammopathy of undetermined significance and smouldering MM; (ii) levels of sICOS and sICOSL variably correlate with several markers of tumour burden; and (iii) sICOS levels tend to be higher in Durie-Salmon stage II/III versus stage I MM and correlate with overall survival as an independent variable. Moreover, surface ICOS and ICOSL are expressed in both myeloma cells and normal plasma cells, where they probably regulate different functional stages. Finally, ICOSL triggering inhibits the migration of myeloma cell lines in vitro and the growth of ICOSL+ MOPC-21 myeloma cells in vivo. These results suggest that ICOS and ICOSL represent novel markers and therapeutic targets for MM.
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Affiliation(s)
- Elena Boggio
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Casimiro Luca Gigliotti
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Riccardo Moia
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | | | - Ilaria Crespi
- Maggiore della Carità University Hospital, Novara, Italy
| | - Paola Boggione
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Lorenzo De Paoli
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Clara Deambrogi
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Massimiliano Garzaro
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Matteo Vidali
- Maggiore della Carità University Hospital, Novara, Italy
| | - Annalisa Chiocchetti
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Ian Stoppa
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Roberta Rolla
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Chiara Dianzani
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Turin, Italy
| | - Chiara Monge
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Turin, Italy
| | - Nausicaa Clemente
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Umberto Dianzani
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
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Karakaya B, van Moorsel CHM, Veltkamp M, Roodenburg-Benschop C, Kazemier KM, van der Helm-van Mil AHM, Huizinga TWJ, Grutters JC, Rijkers GT. A Polymorphism in C-C Chemokine Receptor 5 (CCR5) Associates with Löfgren's Syndrome and Alters Receptor Expression as well as Functional Response. Cells 2021; 10:1967. [PMID: 34440736 PMCID: PMC8394428 DOI: 10.3390/cells10081967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 11/23/2022] Open
Abstract
C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren's syndrome. Löfgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren's syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren's syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren's syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22-2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren's syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.
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Affiliation(s)
- Bekir Karakaya
- Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands; (C.H.M.v.M.); (M.V.); (C.R.-B.); (J.C.G.)
| | - Coline H. M. van Moorsel
- Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands; (C.H.M.v.M.); (M.V.); (C.R.-B.); (J.C.G.)
- Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands;
| | - Marcel Veltkamp
- Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands; (C.H.M.v.M.); (M.V.); (C.R.-B.); (J.C.G.)
- Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands;
| | - Claudia Roodenburg-Benschop
- Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands; (C.H.M.v.M.); (M.V.); (C.R.-B.); (J.C.G.)
| | - Karin M. Kazemier
- Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands;
- Center for Translational Immunology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Annette H. M. van der Helm-van Mil
- Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (A.H.M.v.d.H.-v.M.); (T.W.J.H.)
| | - Tom W. J. Huizinga
- Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; (A.H.M.v.d.H.-v.M.); (T.W.J.H.)
| | - Jan C. Grutters
- Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands; (C.H.M.v.M.); (M.V.); (C.R.-B.); (J.C.G.)
- Division of Heart & Lungs, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands;
| | - Ger T. Rijkers
- Department of Science, University College Roosevelt, P.O. Box 94, 4330 AB Middelburg, The Netherlands;
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A structural perspective on the design of decoy immune modulators. Pharmacol Res 2021; 170:105735. [PMID: 34146695 DOI: 10.1016/j.phrs.2021.105735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/23/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Therapeutic mAbs have dominated the class of immunotherapeutics in general and immune checkpoint inhibitors in particular. The high specificity of mAbs to the target molecule as well as their extended half-life and (or) the effector functions raised by the Fc part are some of the important aspects that contribute to the success of this class of therapeutics. Equally potential candidates are decoys and their fusions that can address some of the inherent limitations of mAbs, like immunogenicity, resistance development, low bio-availability and so on, besides maintaining the advantages of mAbs. The decoys are molecules that trap the ligands and prevent them from interacting with the signaling receptors. Although a few FDA-approved decoy immune modulators are very successful, the potential of this class of drugs is yet to be fully realized. Here, we review various strategies employed in fusion protein therapeutics with a focus on the design of decoy immunomodulators from the structural perspective and discuss how the information on protein structure and function can strategically guide the development of next-generation immune modulators.
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Mahjoubin-Tehran M, Teng Y, Jalili A, Aghaee-Bakhtiari SH, Markin AM, Sahebkar A. Decoy Technology as a Promising Therapeutic Tool for Atherosclerosis. Int J Mol Sci 2021; 22:4420. [PMID: 33922585 PMCID: PMC8122884 DOI: 10.3390/ijms22094420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 12/26/2022] Open
Abstract
Cardiovascular diseases (CVDs) have been classified into several types of disease, of which atherosclerosis is the most prevalent. Atherosclerosis is characterized as an inflammatory chronic disease which is caused by the formation of lesions in the arterial wall. Subsequently, lesion progression and disruption ultimately lead to heart disease and stroke. The development of atherosclerosis is the underlying cause of approximately 50% of all deaths in westernized societies. Countless studies have aimed to improve therapeutic approaches for atherosclerosis treatment; however, it remains high on the global list of challenges toward healthy and long lives. Some patients with familial hypercholesterolemia could not get intended LDL-C goals even with high doses of traditional therapies such as statins, with many of them being unable to tolerate statins because of the harsh side effects. Furthermore, even in patients achieving target LDL-C levels, the residual risk of traditional therapies is still significant thus highlighting the necessity of ongoing research for more effective therapeutic approaches with minimal side effects. Decoy-based drug candidates represent an opportunity to inhibit regulatory pathways that promote atherosclerosis. In this review, the potential roles of decoys in the treatment of atherosclerosis were described based on the in vitro and in vivo findings.
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Affiliation(s)
- Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; (M.M.-T.); (A.J.)
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Amin Jalili
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran; (M.M.-T.); (A.J.)
| | | | - Alexander M. Markin
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia;
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
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Chiu JW, Binte Hanafi Z, Chew LCY, Mei Y, Liu H. IL-1α Processing, Signaling and Its Role in Cancer Progression. Cells 2021; 10:E92. [PMID: 33430381 PMCID: PMC7827341 DOI: 10.3390/cells10010092] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 12/23/2022] Open
Abstract
Interleukin-1α (IL-1α) is a major alarmin cytokine which triggers and boosts the inflammatory responses. Since its discovery in the 1940s, the structure and bioactivity of IL-1α has been extensively studied and emerged as a vital regulator in inflammation and hematopoiesis. IL-1α is translated as a pro-form with minor bioactivity. The pro-IL-1α can be cleaved by several proteases to generate the N terminal and C terminal form of IL-1α. The C terminal form of IL-1α (mature form) has several folds higher bioactivity compared with its pro-form. IL-1α is a unique cytokine which could localize in the cytosol, membrane, nucleus, as well as being secreted out of the cell. However, the processing mechanism and physiological significance of these differentially localized IL-1α are still largely unknown. Accumulating evidence suggests IL-1α is involved in cancer pathogenesis. The role of IL-1α in cancer development is controversial as it exerts both pro- and anti-tumor roles in different cancer types. Here, we review the recent development in the processing and signaling of IL-1α and summarize the functions of IL-1α in cancer development.
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Affiliation(s)
| | | | | | - Yu Mei
- Immunology Programme, Department of Microbiology and Immunology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; (J.W.C.); (Z.B.H.); (L.C.Y.C.)
| | - Haiyan Liu
- Immunology Programme, Department of Microbiology and Immunology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; (J.W.C.); (Z.B.H.); (L.C.Y.C.)
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38
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Kuo WC, Lee CC, Chang YW, Pang W, Chen HS, Hou SC, Lo SY, Yang AS, Wang AHJ. Structure-based Development of Human Interleukin-1β-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP. J Mol Biol 2020; 433:166766. [PMID: 33359099 DOI: 10.1016/j.jmb.2020.166766] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/07/2020] [Accepted: 12/14/2020] [Indexed: 02/05/2023]
Abstract
Interleukin-1β (IL-1β) is a potent pleiotropic cytokine playing a central role in protecting cells from microbial pathogen infection or endogenous stress. After it binds to IL-1RI and recruits IL-1 receptor accessory protein (IL-1RAcP), signaling culminates in activation of NF-κB. Many pathophysiological diseases have been attributed to the derailment of IL-1β regulation. Several blocking reagents have been developed based on two mechanisms: blocking the binding of IL-1β to IL-1RI or inhibiting the recruitment of IL-1RAcP to the IL-1β initial complex. In order to simultaneously fulfill these two actions, a human anti-IL-1β neutralizing antibody IgG26 was screened from human genetic phage-display library and furthered structure-optimized to final version, IgG26AW. IgG26AW has a sub-nanomolar binding affinity for human IL-1β. We validated IgG26AW-neutralizing antibodies specific for IL-1β in vivo to prevent human IL-1β-driving IL-6 elevation in C56BL/6 mice. Mice underwent treatments with IgG26AW in A549 and MDA-MB-231 xenograft mouse cancer models have also been observed with tumor shrank and inhibition of tumor metastasis. The region where IgG26 binds to IL-1β also overlaps with the position where IL-1RI and IL-1RAcP bind, as revealed by the 26-Fab/IL-1β complex structure. Meanwhile, SPR experiments showed that IL-1β bound by IgG26AW prevented the further binding of IL-1RI and IL-1RAcP, which confirmed our inference from the result of protein structure. Therefore, the inhibitory mechanism of IgG26AW is to block the assembly of the IL-1β/IL-1RI/IL-1RAcP ternary complex which further inhibits downstream signaling. Based on its high affinity, high neutralizing potency, and novel binding epitope simultaneously occupying both IL-1RI and IL-1RAcP residues that bind to IL-1β, IgG26AW may be a new candidate for treatments of inflammation-related diseases or for complementary treatments of cancers in which the role of IL-1β is critical to pathogenesis.
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Affiliation(s)
- Wen-Chih Kuo
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Cheng-Chung Lee
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Ya-Wen Chang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Wei Pang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Hong-Sen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Shin-Chen Hou
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Shin-Yi Lo
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - An-Suei Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Andrew H-J Wang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
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Conceição M, Forcina L, Wiklander OPB, Gupta D, Nordin JZ, Vrellaku B, McClorey G, Mäger I, Gӧrgens A, Lundin P, Musarò A, Wood MJA, Andaloussi SE, Roberts TC. Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle. Biomaterials 2020; 266:120435. [PMID: 33049461 DOI: 10.1016/j.biomaterials.2020.120435] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/27/2020] [Accepted: 10/04/2020] [Indexed: 12/28/2022]
Abstract
The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two main mechanisms, the classical and trans-signalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 trans-signalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.
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Affiliation(s)
- Mariana Conceição
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
| | - Laura Forcina
- DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, IMM, Sapienza University of Rome, Rome, Italy
| | - Oscar P B Wiklander
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
| | - Dhanu Gupta
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
| | - Joel Z Nordin
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
| | | | - Graham McClorey
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK
| | - Imre Mäger
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK
| | - André Gӧrgens
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford Science Park, Oxford, UK; Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - Per Lundin
- Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
| | - Antonio Musarò
- DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, IMM, Sapienza University of Rome, Rome, Italy; Center for Life Nano Science @Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Matthew J A Wood
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
| | - Samir El Andaloussi
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
| | - Thomas C Roberts
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK.
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Mukhtar I. Inflammatory and immune mechanisms underlying epileptogenesis and epilepsy: From pathogenesis to treatment target. Seizure 2020; 82:65-79. [PMID: 33011590 DOI: 10.1016/j.seizure.2020.09.015] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Epilepsy is a brain disease associated with epileptic seizures as well as with neurobehavioral outcomes of this condition. In the last century, inflammation emerged as a crucial factor in epilepsy etiology. Various brain insults through activation of neuronal and non-neuronal brain cells initiate a series of inflammatory events. Growing observations strongly suggest that abnormal activation of critical inflammatory processes contributes to epileptogenesis, a gradual process by which a normal brain transforms into the epileptic brain. Increased knowledge of inflammatory pathways in epileptogenesis has unveiled mechanistic targets for novel antiepileptic therapies. Molecules specifically targeting the pivotal inflammatory pathways may serve as promising candidates to halt the development of epilepsy. The present paper reviews the pieces of evidence conceptually supporting the potential role of inflammatory mechanisms and the relevant blood-brain barrier (BBB) disruption in epileptogenesis. Also, it discusses the mechanisms underlying inflammation-induced neuronal-glial network impairment and highlights innovative neuroregulatory actions of typical inflammatory molecules. Finally, it presents a brief analysis of observations supporting the therapeutic role of inflammation-targeting tiny molecules in epileptic seizures.
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Affiliation(s)
- Iqra Mukhtar
- H.E.J Research Institute of Chemistry, International Center For Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Spalinger MR, Schwarzfischer M, Scharl M. The Role of Protein Tyrosine Phosphatases in Inflammasome Activation. Int J Mol Sci 2020; 21:E5481. [PMID: 32751912 PMCID: PMC7432435 DOI: 10.3390/ijms21155481] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022] Open
Abstract
Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.
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Affiliation(s)
- Marianne R. Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland; (M.S.); (M.S.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
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Wang J, Belosevic M, Stafford JL. Identification of goldfish (Carassius auratus L.) leukocyte immune-type receptors shows alternative splicing as a potential mechanism for receptor diversification. Mol Immunol 2020; 125:83-94. [PMID: 32652363 DOI: 10.1016/j.molimm.2020.06.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/15/2020] [Accepted: 06/20/2020] [Indexed: 12/31/2022]
Abstract
Leukocyte immune-type receptors (LITRs) are a multigene family of teleost immunoregulatory proteins that share structural, phylogenetic, and likely functional relationships with several innate immune receptor proteins in other vertebrates, including mammals. Originally discovered in channel catfish (Ictalurus punctatus), representative IpLITR-types have been shown to regulate diverse innate immune cell effector responses including phagocytosis, degranulation, and cytokine secretion. To date, IpLITRs have been primarily characterized using mammalian cell line expression systems, therefore many unanswered questions remain regarding their actual regulatory roles in fish immunity. In the present study, we report on the preliminary molecular characterization of five goldfish (Carassius auratus) CaLITR-types and the identification of several putative splice variants of these receptors cloned from various goldfish tissues and primary myeloid cell cultures. In general, CaLITR mRNA transcripts were detected in all goldfish tissues tested, and also in primary kidney macrophage and neutrophil cultures. Specifically, CaLITR1 is a functionally ambiguous receptor with no charged amino acids in its transmembrane (TM) segment and is devoid of tyrosine-based signaling motifs in its short cytoplasmic tail (CYT) region. CaLITR2 is a putative activating receptor-type that contains immunotyrosine-based activation motifs (ITAMs) within its long CYT region, and CaLITR3 has a positively charged TM segment, suggesting that it may recruit intracellular stimulatory adaptor signaling molecules. CaLITR4 and CaLITR5 appear to have diverse signaling capabilities since they contain various immunoregulatory signaling motifs within their CYT regions including putative Nck and STAT recruitment motifs as well as ITAM-like and ITIM sequences. We also identified putative CaLITR splice variants with altered extracellular Ig-like domain compositions and variable CYT regions. Interestingly, this suggests that alternative splicing-mediated diversification of CaLITRs can generate receptor forms with possible variable binding and/or intracellular signaling abilities. Overall, these findings reveal new information about the teleost LITRs and sets the stage for exploring how alternative splicing leads to the functional diversification of this complex multigene immunoregulatory receptor family.
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Affiliation(s)
- Jiahui Wang
- Department of Biological Sciences, University of Alberta, Alberta, Canada
| | - Miodrag Belosevic
- Department of Biological Sciences, University of Alberta, Alberta, Canada
| | - James L Stafford
- Department of Biological Sciences, University of Alberta, Alberta, Canada.
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Liu P, Lu Z, Wu Y, Shang D, Zhao Z, Shen Y, Zhang Y, Zhu F, Liu H, Tu Z. Cellular Senescence-Inducing Small Molecules for Cancer Treatment. Curr Cancer Drug Targets 2020; 19:109-119. [PMID: 29848278 DOI: 10.2174/1568009618666180530092825] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 02/10/2018] [Accepted: 03/07/2018] [Indexed: 01/22/2023]
Abstract
Recently, the chemotherapeutic drug-induced cellular senescence has been considered a promising anti-cancer approach. The drug-induced senescence, which shows both similar and different hallmarks from replicative and oncogene-induced senescence, was regarded as a key determinant of tumor response to chemotherapy in vitro and in vivo. To date, an amount of effective chemotherapeutic drugs that can evoke senescence in cancer cells have been reported. The targets of these drugs differ substantially, including senescence signaling pathways, DNA replication process, DNA damage pathways, epigenetic modifications, microtubule polymerization, senescence-associated secretory phenotype (SASP), and so on. By summarizing senescence-inducing small molecule drugs together with their specific traits and corresponding mechanisms, this review is devoted to inform scientists to develop novel therapeutic strategies against cancer through inducing senescence.
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Affiliation(s)
- Peng Liu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Yanfang Wu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Dongsheng Shang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.,School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Zhicong Zhao
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Yanting Shen
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Yafei Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Feifei Zhu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Zhigang Tu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
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Zwiri A, Al-Hatamleh MAI, W. Ahmad WMA, Ahmed Asif J, Khoo SP, Husein A, Ab-Ghani Z, Kassim NK. Biomarkers for Temporomandibular Disorders: Current Status and Future Directions. Diagnostics (Basel) 2020; 10:E303. [PMID: 32429070 PMCID: PMC7277983 DOI: 10.3390/diagnostics10050303] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022] Open
Abstract
Numerous studies have been conducted in the previous years with an objective to determine the ideal biomarker or set of biomarkers in temporomandibular disorders (TMDs). It was recorded that tumour necrosis factor (TNF), interleukin 8 (IL-8), IL-6, and IL-1 were the most common biomarkers of TMDs. As of recently, although the research on TMDs biomarkers still aims to find more diagnostic agents, no recent study employs the biomarker as a targeting point of pharmacotherapy to suppress the inflammatory responses. This article represents an explicit review on the biomarkers of TMDs that have been discovered so far and provides possible future directions towards further research on these biomarkers. The potential implementation of the interactions of TNF with its receptor 2 (TNFR2) in the inflammatory process has been interpreted, and thus, this review presents a new hypothesis towards suppression of the inflammatory response using TNFR2-agonist. Subsequently, this hypothesis could be explored as a potential pain elimination approach in patients with TMDs.
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Affiliation(s)
- Abdalwhab Zwiri
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
| | - Mohammad A. I. Al-Hatamleh
- Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Wan Muhamad Amir W. Ahmad
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
| | - Jawaad Ahmed Asif
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Suan Phaik Khoo
- Department of Oral Diagnostic and Surgical Sciences, School of Dentistry, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia;
| | - Adam Husein
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Zuryati Ab-Ghani
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Nur Karyatee Kassim
- School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (A.Z.); (W.M.A.W.A.); (J.A.A.); (A.H.)
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
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Pancreatic Cancer UK Grand Challenge: Developments and challenges for effective CAR T cell therapy for pancreatic ductal adenocarcinoma. Pancreatology 2020; 20:394-408. [PMID: 32173257 DOI: 10.1016/j.pan.2020.02.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/11/2022]
Abstract
Death from pancreatic ductal adenocarcinoma (PDAC) is rising across the world and PDAC is predicted to be the second most common cause of cancer death in the USA by 2030. Development of effective biotherapies for PDAC are hampered by late presentation, a low number of differentially expressed molecular targets and a tumor-promoting microenvironment that forms both a physical, collagen-rich barrier and is also immunosuppressive. In 2017 Pancreatic Cancer UK awarded its first Grand Challenge Programme award to tackle this problem. The team plan to combine the use of novel CAR T cells with strategies to overcome the barriers presented by the tumor microenvironment. In advance of publication of those data this review seeks to highlight the key problems in effective CAR T cell therapy of PDAC and to describe pre-clinical and clinical progress in CAR T bio-therapeutics.
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Mahjoubin-Tehran M, Rezaei S, Jalili A, Aghaee-Bakhtiari SH, Orafai HM, Jamialahmadi T, Sahebkar A. Peptide decoys: a new technology offering therapeutic opportunities for breast cancer. Drug Discov Today 2020; 25:593-598. [PMID: 31978387 DOI: 10.1016/j.drudis.2020.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/28/2019] [Accepted: 01/15/2020] [Indexed: 12/23/2022]
Abstract
Breast cancer is the most common cancer among women. Absence of hormone receptors (estrogen and progesterone) and lack of overexpression of Human Epidermal Growth Factor 2 (HER2) make triple-negative breast cancer (TNBC) an aggressive subtype of breast cancer that is resistant to conventional therapies. Peptide decoys have emerged as a novel therapeutic approach for the treatment of breast cancer. Decoy peptide technology entails the use of soluble proteins or peptides, including binding proteins or inactive cell surface receptors. Peptide decoys bind to certain ligands (e.g., inflammatory cytokines) with high affinity and specificity as receptors but cannot initiate any signaling pathway that is involved in the pathogenesis of breast cancer. In this review, we discuss the use of decoy peptides as a novel therapeutic approach for breast cancer treatment.
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Affiliation(s)
- Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Rezaei
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Jalili
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hossein M Orafai
- Department of Pharmaceutics, Faculty of Pharmacy, University of Ahl Al Bayt, Karbala, Iraq; Department of Pharmaceutics, Faculty of Pharmacy, Al-Zahraa University, Karbala, Iraq
| | - Tannaz Jamialahmadi
- Halal Research Center of IRI, FDA, Tehran, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhou X, Chen J, Tao H, Cai Y, Huang L, Zhou H, Chen Y, Cui L, Zhong W, Li K. Intranasal Delivery of miR-155-5p Antagomir Alleviates Acute Seizures Likely by Inhibiting Hippocampal Inflammation. Neuropsychiatr Dis Treat 2020; 16:1295-1307. [PMID: 32547033 PMCID: PMC7251485 DOI: 10.2147/ndt.s247677] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/17/2020] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION To confront the resistance to existing antiepileptic drugs, studies have gradually begun to investigate alternative pathologies distinct from the traditional treatments that overwhelmingly target ion channels. Microglia activation is the first inflammatory response in the brain, in which miR-155-5p plays a key proinflammatory role and thus represents a promising target for inflammatory modulation in epilepsy pathologies. METHODS In this study, a pentetrazol-induced acute seizure model was established, and the seizure degree was evaluated within 60 min after pentetrazol administration. Animals were then sacrificed for hippocampal tissue collection for biological experiments. RESULTS Intranasal delivery of miR-155-5p antagomir (30 min before pentetrazol administration) increased the percentage of animals with no induced seizures by 20%, extended the latency to generalized convulsions, and decreased seizure severity. In addition, miR-155-5p antagomir treatment alleviated hippocampal damage and decreased the expression of typical inflammatory modulators (TNF-α, IL-1β and IL-6). Further research revealed that intranasal delivery of miR-155-5p antagomir significantly decreased the relative level of miR-155-5p and increased the expression of its targets LXRα and SOCS1 in IBA1-labeled microglial cells in the hippocampus. CONCLUSION These findings demonstrate that intranasal delivery of miR-155-5p antagomir alleviated acute seizures, likely by blocking hippocampal inflammation. However, other potential mechanisms of the effects of miR-155-5p antagomir and its long-term safety for epilepsy treatment remain to be investigated.
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Affiliation(s)
- Xu Zhou
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Jun Chen
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Hua Tao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China.,Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Yujie Cai
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Lidan Huang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Haihong Zhou
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Yanyan Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Lili Cui
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Wangtao Zhong
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China
| | - Keshen Li
- Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001 China; Stroke Center, Neurology & Neurosurgery Division, Clinical Medicine Research Institute & The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, People's Republic of China
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Filipe J, Bronzo V, Curone G, Castiglioni B, Vigo D, Smith B, Herrera V, Roccabianca P, Moroni P, Riva F. Staphylococcus aureus intra-mammary infection affects the expression pattern of IL-R8 in goat. Comp Immunol Microbiol Infect Dis 2019; 66:101339. [PMID: 31437679 DOI: 10.1016/j.cimid.2019.101339] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 01/23/2023]
Abstract
IL-1R8 is a member of Interleukin-1 receptor family acting as a negative regulator of inflammation reliant on ILRs and TLRs activation. IL-1R8 role has never been evaluated in acute bacterial mastitis. We first investigated IL-1R8 sequence conservation among different species and its pattern of expression in a wide panel of organs from healthy goats. Then, modulation of IL-1R8 during natural and experimental mammary infection was evaluated and compared in blood, milk and mammary tissues from healthy and Staphylococcus aureus infected goats. IL-1R8 has a highly conserved sequence among vertebrates. Goat IL-1R8 was ubiquitously expressed in epithelial and lymphoid tissues with highest levels in pancreas. IL-1R8 was down-regulated in epithelial mammary cells following S. aureus infection. Interestingly it was up-regulated in leukocytes infiltrating the infected mammary tissues suggesting that it could represent a target of S. aureus immune evasion.
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Affiliation(s)
- J Filipe
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - V Bronzo
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - G Curone
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - B Castiglioni
- Istituto di Biologia e Biotecnologia Agraria, Consiglio Nazionale delle Ricerche, 26900, Lodi, Italy.
| | - D Vigo
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - B Smith
- University of California, Davis, Wildlife Health Center, Davis, CA 95616, USA.
| | - V Herrera
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - P Roccabianca
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
| | - P Moroni
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy; Cornell University, Animal Health Diagnostic Center, Quality Milk Production Services, Ithaca, NY 14853, USA.
| | - F Riva
- Università degli Studi di Milano, Dipartimento di Medicina Veterinaria, via Celoria 10, 20133, Milan, Italy.
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Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D, Sánchez-Ruano JJ, Artaza-Varasa T, Martin-Vicente M, Fernández-Rodríguez A, Martínez I, Resino S. Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study. Biomolecules 2019; 9:E143. [PMID: 30970632 PMCID: PMC6523653 DOI: 10.3390/biom9040143] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/05/2019] [Accepted: 04/07/2019] [Indexed: 02/07/2023] Open
Abstract
: The Duffy antigen receptor for chemokines (DARC) rs12075 polymorphism regulates leukocyte trafficking and proinflammatory chemokine homeostasis. Hepatitis C virus (HCV)-mediated liver fibrosis is associated with an uncontrolled inflammatory response. In this study, we evaluate the association between the DARC rs12075 polymorphism and liver stiffness progression in HCV-infected patients. We carried out a retrospective cohort study (repeated measures design) in 208 noncirrhotic patients with chronic hepatitis C (CHC) who had at least two liver stiffness measurements (LSM) with a separation of at least 12 months. We used generalized linear models to analyze the association between DARC rs12075 polymorphism and outcome variables. During a follow-up of 46.6 months, the percentage of patients with stages of fibrosis F0/F1 decreased (p < 0.001), while LSM values and the percentage of patients with cirrhosis increased (p < 0.001). This pattern of changes was maintained in each of the groups of patients analyzed according to their rs12075 genotypes (AA or AG/GG). However, the variations in liver stiffness characteristics were lower in patients with the rs12075 AG/GG genotype (AG/GG versus AA). Thereby, in the adjusted analysis, patients with the rs12075 AG/GG genotype had a lower risk of an increased value of LSM2/LSM1 arithmetic mean ratio (AMR = 0.83; p = 0.001) and of an increase in LSM ≥ 5 kPa (odds ratio (OR) = 0.28; p = 0.009). Besides, patients with rs12075 AG/GG had a lower risk of cirrhosis progression (OR = 0.24; p = 0.009). No significant associations were found for an increase in LSM ≥ 10 kPa. We found an association between the DARC rs12075 single nucleotide polymorphism (SNP) and CHC progression. Specifically, patients with the DARC rs12075 AG/GG genotype had a lower risk of liver fibrosis progression and development of cirrhosis.
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Affiliation(s)
- María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Spain.
| | | | - Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital de Antequera, 29200 Málaga, Spain.
| | | | | | - María Martin-Vicente
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Spain.
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Spain.
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Spain.
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Spain.
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Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor. PLoS Pathog 2019; 15:e1007658. [PMID: 30947296 PMCID: PMC6448830 DOI: 10.1371/journal.ppat.1007658] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 02/25/2019] [Indexed: 02/07/2023] Open
Abstract
Throughout evolution, cytomegaloviruses (CMVs) have been capturing genes from their hosts, employing the derived proteins to evade host immune defenses. We have recently reported the presence of a number of CD48 homologs (vCD48s) encoded by different pathogenic viruses, including several CMVs. However, their properties and biological relevance remain as yet unexplored. CD48, a cosignaling molecule expressed on the surface of most hematopoietic cells, modulates the function of natural killer (NK) and other cytotoxic cells by binding to its natural ligand 2B4 (CD244). Here, we have characterized A43, the vCD48 exhibiting the highest amino acid sequence identity with host CD48. A43, which is encoded by owl monkey CMV, is a soluble molecule released from the cell after being proteolytically processed through its membrane proximal region. A43 is expressed with immediate-early kinetics, yielding a protein that is rapidly detected in the supernatant of infected cells. Remarkably, surface plasmon resonance assays revealed that this viral protein binds to host 2B4 with high affinity and slow dissociation rates. We demonstrate that soluble A43 is capable to abrogate host CD48:2B4 interactions. Moreover, A43 strongly binds to human 2B4 and prevents 2B4-mediated NK-cell adhesion to target cells, therefore reducing the formation of conjugates and the establishment of immunological synapses between human NK cells and CD48-expressing target cells. Furthermore, in the presence of this viral protein, 2B4-mediated cytotoxicity and IFN-γ production by NK cells are severely impaired. In summary, we propose that A43 may serve as a functional soluble CD48 decoy receptor by binding and masking 2B4, thereby impeding effective NK cell immune control during viral infections. Thus, our findings provide a novel example of the immune evasion strategies developed by viruses. In order to evade detection and destruction by cytotoxic lymphocytes and successfully persist within their hosts, cytomegalovirus (CMVs) have evolved a number of genes dedicated to block immune recognition. Certain CMVs and other large DNA viruses encode homologs of the cell-surface molecule CD48, a ligand of the 2B4 receptor involved in regulating the function of cytotoxic lymphocytes. Here, we have investigated for the first time the immunomodulatory potential of one of these viral molecules. We show that A43, a CD48 homolog encoded by owl monkey CMV, is a soluble molecule that exhibits exceptional binding kinetics for 2B4, and is furthermore capable of blocking the interaction with its counter-receptor CD48. Moreover, we reveal how this viral protein interferes with human NK cell-mediated cytotoxicity by inhibiting the immune synapse between human NK cells and target cells. Thus, these findings not only underscore the importance of 2B4-mediated immune responses in controlling CMV infections, but also unveil the shedding of a virally-encoded soluble variant of CD48 as a new viral counteract mechanism for subverting immune surveillance.
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