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Jameie M, Bordbar S, Samiee R, Amanollahi M, Azizmohammad Looha M, Aleyasin MS, Abdol Homayuni MR, Mozafar M, Jameie SB, Akhondzadeh S. Monocytic TLR4 expression and activation in schizophrenia: A systematic review and meta-analysis. PLoS One 2025; 20:e0319171. [PMID: 40153412 PMCID: PMC11952227 DOI: 10.1371/journal.pone.0319171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 01/29/2025] [Indexed: 03/30/2025] Open
Abstract
BACKGROUND The role of toll-like receptor 4 (TLR4) in schizophrenia remains unclear, with studies reporting conflicting results on its expression and activation in persons with schizophrenia (PwSCZ). This systematic review/meta-analysis compared basal monocytic TLR4 expression, as well as its activation pattern between PwSCZ and healthy controls (HCs). METHODS This study was registered with PROSPERO (CRD42021273858) and adhered to the PRISMA guidelines. A systematic search was conducted through MEDLINE (via PubMed), Web of Science, and Scopus from inception to December 12, 2023. Quantitative syntheses were conducted for (a) basal monocytic TLR4 density, (b) basal percentage of TLR4+ monocytes, and (c) basal TLR4 gene expression. Effect sizes were computed using Hedges' g for mean differences. Random-effect models with restricted maximum-likelihood estimation were used, and subgrouping was conducted based on antipsychotic status. The studies' risk of bias was assessed using the Joanna Briggs Institute (JBI) tool. RESULTS Eleven studies (473 PwSCZ, 416 HCs) were included. Pooled analysis revealed a nonsignificant trend toward increased basal monocytic TLR4 density in PwSCZ (Hedges' g = 0.317 [95% CI: -0.060, 0.694], τ2 = 0.127, I2 = 68.91%). The difference became significant after sensitivity analysis and excluding one study (Hedges' g = 0.469 [0.195,0.742], p = 0.001). No significant difference was found between the groups in terms of TLR4+ monocytes percentage (Hedges' g = 0.235 [-0.245, 0.715], τ2 = 0.31, I2 = 87.30%) or TLR4 gene expression (Hedges' g = 0.179 [-0.502, 0.861], τ2 = 0.29, I2 = 79.04%). According to qualitative synthesis, TLR4 stimulation resulted in reduced monocytic activation in PwSCZ compared to HCs. CONCLUSIONS This study suggested a trend toward an increased basal monocytic TLR4 density in PwSCZ, with no difference in the basal percentage of TLR4+ monocytes or TLR4 gene expression. However, the limited available data underscores the need for future studies.
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Affiliation(s)
- Melika Jameie
- Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sanaz Bordbar
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Samiee
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mobina Amanollahi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Translational Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Azizmohammad Looha
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Sajjad Aleyasin
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Abdol Homayuni
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- NCweb association, Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Mozafar
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Zhou MY, Feng HY, Wang TT, Xu ZS, Gu SL, Li LL, Cai L, Li R. TLR3 as an emerging molecule facilitating pyroptosis in the context of rheumatoid arthritis: A study combined bioinformatics and experimental validation. Cytokine 2025; 187:156875. [PMID: 39884182 DOI: 10.1016/j.cyto.2025.156875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/03/2025] [Accepted: 01/24/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an inflammatory disease of the joints mediated by immune cells. As an immune-related mode of cell death, pyroptosis has yet to be fully understood in RA. This research identified novel pyroptosis-related markers in RA and confirmed its functional significance in RA. METHODS Initially, crucial pyroptosis-related genes of RA were identified through GEO database, and biological pathways were determined through enrichment analysis. Then, PPI network, WGCNA and CIBERSORT analysis was utilized to screen hub genes and evaluate immune cell infiltration levels. Finally, validation experiments determined hub genes expression and regulatory roles in RA pathogenesis, and screened potential therapeutic drugs. RESULTS A total of 46 DEPRGs in RA were identified, which involved in NOD-like receptor and Toll-like receptor signaling pathway. Further screening revealed 3 crucial hub genes: CCL5, LY96, and TLR3 had significantly increased expression in RA synovial tissue and FLS, which might become diagnostic markers of RA. Analysis of immune infiltration revealed that hub genes exhibited associations with plasma cells, T lymphocytes, and macrophages. Further study on the crucial hub gene TLR3 revealed that knocking down TLR3 significantly inhibited the RA FLS hyperproliferation and pyroptosis, and dexamethasone and doxorubicin, as potential drugs, could treat RA by inhibiting TLR3. CONCLUSION Our study indicates that high expression of TLR3 promotes FLS pyroptosis and RA progression, suggesting its potential as both a biomarker and a therapeutic target for RA.
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Affiliation(s)
- Meng-Yuan Zhou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Hong-Yan Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Tian-Tian Wang
- Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Ze-Shan Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Sheng-Long Gu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Ling-Ling Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Li Cai
- Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China.
| | - Rong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui Province, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230026, Anhui Province, China.
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3
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Chung CC, Kao YH, Chen YC, Lin YK, Higa S, Hsu KC, Chen YJ. PCSK9 Enhances Cardiac Fibrogenesis via the Activation of Toll-like Receptor and NLRP3 Inflammasome Signaling. Int J Mol Sci 2025; 26:1921. [PMID: 40076547 PMCID: PMC11900342 DOI: 10.3390/ijms26051921] [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: 01/05/2025] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for reducing low-density lipoprotein cholesterol. PCSK9 activates the atherosclerosis process through pro-inflammation signaling. Furthermore, the serum level of PCSK9 is positively correlated with mortality in patients with heart failure (HF). Cardiac fibrosis plays a crucial role in the pathophysiology of HF. In this study, we intended to examine whether PCSK9 can increase fibroblast activities and explore what its underlying mechanisms are. Migration, proliferation analyses, and Western blotting were used on human cardiac fibroblasts with and without PCSK9. Alirocumab (a PCSK9 inhibitor, 10 mg/kg/week intra-peritoneally for 28 consecutive days) was treated in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. PCSK9 (50, 100 ng/mL) increased proliferation, myofibroblast differentiation capability, and collagen type I production. Compared with control cells, PCSK9 (100 ng/mL)-treated cardiac fibroblasts showed higher nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), interleukin (IL)-1, myofibroblast differentiation, and collagen production capabilities, which were attenuated by MCC950 (an NLRP3 inhibitor, 100 μmol/L). PCSK9 upregulated Myd88 and NF-κB signaling, which were reduced by TAK242 (a toll-like receptor (TLR) 4 inhibitor, 10 μmol/L). Moreover, alirocumab significantly improved left ventricular systolic function and attenuated fibrosis in HF rats. In conclusion, PCSK9 upregulates NLRP3 signaling and the profibrotic activities of cardiac fibroblasts through the activation of TLR4/Myd88/NF-κB signaling.
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Affiliation(s)
- Cheng-Chih Chung
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (Y.-K.L.)
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yung-Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (Y.-K.L.)
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 1199, Japan;
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
| | - Yi-Jen Chen
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (C.-C.C.); (Y.-K.L.)
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
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Son GY, Zou A, Wahl A, Huang KT, Zorgit S, Vinu M, Zhou F, Wagner L, Idaghdour Y, Yule DI, Feske S, Lacruz RS. Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease. FUNCTION 2025; 6:zqae047. [PMID: 39479800 PMCID: PMC11815586 DOI: 10.1093/function/zqae047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/02/2024] [Accepted: 10/28/2024] [Indexed: 11/06/2024] Open
Abstract
Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.
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Affiliation(s)
- Ga-Yeon Son
- Department of Molecular Pathobiology, New York University College of Dentistry, New York 10010, USA
| | - Anna Zou
- Department of Molecular Pathobiology, New York University College of Dentistry, New York 10010, USA
| | - Amanda Wahl
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA
| | - Kai Ting Huang
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA
| | - Saruul Zorgit
- Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates
| | - Manikandan Vinu
- Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates
| | - Fang Zhou
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10010, USA
| | - Larry Wagner
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA
| | - Youssef Idaghdour
- Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates
| | - David I Yule
- Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA
| | - Stefan Feske
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10010, USA
| | - Rodrigo S Lacruz
- Department of Molecular Pathobiology, New York University College of Dentistry, New York 10010, USA
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Maia AR, Gonzalez L, Bounab B, Grassi L, Mousset C, Fromont-Hankard G, Cezard A, Hiemstra P, Baranek T, Paget C, Crabbé A, Si-Tahar M. Intranasal exposure to commensal bacterium Rothia mucilaginosa protects against influenza A virus infection. Antiviral Res 2025; 234:106076. [PMID: 39755332 DOI: 10.1016/j.antiviral.2025.106076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/06/2025]
Abstract
The respiratory tract hosts a diverse microbial community whose composition varies with anatomical location and throughout life. Rothia mucilaginosa, a common commensal of the upper respiratory tract and oral cavity, has recently been recognized for its ability to inhibit bacteria-triggered pro-inflammatory responses. However, its role in modulating the immune response to viral infections such as influenza A virus (IAV) pneumonia, remains unknown. Here, we demonstrate that R. mucilaginosa enhances protection against IAV, promoting viral clearance, reducing inflammation, preserving bronchial and alveolar structures, and improving survival in a mouse model of influenza pneumonia. The enhanced viral clearance observed in R. mucilaginosa-treated mice is associated with the recruitment of innate immune cells to the lungs, including PD-L1-expressing neutrophils, alongside the production of the anti-inflammatory cytokine IL-10, both of which are known to play regulatory roles in the context of IAV infection. Together, these findings highlight R. mucilaginosa-mediated innate immune priming as a key protective mechanism in the respiratory tract against IAV infection.
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Affiliation(s)
- Ana Raquel Maia
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Loïc Gonzalez
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Badreddine Bounab
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Lucia Grassi
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium
| | - Coralie Mousset
- Department of Pathology, CHU of Tours, University of Tours, Tours, France
| | | | - Adeline Cezard
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Pieter Hiemstra
- Department of Pulmonology, Leiden University Medical Centre, Leiden, Netherlands
| | - Thomas Baranek
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Christophe Paget
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France
| | - Aurélie Crabbé
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
| | - Mustapha Si-Tahar
- INSERM, Research Center for Respiratory Diseases, UMR 1100, University of Tours, France.
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Wiger CW, Ranheim T, Arnesen H, Vaage J, Pischke SE, Yndestad A, Stensløkken K, Torp M. TLR4 Inhibition Attenuated LPS-Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes. Immun Inflamm Dis 2025; 13:e70133. [PMID: 39853914 PMCID: PMC11760985 DOI: 10.1002/iid3.70133] [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: 07/09/2024] [Revised: 12/20/2024] [Accepted: 01/07/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll-like receptor 4 (TLR4) can recognize pathogen-associated-molecular-patterns (PAMPs) and damage-associated molecular patterns (DAMPs); the latter are released during tissue injury. We hypothesized that TLR4 inhibition reduces proinflammatory signaling and cytokine release in: (1) LPS or Escherichia coli-treated isolated mouse heart; (2) LPS-treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia-reperfusion. METHODS Isolated C57BL/6N male mouse hearts were perfused for 120 min, with either LPS, E. coli, with and without CLI-095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS + CLI-095. Isolated hearts, exposed to 35 min of global ischemia, were treated with either vehicle or CLI-095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR. RESULTS In isolated hearts, E. coli increased the expression of proinflammatory cytokines (IL-6 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (p = 0.004) and release of IL-6 (p < 0.0001) in LPS-exposed isolated hearts. LPS activated the nuclear-factor κ-light-chain-enhancer of activated B cells signaling pathway (NF-κB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS-induced mRNA expression and release of IL-6 in primary adult cardiomyocytes. Isolated hearts treated with CLI-095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39 ± 17% to 26 ± 8%, p = 0.034) and decreased IL-6 release (p = 0.006). CONCLUSION Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS-treated and ischemia-reperfused isolated mouse hearts and in primary adult murine cardiomyocytes.
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Affiliation(s)
- Christine W. Wiger
- Division of Physiology, Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Trine Ranheim
- Research Institute of Internal Medicine, Oslo University HospitalOsloNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Henriette Arnesen
- Division of Physiology, Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Jarle Vaage
- Division of Physiology, Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
- Department of Research and Innovation, Division of Emergencies and Critical CareOslo University HospitalOsloNorway
| | | | - Arne Yndestad
- Research Institute of Internal Medicine, Oslo University HospitalOsloNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Kåre‐Olav Stensløkken
- Division of Physiology, Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - May‐Kristin Torp
- Division of Physiology, Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
- Østfold Hospital TrustGrålumNorway
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Golino M, Harding D, Del Buono MG, Fanti S, Mohiddin S, Toldo S, Smyth J, Sanna T, Marelli-Berg F, Abbate A. Innate and adaptive immunity in acute myocarditis. Int J Cardiol 2024; 404:131901. [PMID: 38403204 PMCID: PMC11450758 DOI: 10.1016/j.ijcard.2024.131901] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 02/27/2024]
Abstract
Acute myocarditis is an acute inflammatory cardiomyopathy associated with cardiac damage triggered by a virus or a pathological immune activation. It may present with a wide range of clinical presentations, ranging from mild symptoms to severe forms like fulminant myocarditis, characterized by hemodynamic compromise and cardiogenic shock. The immune system plays a central role in the pathogenesis of myocarditis. In fact, while its function is primarily protective, aberrant responses can be detrimental. In this context, both innate and adaptive immunity play pivotal roles; notably, the innate system offers a non-specific and immediate defense, while the adaptive provides specialized protection with immunological memory. However, dysregulation in these systems can misidentify cardiac tissue, triggering autoimmune reactions and possibly leading to significant cardiac tissue damage. This review highlights the importance of innate and adaptive immune responses in the progression and treatment of acute myocarditis.
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Affiliation(s)
- Michele Golino
- Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States of America; Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Daniel Harding
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
| | - Marco Giuseppe Del Buono
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Silvia Fanti
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom
| | - Saidi Mohiddin
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom; Barts Heart Centre, London, United Kingdom
| | - Stefano Toldo
- Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States of America
| | - James Smyth
- Fralin Biomedical Research Institute at Virginia Tech Carillion, Roanoke, VA, United States of America; Virginia Tech Carilion School of Medicine, Roanoke, VA, United States of America; Department of Biological Sciences, College of Science, Virginia Tech, Blacksburg, VA, United States of America
| | - Tommaso Sanna
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Federica Marelli-Berg
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
| | - Antonio Abbate
- Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States of America.
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8
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Fagone P, Mangano K, Basile MS, Munoz-Valle JF, Perciavalle V, Nicoletti F, Bendtzen K. Evaluation of Toll-like Receptor 4 (TLR4) Involvement in Human Atrial Fibrillation: A Computational Study. Genes (Basel) 2024; 15:634. [PMID: 38790263 PMCID: PMC11121426 DOI: 10.3390/genes15050634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
In the present study, we have explored the involvement of Toll-like Receptor 4 (TLR4) in atrial fibrillation (AF), by using a meta-analysis of publicly available human transcriptomic data. The meta-analysis revealed 565 upregulated and 267 downregulated differentially expressed genes associated with AF. Pathway enrichment analysis highlighted a significant overrepresentation in immune-related pathways for the upregulated genes. A significant overlap between AF differentially expressed genes and TLR4-modulated genes was also identified, suggesting the potential role of TLR4 in AF-related transcriptional changes. Additionally, the analysis of other Toll-like receptors (TLRs) revealed a significant association with TLR2 and TLR3 in AF-related gene expression patterns. The examination of MYD88 and TICAM1, genes associated with TLR4 signalling pathways, indicated a significant yet nonspecific enrichment of AF differentially expressed genes. In summary, this study offers novel insights into the molecular aspects of AF, suggesting a pathophysiological role of TLR4 and other TLRs. By targeting these specific receptors, new treatments might be designed to better manage AF, offering hope for improved outcomes in affected patients.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy
| | | | - José Francisco Munoz-Valle
- Institute for Research in Biomedical Sciences, University Center for Health Sciences, University of Guadalajara, Guadalajara 44100, Jalisco, Mexico
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy
| | - Klaus Bendtzen
- Institute for Inflammation Research, Rigshospitalet University Hospital, 2100 Copenhagen, Denmark
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9
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Ninni S, Dombrowicz D, de Winther M, Staels B, Montaigne D, Nattel S. Genetic Factors Altering Immune Responses in Atrial Fibrillation: JACC Review Topic of the Week. J Am Coll Cardiol 2024; 83:1163-1176. [PMID: 38508850 DOI: 10.1016/j.jacc.2023.12.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 03/22/2024]
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with a range of adverse clinical outcomes. Accumulating evidence points to inflammatory processes resulting from innate immune responses as a cornerstone in AF pathogenesis. Genetic and epigenetic factors affecting leukocytes have been identified as key modulators of the inflammatory response. Inherited variants in genes encoding proteins involved in the innate immune response have been associated with increased risk for AF recurrence and stroke in AF patients. Furthermore, acquired somatic mutations associated with clonal hematopoiesis of indeterminate potential, leukocyte telomere shortening, and epigenetic age acceleration contribute to increased AF risk. In individuals carrying clonal hematopoiesis of indeterminate potential, myocardial monocyte-derived macrophage shift toward a proinflammatory phenotype may precipitate AF. Further studies are needed to better understand the role of genetic regulation of the native immune response in atrial arrhythmogenesis and its therapeutic potential as a target for personalized medicine.
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Affiliation(s)
- Sandro Ninni
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France; Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada
| | - David Dombrowicz
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Menno de Winther
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis & Ischemic Syndromes; Amsterdam Infection and Immunity: Inflammatory diseases; Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - David Montaigne
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Stanley Nattel
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center Essen, University Hospital Essen, Essen, Germany; Institut hospitalo-universitaire Liryc and Fondation Bordeaux Université, Bordeaux, France.
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10
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Perkins RK, Lavin KM, Raue U, Jemiolo B, Trappe SW, Trappe TA. Effects of aging and lifelong aerobic exercise on expression of innate immune components in skeletal muscle of women. J Appl Physiol (1985) 2024; 136:482-491. [PMID: 38205547 PMCID: PMC11212804 DOI: 10.1152/japplphysiol.00444.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/12/2024] Open
Abstract
This study examined the effects of aging and lifelong aerobic exercise on innate immune system components in the skeletal muscle of healthy women in the basal state and after an unaccustomed resistance exercise (RE) challenge. We also made exploratory between-sex comparisons with our previous report on men. Three groups of women were studied: young exercisers (YE, n = 10, 25 ± 1 yr, V̇o2max: 44 ± 2 mL/kg/min), lifelong aerobic exercisers with a 48 ± 2 yr training history (LLE, n = 7, 72 ± 2 yr, V̇o2max: 26 ± 2 mL/kg/min), and old healthy nonexercisers (OH, n = 10, 75 ± 1 yr, V̇o2max: 18 ± 1 mL/kg/min). Ten Toll-like receptors (TLRs)1-10, TLR adaptors (Myd88, TRIF), and NF-κB pathway components (IκBα, IKKβ) were assessed at the mRNA level in vastus lateralis biopsies before and 4 h after RE [3×10 repetitions, 70% 1-repetition maximum (1RM)]. Basal TLR1-10 expression was minimally influenced by age or LLE in women (TLR9 only; OH > YE, +43%, P < 0.05; OH > LLE, +30%, P < 0.10) and was on average 24% higher in women versus men. Similarly, basal adaptor expression was not influenced (P > 0.05) by age or LLE in women but was on average 26% higher (myeloid differentiation primary response 88, Myd88) and 23% lower [Toll interleukin (IL)-1 receptor-containing adaptor-inducing interferon-γ, TRIF] in women versus men. RE-induced changes in women, independent of the group, in TLR3, TLR4, TLR6 (∼2.1-fold, P < 0.05), Myd88 (∼1.2-fold, P < 0.10), and IκBα (∼0.3-fold, P < 0.05). Although there were some similar RE responses in men (TLR4: 2.1-fold, Myd88: 1.2-fold, IκBα: 0.4-fold), several components responded only in men to RE (TLR1, TLR8, TRIF, and IKKβ). Our findings support the sexual dimorphism of immunity, with women having greater basal skeletal muscle TLR expression and differential response to unaccustomed exercise than men.NEW & NOTEWORTHY We recently reported that aging increases basal expression of many Toll-like receptors (TLRs) in men and lifelong aerobic exercise does not prevent this effect. In addition, a resistance exercise (RE) challenge increased the expression of many TLRs. Here we show that basal TLR expression is minimally influenced by aging in women and findings support the sexual dimorphism of immunity, with women having greater basal skeletal muscle TLR expression and a differential response to unaccustomed exercise than men.
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Affiliation(s)
- Ryan K Perkins
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
| | - Kaleen M Lavin
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
| | - Ulrika Raue
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
| | - Bozena Jemiolo
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
| | - Scott W Trappe
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
| | - Todd A Trappe
- Human Performance Laboratory, Ball State University, Muncie, Indiana, United States
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11
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Wang A, Uchida K, Yokoyama A, Higashino F, Yasuda M. Human adenovirus oncolytic properties and the inhibitory role of E4 orf4 and E4 orf6/7 on endogenously activated NF-κB. Biochem Biophys Rep 2024; 37:101616. [PMID: 38205184 PMCID: PMC10776911 DOI: 10.1016/j.bbrep.2023.101616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
Human adenovirus is a promising tool for cancer therapy as an oncolytic virus. To predict which region of the oncolytic adenovirus E4 gene could be deleted, we investigated the relationship between the E4 proteins and NF-κB. Here, we report that TLR2-dependent NF-κB activation in Ad5-infected cells was significantly inhibited 24 h post-infection. Among the six E4 proteins, E4 orf4 and E4 orf6/7 exhibited notable suppressive effects on NF-κB activation. However, only E4 orf4 was co-immunoprecipitated with the RelA protein, also known as p65. It appears likely that E4 orf6/7 represses NF-κB activation via E2F-dependent pathways. Our results suggest that both E4 orf4 and E4 orf6/7 are novel inhibitors of NF-κB activation. The inhibition of endogenous NF-κB activation by E4 proteins during the late phase of infection also appears to elucidate the previously reported suppression of E1A expression in the late phase of infection. These redundant suppressive effects of E4 orf4 and E4 orf6/7 on NF-κB suggest that these proteins may play a major role in the anticancer properties of oncolytic adenovirus.
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Affiliation(s)
- Anran Wang
- Department of Oral Functional Prosthodontics, Division of Oral Functional Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Japan
| | - Kazuki Uchida
- Department of Oral and Maxillofacial Surgery, Division of Oral Pathobiological Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Japan
| | - Atsuro Yokoyama
- Department of Oral Functional Prosthodontics, Division of Oral Functional Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Japan
| | - Fumihiro Higashino
- Department of Medical Management and Informatics Medical Management and Informatics Clinical Engineering, Hokkaido Information University, Japan
| | - Motoaki Yasuda
- Department of Oral Molecular Microbiology, Division of Oral Pathobiological Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Japan
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12
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Cicchinelli S, Pignataro G, Gemma S, Piccioni A, Picozzi D, Ojetti V, Franceschi F, Candelli M. PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications. Int J Mol Sci 2024; 25:962. [PMID: 38256033 PMCID: PMC10815927 DOI: 10.3390/ijms25020962] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/31/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed® and Cochrane®. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.
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Affiliation(s)
- Sara Cicchinelli
- Department of Emergency, S.S. Filippo e Nicola Hospital, 67051 Avezzano, Italy;
| | - Giulia Pignataro
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Stefania Gemma
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Andrea Piccioni
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Domitilla Picozzi
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Veronica Ojetti
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Francesco Franceschi
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
| | - Marcello Candelli
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario Agostino Gemelli—IRRCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.P.); (S.G.); (A.P.); (D.P.); (V.O.); (F.F.)
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13
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Son GY, Zou A, Wahl A, Huang KT, Vinu M, Zorgit S, Zhou F, Wagner L, Idaghdour Y, Yule DI, Feske S, Lacruz RS. Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574702. [PMID: 38260625 PMCID: PMC10802497 DOI: 10.1101/2024.01.08.574702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Sjogren's disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca 2+ signals that activate the store operated Ca 2+ entry (SOCE) pathway eliciting sustained Ca 2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca 2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models and its impact on SjD. Here we report that male and female mice lacking Stim1 and Stim2 ( Stim1/2 K14Cre ) in salivary glands showed reduced intracellular Ca 2+ levels via SOCE in parotid acini and hyposalivate upon pilocarpine stimulation. Bulk RNASeq of the parotid glands of Stim1/2 K14Cre mice showed a decrease in the expression of Stim1/2 but no other Ca 2+ associated genes mediating saliva fluid secretion. SOCE was however functionally required for the activation of the Ca 2+ activated chloride channel ANO1. Despite hyposalivation, ageing Stim1/2 K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum, which may be linked to the downregulation of the toll-like receptor 8 ( Tlr8 ). By contrast, salivary gland biopsies of SjD patients showed increased STIM1 and TLR8 expression, and induction of SOCE in a salivary gland cell line increased the expression of TLR8 . Our data demonstrate that SOCE is an important activator of ANO1 function and saliva fluid secretion in salivary glands. They also provide a novel link between SOCE and TLR8 signaling which may explain why loss of SOCE does not result in SjD.
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14
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Fang YD, Liu JY, Xie F, Liu LP, Zeng WW, Wang WH. Antibody preparation and age-dependent distribution of TLR8 in Bactrian camel spleens. BMC Vet Res 2023; 19:276. [PMID: 38104080 PMCID: PMC10725000 DOI: 10.1186/s12917-023-03812-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: 05/19/2023] [Accepted: 11/10/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Toll-like receptor 8 (TLR8) can recognize specific pathogen-associated molecular patterns and exert multiple immunological functions through activation of signaling cascades. However, the precise distribution and age-related alterations of TLR8 in the spleens of Bactrian camels have not yet been investigated. This study aimed to prepare a rabbit anti-Bactrian camel TLR8 polyclonal antibody and elucidate the distribution of TLR8 in the spleens of Bactrian camels at different age groups. The methodology involved the construction of the pET-28a-TLR8 recombinant plasmid, followed by the expression of TLR8 recombinant protein via prokaryotic expression. Subsequently, rabbits were immunized with the purified protein to prepare the TLR8 polyclonal antibody. Finally, twelve Alashan Bactrian camels were categorized into four groups: young (1-2 years), pubertal (3-5 years), middle-aged (6-16 years) and old (17-20 years). These camels received intravenous sodium pentobarbital (20 mg/kg) anesthesia and were exsanguinated to collect spleen samples. Immunohistochemical techniques were employed to observe and analyze the distribution patterns and age-related changes of TLR8 in the spleen. RESULTS The results showed that the TLR8 recombinant protein was expressed in the form of inclusion body with a molecular weight of 52 kDa, and the optimal induction condition involved 0.3 mmol/L IPTG induction for 8 h. The prepared antibody yielded a titer of 1:32 000, and the antibody demonstrated specific binding to TLR8 recombinant protein. TLR8 positive cells exhibited a consistent distribution pattern in the spleen across different age groups of Bactrian camels, primarily scattered within the periarterial lymphatic sheath of the white pulp, marginal zone, and red pulp. The predominant cell type expressing TLR8 was macrophages, with expression also observed in neutrophils and dendritic cells. Statistical analysis revealed that there were significant differences in the distribution density of TLR8 positive cells among different spleen regions at the same age, with the red pulp, marginal zone, and white pulp showing a descending order (P<0.05). Age-related changes indicated that the distribution density in the marginal zone and red pulp exhibited a similar trend of initially increasing and subsequently decreasing from young to old camels. As camels age, there was a significant decrease in the distribution density across all spleen regions (P<0.05). CONCLUSIONS The results confirmed that this study successfully prepared a rabbit anti-Bactrian camel TLR8 polyclonal antibody with good specificity. TLR8 positive cells were predominantly located in the red pulp and marginal zone of the spleen, signifying their pivotal role in the innate immune response of the spleen. Aging was found to significantly reduce the density of TLR8 positive cells, while leaving their scattered distribution characteristics unaffected. These findings provide valuable support for further investigations into the immunomorphology and immunosenescence of the spleen in Bactrian camels.
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Affiliation(s)
- Ying-Dong Fang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jing-Yu Liu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Fei Xie
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Li-Ping Liu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wei-Wei Zeng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wen-Hui Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China.
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15
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Perkins RK, Miranda ER, Varshney P, Farabi SS, Quinn LT, Haus JM. Effects of acute aerobic exercise on circulating sTLR and sRAGE profiles in normal- and abnormal-glucose-tolerant individuals. Physiol Rep 2023; 11:e15859. [PMID: 37985201 PMCID: PMC10659941 DOI: 10.14814/phy2.15859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/11/2023] [Accepted: 10/29/2023] [Indexed: 11/22/2023] Open
Abstract
BMI-matched normal- (NGT, n = 10, 41 ± 4y, 35.6 ± 3.0 kg/m2 ) and abnormal-glucose-tolerant (AGT, n = 16, 51 ± 3y, 34.3 ± 1.5 kg/m2 ) participants were evaluated for body composition, metabolic health (oral glucose tolerance test [OGTT]), and VO2 max. Participants also completed a treadmill walking test at 65% VO2 max for 30 min. Total sRAGE, esRAGE, sTLR2, and sTLR4 were assessed via ELISA, and cRAGE was calculated. AGT exhibited greater (p < 0.05) body fat % (+24%), fasting plasma glucose (+37%), OGTT AUC (+59%), and HOMA-IR (+55%) and lower (p < 0.05) VO2 max (-24%). sTLR2 was 33% lower in AGT than NGT (main effect, p = 0.034). However, sTLR2 did not change (p > 0.05) following AE. sTLR4 tended to be 36% lower in AGT than NGT (main effect, p = 0.096) and did not change following AE (p > 0.05). Total sRAGE and isoforms were similar (p > 0.05) between groups and did not change following AE (p > 0.05). sTLR2 was correlated with (p < 0.05) basal BG (r = -0.505) and OGTT AUC (r = -0.687). sTLR4 was correlated with basal BG (p < 0.10, r = -0.374) and OGTT AUC (p < 0.05, r = -0.402). Linear regressions were predictive of sTLRs in the basal state (sTLR2: R2 = 0.641, p = 0.01; sTLR4: R2 = 0.566, p = 0.037) and after acute exercise state (sTLR2: R2 = 0.681, p = 0.004, sTLR4: R2 = 0.568, p = 0.036).These findings show circulating sTLR profiles are disrupted in AGT and acute AE minimally modulates their levels.
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Affiliation(s)
- Ryan K. Perkins
- Department of KinesiologyCalifornia State University, ChicoChicoCaliforniaUSA
| | | | | | - Sarah S. Farabi
- Center for Human NutritionWashington University School of MedicineSt. LouisMissouriUSA
- Goldfarb School of Nursing at Barnes‐Jewish CollegeSt. LouisMissouriUSA
| | - Lauretta T. Quinn
- Department of Behavioral Health SciencesUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Jacob M. Haus
- School of KinesiologyUniversity of MichiganAnn ArborMichiganUSA
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16
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Robinson TP, Hamidi T, Counts B, Guttridge DC, Ostrowski MC, Zimmers TA, Koniaris LG. The impact of inflammation and acute phase activation in cancer cachexia. Front Immunol 2023; 14:1207746. [PMID: 38022578 PMCID: PMC10644737 DOI: 10.3389/fimmu.2023.1207746] [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: 04/18/2023] [Accepted: 10/13/2023] [Indexed: 12/01/2023] Open
Abstract
The development of cachexia in the setting of cancer or other chronic diseases is a significant detriment for patients. Cachexia is associated with a decreased ability to tolerate therapies, reduction in ambulation, reduced quality of life, and increased mortality. Cachexia appears intricately linked to the activation of the acute phase response and is a drain on metabolic resources. Work has begun to focus on the important inflammatory factors associated with the acute phase response and their role in the immune activation of cachexia. Furthermore, data supporting the liver, lung, skeletal muscle, and tumor as all playing a role in activation of the acute phase are emerging. Although the acute phase is increasingly being recognized as being involved in cachexia, work in understanding underlying mechanisms of cachexia associated with the acute phase response remains an active area of investigation and still lack a holistic understanding and a clear causal link. Studies to date are largely correlative in nature, nonetheless suggesting the possibility for a role for various acute phase reactants. Herein, we examine the current literature regarding the acute phase response proteins, the evidence these proteins play in the promotion and exacerbation of cachexia, and current evidence of a therapeutic potential for patients.
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Affiliation(s)
- Tyler P. Robinson
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Tewfik Hamidi
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Brittany Counts
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Denis C. Guttridge
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Michael C. Ostrowski
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Teresa A. Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
| | - Leonidas G. Koniaris
- Department of Surgery, Oregon Health Sciences University, Portland, OR, United States
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17
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Al-Gazally ME, Khan R, Imran M, Ramírez-Coronel AA, Alshahrani SH, Altalbawy FMA, Turki Jalil A, Romero-Parra RM, Zabibah RS, Shahid Iqbal M, Karampoor S, Mirzaei R. The role and mechanism of action of microRNA-122 in cancer: Focusing on the liver. Int Immunopharmacol 2023; 123:110713. [PMID: 37523968 DOI: 10.1016/j.intimp.2023.110713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 07/08/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023]
Abstract
microRNA-122 (miR-122) is a highly conserved microRNA that is predominantly expressed in the liver and plays a critical role in the regulation of liver metabolism. Recent studies have shown that miR-122 is involved in the pathogenesis of various types of cancer, particularly liver cancer. In this sense, The current findings highlighted the potential role of miR-122 in regulating many vital processes in cancer pathophysiology, including apoptosis, signaling pathway, cell metabolism, immune system response, migration, and invasion. These results imply that miR-122, which has been extensively studied for its biological functions and potential therapeutic applications, acts as a tumor suppressor or oncogene in cancer development. We first provide an overview and summary of the physiological function and mode of action of miR-122 in liver cancer. We will examine the various signaling pathways and molecular mechanisms through which miR-122 exerts its effects on cancer cells, including the regulation of oncogenic and tumor suppressor genes, the modulation of cell proliferation and apoptosis, and the regulation of metastasis. Most importantly, we will also discuss the potential diagnostic and therapeutic applications of miR-122 in cancer, including the development of miRNA-based biomarkers for cancer diagnosis and prognosis, and the potential use of miR-122 as a therapeutic target for cancer treatment.
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Affiliation(s)
| | - Ramsha Khan
- MBBS, Nawaz Sharif Medical College, Gujrat, Pakistan
| | - Muhammad Imran
- MBBS, Multan Medical and Dental College, Multan, Pakistan
| | | | | | - Farag M A Altalbawy
- National Institute of Laser Enhanced Sciences (NILES), University of Cairo, Giza 12613, Egypt; Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla 51001, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, 11942 Alkharj, Saudi Arabia
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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18
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Patlola SR, Donohoe G, McKernan DP. Counting the Toll of Inflammation on Schizophrenia-A Potential Role for Toll-like Receptors. Biomolecules 2023; 13:1188. [PMID: 37627253 PMCID: PMC10452856 DOI: 10.3390/biom13081188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer's, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.
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Affiliation(s)
- Saahithh Redddi Patlola
- Department of Pharmacology & Therapeutics, School of Medicine, University of Galway, H91 TK33 Galway, Ireland;
| | - Gary Donohoe
- School of Psychology, University of Galway, H91 TK33 Galway, Ireland;
| | - Declan P. McKernan
- Department of Pharmacology & Therapeutics, School of Medicine, University of Galway, H91 TK33 Galway, Ireland;
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19
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Lang CH. IMPORTANCE OF THE INNATE IMMUNE RESPONSE IN SKELETAL MUSCLE TO SEPSIS-INDUCED ALTERATIONS IN PROTEIN BALANCE. Shock 2023; 59:214-223. [PMID: 36730901 PMCID: PMC9957944 DOI: 10.1097/shk.0000000000002029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
ABSTRACT There is growing appreciation that skeletal muscle is a fully functional component of the body's innate immune system with the potential to actively participate in the host response to invading bacteria as opposed to being a passive target. In this regard, skeletal muscle in general and myocytes specifically possess an afferent limb that recognizes a wide variety of host pathogens via their interaction with multiple classes of cell membrane-bound and intracellular receptors, including toll-like receptors, cytokine receptors, NOD-like receptors, and the NLRP inflammasome. The efferent limb of the innate immune system in muscle is equally robust and with an increased synthesis and secretion of a variety of myocyte-derived cytokines (i.e., myokines), including TNF-α, IL-1, IL-6, and NO as well as multiple chemokines in response to appropriate stimulation. Herein, the current narrative review focuses primarily on the immune response of myocytes per se as opposed to other cell types within whole muscle. Moreover, because there are important differences, this review focuses specifically on systemic infection and inflammation as opposed to the response of muscle to direct injury and various types of muscular dystrophies. To date, however, there are few definitive muscle-specific studies that are necessary to directly address the relative importance of muscle-derived immune activation as a contributor to either the systemic immune response or the local immune microenvironment within muscle during sepsis and the resultant downstream metabolic disturbances.
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Affiliation(s)
- Charles H Lang
- Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania
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20
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Zhou J, Lin H, Lv T, Hao J, Zhang H, Sun S, Yang J, Chi J, Guo H. Inappropriate Activation of TLR4/NF-κB is a Cause of Heart Failure. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2022. [DOI: 10.15212/cvia.2022.0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Significance: Heart failure, a disease with extremely high incidence, is closely associated with inflammation and oxidative stress. The Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway plays an important role in the occurrence and development of heart failure.
Recent advances: Previous studies have shown that TLR4/NF-κB causes heart failure by inducing oxidative stress and inflammation; damaging the endothelia; promoting fibrosis; and inducing myocardial hypertrophy, apoptosis, pyroptosis, and autophagy.
Critical issues: Understanding the pathogenesis of heart failure is essential for the treatment of this disease. In this review, we outline the mechanisms underlying TLR4/NF-κB pathway-mediated heart failure and discuss drugs that alleviate heart failure by regulating the TLR4/NF-κB pathway.
Future directions: During TLR4/NF-κB overactivation, interventions targeting specific receptor antagonists may effectively alleviate heart failure, thus providing a basis for the development of new anti-heart failure drugs.
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Affiliation(s)
- Jiedong Zhou
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Hui Lin
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Tingting Lv
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jinjin Hao
- Zhejiang University School of Medicine, Hangzhou, China
| | - Hanlin Zhang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Shimin Sun
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Juntao Yang
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jufang Chi
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Hangyuan Guo
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
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21
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Ciaston I, Dobosz E, Potempa J, Koziel J. The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases. Mol Aspects Med 2022; 88:101143. [PMID: 36152458 PMCID: PMC9924004 DOI: 10.1016/j.mam.2022.101143] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/29/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs). The recognition of specific microbial ligands by TLRs triggers an innate immune response and also promotes adaptive immunity, which is necessary for the efficient elimination of invading pathogens. Successful pathogens have therefore evolved strategies to subvert and/or manipulate TLR signaling. Both the impairment and uncontrolled activation of TLR signaling can harm the host, causing tissue destruction and allowing pathogens to proliferate, thus favoring disease progression. In this context, microbial proteases are key virulence factors that modify components of the TLR signaling pathway. In this review, we discuss the role of bacterial and viral proteases in the manipulation of TLR signaling, highlighting the importance of these enzymes during the development of infectious diseases.
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Affiliation(s)
- Izabela Ciaston
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Oral Health and Systemic Disease, University of Louisville School of Dentistry, University of Louisville, Louisville, KY, USA.
| | - Joanna Koziel
- Department of Microbiology Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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22
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Clerbaux LA, Albertini MC, Amigó N, Beronius A, Bezemer GFG, Coecke S, Daskalopoulos EP, del Giudice G, Greco D, Grenga L, Mantovani A, Muñoz A, Omeragic E, Parissis N, Petrillo M, Saarimäki LA, Soares H, Sullivan K, Landesmann B. Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework. J Clin Med 2022; 11:4464. [PMID: 35956081 PMCID: PMC9369763 DOI: 10.3390/jcm11154464] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 12/10/2022] Open
Abstract
Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.
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Affiliation(s)
- Laure-Alix Clerbaux
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | | | - Núria Amigó
- Biosfer Teslab SL., 43204 Reus, Spain;
- Department of Basic Medical Sciences, Universitat Rovira i Virgili (URV), 23204 Reus, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Anna Beronius
- Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden;
| | - Gillina F. G. Bezemer
- Impact Station, 1223 JR Hilversum, The Netherlands;
- Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Sandra Coecke
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Evangelos P. Daskalopoulos
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Giusy del Giudice
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Dario Greco
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SPI, F-30200 Bagnols-sur-Ceze, France;
| | - Alberto Mantovani
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Amalia Muñoz
- European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium;
| | - Elma Omeragic
- Faculty of Pharmacy, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
| | - Nikolaos Parissis
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Mauro Petrillo
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
| | - Laura A. Saarimäki
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland; (G.d.G.); (D.G.); (L.A.S.)
| | - Helena Soares
- Laboratory of Immunobiology and Pathogenesis, Chronic Diseases Research Centre, Faculdade de Ciências Médicas Medical School, University of Lisbon, 1649-004 Lisbon, Portugal;
| | - Kristie Sullivan
- Physicians Committee for Responsible Medicine, Washington, DC 20016, USA;
| | - Brigitte Landesmann
- European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy; (S.C.); (E.P.D.); (N.P.); (M.P.); (B.L.)
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23
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Chun KH. Molecular Targets and Signaling Pathways of microRNA-122 in Hepatocellular Carcinoma. Pharmaceutics 2022; 14:1380. [PMID: 35890276 PMCID: PMC9316959 DOI: 10.3390/pharmaceutics14071380] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading global causes of cancer mortality. MicroRNAs (miRNAs) are small interfering RNAs that alleviate the levels of protein expression by suppressing translation, inducing mRNA cleavage, and promoting mRNA degradation. miR-122 is the most abundant miRNA in the liver and is responsible for several liver-specific functions, including metabolism, cellular growth and differentiation, and hepatitis virus replication. Recent studies have shown that aberrant regulation of miR-122 is a key factor contributing to the development of HCC. In this review, the signaling pathways and the molecular targets of miR-122 involved in the progression of HCC have been summarized, and the importance of miR-122 in therapy has been discussed.
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Affiliation(s)
- Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Korea
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24
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Understanding the Immune System in Fetal Protection and Maternal Infections during Pregnancy. J Immunol Res 2022; 2022:7567708. [PMID: 35785037 PMCID: PMC9249541 DOI: 10.1155/2022/7567708] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 05/20/2022] [Indexed: 11/18/2022] Open
Abstract
The fetal-maternal immune system determines the fate of pregnancy. The trophoblast cells not only give an active response against external stimuli but are also involved in secreting most of the cytokines. These cells have an essential function in fetal acceptance or fetal rejection. Other immune cells also play a pivotal role in carrying out a successful pregnancy. The disruption in this mechanism may lead to harmful effects on pregnancy. The placenta serves as an immune barrier in fetus protection against invading pathogens. Once the infections prevail, they may localize in placental and fetal tissues, and the presence of inflammation due to cytokines may have detrimental effects on pregnancy. Moreover, some pathogens are responsible for congenital fetal anomalies and affect almost all organs of the developing fetus. This review article is designed to address the bacterial and viral infections that threaten pregnancy and their possible outcomes. Moreover, training of the fetal immune system against the exposure of infections and the role of CD49a + NK cells in embryonic development will also be highlighted.
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25
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Martín-Medina A, Cerón-Pisa N, Martinez-Font E, Shafiek H, Obrador-Hevia A, Sauleda J, Iglesias A. TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer. Int J Mol Sci 2022; 23:6539. [PMID: 35742983 PMCID: PMC9224119 DOI: 10.3390/ijms23126539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023] Open
Abstract
The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.
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Affiliation(s)
- Aina Martín-Medina
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Noemi Cerón-Pisa
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Esther Martinez-Font
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Medical Oncology Department, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Hanaa Shafiek
- Chest Diseases Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
| | - Antònia Obrador-Hevia
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Molecular Diagnosis Unit, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Jaume Sauleda
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Department of Respiratory Medicine, Hospital Universitario Son Espases, 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Amanda Iglesias
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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26
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Horn KJ, Schopper MA, Drigot ZG, Clark SE. Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung. Nat Commun 2022; 13:3321. [PMID: 35680890 PMCID: PMC9184549 DOI: 10.1038/s41467-022-31074-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 05/31/2022] [Indexed: 12/13/2022] Open
Abstract
This study investigates how specific members of the lung microbiome influence the early immune response to infection. Prevotella species are a major component of the endogenous airway microbiota. Increased abundance of Prevotella melaninogenica correlates with reduced infection with the bacterial pathogen Streptococcus pneumoniae, indicating a potentially beneficial role. Here, we show that P. melaninogenica enhances protection against S. pneumoniae, resulting in rapid pathogen clearance from the lung and improved survival in a mouse lung co-infection model. This response requires recognition of P. melaninogenica lipoproteins by toll-like receptor (TLR)2, the induction of TNFα, and neutrophils, as the loss of any of these factors abrogates Prevotella-induced protection. Improved clearance of S. pneumoniae is associated with increased serine protease-mediated killing by lung neutrophils and restraint of P. melaninogenica-induced inflammation by IL-10 in co-infected mice. Together, these findings highlight innate immune priming by airway Prevotella as an important protective feature in the respiratory tract. How the airway microbiome protects against bacterial pneumonia remains unclear. Here, the authors identify airway bacterial species that activate the immune system to facilitate rapid clearance of the pathogen Streptococcus pneumoniae from the lung.
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Affiliation(s)
- Kadi J Horn
- University of Colorado School of Medicine, Department of Otolaryngology, Aurora, CO, 80045, USA
| | - Melissa A Schopper
- University of Colorado School of Medicine, Department of Otolaryngology, Aurora, CO, 80045, USA
| | - Zoe G Drigot
- University of Colorado School of Medicine, Department of Otolaryngology, Aurora, CO, 80045, USA.,University of Colorado Boulder, College of Arts and Sciences, Boulder, CO, 80309, USA
| | - Sarah E Clark
- University of Colorado School of Medicine, Department of Otolaryngology, Aurora, CO, 80045, USA.
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27
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Mekonnen TW, Darge HF, Tsai HC, Birhan YS, Hanurry EY, Gebrie HT, Chou HY, Lai JY, Lin SZ, Harn HJ, Chen YS. Combination of ovalbumin-coated iron oxide nanoparticles and poly(amidoamine) dendrimer-cisplatin nanocomplex for enhanced anticancer efficacy. Colloids Surf B Biointerfaces 2022; 213:112391. [PMID: 35158218 DOI: 10.1016/j.colsurfb.2022.112391] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/10/2022] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
Enhancement of drug efficacy is essential in cancer treatment. The immune stimulator ovalbumin (Ova)-coated citric acid (AC-)-stabilized iron oxide nanoparticles (AC-IO-Ova NPs) and enhanced permeability and retention (EPR)-based tumor targeted 4.5 generation poly(amidoamine) dendrimer(4.5GDP)-cisplatin (Cis-pt) nanocomplex (NC) (4.5GDP-Cis-pt NC) were used for enhanced anticancer efficiency. The formations of 4.5GDP-Cis-pt NC, AC-IO, and AC-IO-Ova NPs were examined via FTIR spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The conjugation of Cis-pt with 4.5GDP was confirmed using carbon NMR spectroscopy. The tumor-specific 4.5GDP-Cis-pt NC provided 45%and 28% cumulative cisplatin release in 72 h at pH 6.5 and 7.4, respectively. A significant immune response with high TNF-α and IL-6 cytokine secretion was confirmed for the co-incubation of AC-IO-Ova with RAW 264.7 or HaCaT cells. AC-IO-Ova NPs were biocompatible with different cell lines, even at a high concentration (200 µg mL-1). However, AC-IO-Ova NPs mixed with 4.5GDP-Cis-pt NC (Cis-pt at 15 µg mL-1) significantly increased the cytotoxicity against the cancer cells in a dose-dependent manner with the increasing AC-IO-Ova NPs concentrations. The increased anticancer effects may be attributed to the generation of reactive oxygen species (ROS). Moreover, AC-IO-Ova NPs might assist the efficiency of anticancer cells, inducing an innate immune response via M1 macrophage polarization. We provide a novel synergistic chemoimmunotherapeutic strategy to enhance the anticancer efficacy of cisplatin via a chemotherapeutic agent 4.5GDP-Cis-pt NC and induce proinflammatory cytokines stimulating innate immunity through AC-IO-Ova NPs against tumors.
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Affiliation(s)
- Tefera Worku Mekonnen
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Haile Fentahun Darge
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Hsieh-Chih Tsai
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan, ROC.
| | - Yihenew Simegniew Birhan
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Endiries Yibru Hanurry
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Hailemichael Tegenu Gebrie
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Hsiao-Ying Chou
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Juin-Yih Lai
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan, ROC; Department of Chemical Engineering & Materials Science, Yuan Ze University, Chungli, Taoyuan 320, Taiwan, ROC
| | - Shinn-Zong Lin
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Horng-Jyh Harn
- Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Yu-Shuan Chen
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Taiwan, ROC; Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC; Tzu Chi University of Science and Technology, Taiwan, ROC.
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28
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Sanchez-Petidier M, Guerri C, Moreno-Manzano V. Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells. Stem Cell Res Ther 2022; 13:117. [PMID: 35314006 PMCID: PMC8935849 DOI: 10.1186/s13287-022-02798-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 03/07/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Toll-like receptors (TLRs) represent critical effectors in the host defense response against various pathogens; however, their known function during development has also highlighted a potential role in cell fate determination and neural differentiation. While glial cells and neural precursor cells (NPCs) of the spinal cord express both TLR2 and TLR4, their influence on self-renewal and cell differentiation remains incompletely described. METHODS TLR2, TLR4 knock-out and the wild type mice were employed for spinal cord tissue analysis and NPCs isolation at early post-natal stage. Sox2, FoxJ1 and Ki67 expression among others served to identify the undifferentiated and proliferative NPCs; GFAP, Olig2 and β-III-tubulin markers served to identify astrocytes, oligodendrocytes and neurons respectively after NPC spontaneous differentiation. Multiple comparisons were analyzed using one-way ANOVA, with appropriate corrections such as Tukey's post hoc tests used for comparisons. RESULTS We discovered that the deletion of TLR2 or TLR4 significantly reduced the number of Sox2-expressing NPCs in the neonatal mouse spinal cord. While TLR2-knockout NPCs displayed enhanced self-renewal, increased proliferation and apoptosis, and delayed neural differentiation, the absence of TLR4 promoted the neural differentiation of NPCs without affecting proliferation, producing long projecting neurons. TLR4 knock-out NPCs showed significantly higher expression of Neurogenin1, that would be involved in the activation of this neurogenic program by a ligand and microenvironment-independent mechanism. Interestingly, the absence of both TLR2 and TLR4, which induces also a significant reduction in the expression of TLR1, in NPCs impeded oligodendrocyte precursor cell maturation to a similar degree. CONCLUSIONS Our data suggest that Toll-like receptors are needed to maintain Sox2 positive neural progenitors in the spinal cord, however possess distinct regulatory roles in mouse neonatal spinal cord NPCs-while TLR2 and TLR4 play a similar role in oligodendrocytic differentiation, they differentially influence neural differentiation.
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Affiliation(s)
- Marina Sanchez-Petidier
- Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Institute, Valencia, Spain.,Neuropathology Laboratory, Prince Felipe Research Institute, Valencia, Spain
| | - Consuelo Guerri
- Neuropathology Laboratory, Prince Felipe Research Institute, Valencia, Spain.
| | - Victoria Moreno-Manzano
- Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Institute, Valencia, Spain.
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29
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Fitzpatrick JM, Hackett B, Costelloe L, Hind W, Downer EJ. Botanically-Derived Δ 9-Tetrahydrocannabinol and Cannabidiol, and Their 1:1 Combination, Modulate Toll-like Receptor 3 and 4 Signalling in Immune Cells from People with Multiple Sclerosis. Molecules 2022; 27:1763. [PMID: 35335126 PMCID: PMC8951523 DOI: 10.3390/molecules27061763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 11/29/2022] Open
Abstract
The innate immune response to bacterial and viral molecules involves the coordinated production of cytokines, chemokines, and type I interferons (IFNs), which is orchestrated by toll-like receptors (TLRs). TLRs, and their intracellular signalling intermediates, are closely associated with multiple sclerosis (MS) pathogenesis. Recent data from our laboratory reported that the plant-derived cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), regulate viral and bacterial inflammatory signalling pathways controlled by TLR3 and TLR4 in macrophages. The aim of this study was to assess the impact of THC and CBD, when delivered in isolation and in combination (1:1), on TLR3- and TLR4-dependent signalling in peripheral blood mononuclear cells (PBMCs) from people with MS (pwMS; n = 21) and healthy controls (HCs; n = 26). We employed the use of poly(I:C) and lipopolysaccharide (LPS) to induce viral TLR3 and bacterial TLR4 signalling, and PBMCs were pre-exposed to plant-derived highly purified THC (10 μM), CBD (10 μM), or a combination of both phytocannabinoids (1:1 ratio, 10:10 μM), prior to LPS/poly(I:C) exposure. TLR3 stimulation promoted the protein expression of the chemokine CXCL10 and the type I IFN-β in PBMCs from both cohorts. THC and CBD (delivered in 1:1 combination at 10 μM) attenuated TLR3-induced CXCL10 and IFN-β protein expression in PBMCs from pwMS and HCs, and this effect was not seen consistently when THC and CBD were delivered alone. In terms of LPS, TLR4 activation promoted TNF-α expression in PBMCs from both cohorts, and, interestingly, CBD when delivered alone at 10 μM, and in combination with THC (in 1:1 combination at 10 μM), exacerbated TLR4-induced TNF-α protein expression in PBMCs from pwMS and HCs. THC and CBD displayed no evidence of toxicity in primary PBMCs. No significant alteration in the relative expression of TLR3 and TLR4 mRNA, or components of the endocannabinoid system, including the cannabinoid receptor CB1 (encoded by CNR1 gene) and CB2 (encoded by CNR2 gene), and endocannabinoid metabolising enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL), was determined in PBMCs from pwMS versus HCs. Given their role in inflammation, TLRs are clinical targets, and data herein identify CBD and THC as TLR3 and TLR4 modulating drugs in primary immune cells in vitro. This offers insight on the cellular target(s) of phytocannabinoids in targeting inflammation in the context of MS.
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Affiliation(s)
- John-Mark Fitzpatrick
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, D02 R590 Dublin, Ireland; (J.-M.F.); (B.H.)
| | - Becky Hackett
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, D02 R590 Dublin, Ireland; (J.-M.F.); (B.H.)
| | - Lisa Costelloe
- Department of Neurology, Beaumont Hospital, D09 V2N0 Dublin, Ireland;
| | - William Hind
- GW Research Ltd., Sovereign House, Vision Park, Histon CB24 9BZ, UK;
| | - Eric J. Downer
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, D02 R590 Dublin, Ireland; (J.-M.F.); (B.H.)
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Luo W, Ye L, Hu XT, Wang MH, Wang MX, Jin LM, Xiao ZX, Qian JC, Wang Y, Zuo W, Huang LJ, Liang G. MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease. Clin Transl Med 2022; 12:e777. [PMID: 35343085 PMCID: PMC8958353 DOI: 10.1002/ctm2.777] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. METHODS Wild-type, Md2-/- and bone marrow reconstitution mice fed with high-fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA-seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. RESULTS Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD-mediated suppression of AMP-activated protein kinase (AMPK). This preservation of AMPK in Md2-deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2-increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. CONCLUSION Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1-AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non-inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.
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Affiliation(s)
- Wu Luo
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Lin Ye
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xue-Ting Hu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Mei-Hong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Min-Xiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lei-Ming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhong-Xiang Xiao
- Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing, China
| | - Jian-Chang Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wei Zuo
- Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing, China
| | - Li-Jiang Huang
- Affiliated Xiangshan Hospital, Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, China
| | - Guang Liang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
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Edlinger C, Paar V, Kheder SH, Krizanic F, Lalou E, Boxhammer E, Butter C, Dworok V, Bannehr M, Hoppe UC, Kopp K, Lichtenauer M. Endothelialization and Inflammatory Reactions After Intracardiac Device Implantation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:1-22. [DOI: 10.1007/5584_2022_712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Center SA, Randolph JF, Warner KL, McDonough SP, Lucy JM, Sapa KC. Bacterial culture and immunohistochemical detection of bacteria and endotoxin in cats with suppurative cholangitis-cholangiohepatitis syndrome. J Am Vet Med Assoc 2021; 260:194-211. [PMID: 34936576 DOI: 10.2460/javma.20.10.0552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To characterize the frequency and type of bacterial infection by culture- and immunohistochemical (IHC)-based methods and determine the impact of infection on clinical features and survival time in cats with suppurative cholangitis-cholangiohepatitis syndrome (S-CCHS). ANIMALS 168 client-owned cats with S-CCHS (cases). PROCEDURES Clinical features, bacterial culture results, culture-inoculate sources, and survival details were recorded. Cases were subcategorized by comorbidity (extrahepatic bile duct obstruction, cholelithiasis, cholecystitis, ductal plate malformation, biopsy-confirmed inflammatory bowel disease, and biopsy-confirmed pancreatitis) or treatment by cholecystectomy or cholecystoenterostomy. Culture results, bacterial isolates, Gram-stain characteristics, and IHC staining were compared among comorbidities. Lipoteichoic acid IHC staining detected gram-positive bacterial cell wall components, and toll-like receptor expression IHC reflected pathologic endotoxin (gram-negative bacteria) exposure. RESULTS Clinical features were similar among cases except for more frequent abdominal pain and lethargy in cats with positive culture results and pyrexia, abdominal pain, and hepatomegaly for cats with polymicrobial infections. Bacteria were cultured in 93 of 135 (69%) cats, with common isolates including Enterococcus spp and Escherichia coli. IHC staining was positive in 142 of 151 (94%) cats (lipoteichoic acid, 107/142 [75%]; toll-like receptor 4, 99/142 [70%]). With in-parallel interpretation of culture and IHC-based bacterial detection, 154 of 166 (93%) cats had bacterial infections (gram-positive, 118/154 [77%]; gram-negative, 111/154 [72%]; polymicrobial, 79/154 [51%]). Greater frequency of bacterial isolation occurred with combined tissue, bile, and crushed cholelith inoculates. Infection and gram-positive bacterial isolates were associated with significantly shorter long-term survival times. CLINICAL RELEVANCE S-CCHS was associated with bacterial infection, pathologic endotoxin exposure, and frequent polymicrobial infection in cats. Combined tissue inoculates improved culture detection of associated bacteria.
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Affiliation(s)
- Sharon A Center
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - John F Randolph
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Karen L Warner
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Sean P McDonough
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | | | - Kirk C Sapa
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
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The effect of toll-like receptor ligands on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. Sci Rep 2021; 11:24219. [PMID: 34930972 PMCID: PMC8688447 DOI: 10.1038/s41598-021-03730-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 12/09/2021] [Indexed: 12/25/2022] Open
Abstract
Skeletal muscle plays an important role in glycaemic control and metabolic homeostasis, making it a tissue of interest with respect to type 2 diabetes mellitus. The aim of the present study was to determine if ligands of Toll-like receptors (TLRs) could have an impact on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. The myotubes expressed mRNA for TLRs 1–6. TLR3, TLR4, TLR5 and TLR6 ligands (TLRLs) increased glucose metabolism. Furthermore, TLR4L and TLR5L increased oleic acid metabolism. The metabolic effects of TLRLs were not evident until after at least 24 h pre-incubation of the cells and here the metabolic effects were more evident for the metabolism of glucose than oleic acid, with a shift towards effects on oleic acid metabolism after chronic exposure (168 h). However, the stimulatory effect of TLRLs on myokine expression and secretion was detected after only 6 h, where TLR3-6L stimulated secretion of interleukin-6 (IL-6). TLR5L also increased secretion of interleukin-8 (IL-8), while TLR6L also increased secretion of granulocyte–macrophage colony stimulating factor (GM-CSF). Pre-incubation of the myotubes with IL-6 for 24 h increased oleic acid oxidation but had no effect on glucose metabolism. Thus IL-6 did not mimic all the metabolic effects of the TLRLs, implying metabolic effects beyond the actions of this myokine.
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Kwon J, Suessmilch M, McColl A, Cavanagh J, Morris BJ. Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk. Sci Rep 2021; 11:23841. [PMID: 34903784 PMCID: PMC8668921 DOI: 10.1038/s41598-021-03216-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.
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Affiliation(s)
- Jaedeok Kwon
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
- Institute of Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Maria Suessmilch
- Institute of Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Alison McColl
- Institute of Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Jonathan Cavanagh
- Institute of Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | - Brian J Morris
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
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Bayer AL, Alcaide P. MyD88: At the heart of inflammatory signaling and cardiovascular disease. J Mol Cell Cardiol 2021; 161:75-85. [PMID: 34371036 PMCID: PMC8629847 DOI: 10.1016/j.yjmcc.2021.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease is a leading cause of death worldwide and is associated with systemic inflammation. In depth study of the cell-specific signaling mechanisms mediating the inflammatory response is vital to improving anti-inflammatory therapies that reduce mortality and morbidity. Cellular damage in the cardiovascular system results in the release of damage associated molecular patterns (DAMPs), also known as "alarmins," which activate myeloid cells through the adaptor protein myeloid differentiation primary response 88 (MyD88). MyD88 is broadly expressed in most cell types of the immune and cardiovascular systems, and its role often differs in a cardiovascular disease context and cell specific manner. Herein we review what is known about MyD88 in the setting of a variety of cardiovascular diseases, discussing cell specific functions and the relative contributions of MyD88-dependent vs. independent alarmin triggered inflammatory signaling. The widespread involvement of these pathways in cardiovascular disease, and their largely unexplored complexity, sets the stage for future in depth mechanistic studies that may place MyD88 in both immune and non-immune cell types as an attractive target for therapeutic intervention in cardiovascular disease.
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Affiliation(s)
- Abraham L Bayer
- Department of Immunology, Tufts University School of Medicine. 136 Harrison Ave, Boston, MA 02111, United States of America.
| | - Pilar Alcaide
- Department of Immunology, Tufts University School of Medicine. 136 Harrison Ave, Boston, MA 02111, United States of America.
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Toll-Like Receptors as Drug Targets in the Intestinal Epithelium. Handb Exp Pharmacol 2021; 276:291-314. [PMID: 34783909 DOI: 10.1007/164_2021_563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Toll-like receptors (TLRs) receptors are responsible for initiation of inflammatory responses by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) or in molecules released following tissue damage in disease states. Expressed in the intestinal epithelium, they initiate an intracellular signalling cascade in response to molecular patterns resulting in the activation of transcription factors and the release of cytokines, chemokines and vasoactive molecules. Intestinal epithelial cells are exposed to microorganisms on a daily basis and form part of the primary defence against pathogens by using TLRs. TLRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. TLRs have more recently been associated with chronic inflammatory diseases as a result of inappropriate regulation, this can be damaging and lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Targeting Toll-like receptors offers a potential therapeutic approach for IBD. In this review, the current knowledge on the TLRs is reviewed along with their association with intestinal diseases. Finally, compounds that target TLRs in animal models of IBD, clinic trials and their future merit as targets are discussed.
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TLR Signaling in Brain Immunity. Handb Exp Pharmacol 2021; 276:213-237. [PMID: 34761292 DOI: 10.1007/164_2021_542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Toll-like receptors (TLRs) comprise a group of transmembrane proteins with crucial roles in pathogen recognition, immune responses, and signal transduction. This family represented the first line of immune homeostasis in an evolutionarily conserved manner. Extensive researches in the past two decades had emphasized their structural and functional characteristics under both healthy and pathological conditions. In this review, we summarized the current understanding of TLR signaling in the central nervous system (CNS), which had been viewed as a previously "immune-privileged" but now "immune-specialized" area, with major implications for further investigation of pathological nature as well as potential therapeutic manipulation of TLR signaling in various neurological disorders.
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Dubuisson N, Versele R, Davis-López de Carrizosa MA, Selvais CM, Brichard SM, Abou-Samra M. Walking down Skeletal Muscle Lane: From Inflammasome to Disease. Cells 2021; 10:cells10113023. [PMID: 34831246 PMCID: PMC8616386 DOI: 10.3390/cells10113023] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/14/2022] Open
Abstract
Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders.
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Affiliation(s)
- Nicolas Dubuisson
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
- Neuromuscular Reference Center, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium
- Correspondence:
| | - Romain Versele
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - María A. Davis-López de Carrizosa
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain
| | - Camille M. Selvais
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - Sonia M. Brichard
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
| | - Michel Abou-Samra
- Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, Université Catholique de Louvain, 1200 Brussels, Belgium; (R.V.); (M.A.D.-L.d.C.); (C.M.S.); (S.M.B.); (M.A.-S.)
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Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021; 284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
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Dogra SK, Cheong Kwong C, Wang D, Sakwinska O, Colombo Mottaz S, Sprenger N. Nurturing the Early Life Gut Microbiome and Immune Maturation for Long Term Health. Microorganisms 2021; 9:2110. [PMID: 34683431 PMCID: PMC8537230 DOI: 10.3390/microorganisms9102110] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 12/21/2022] Open
Abstract
Early life is characterized by developmental milestones such as holding up the head, turning over, sitting up and walking that are typically achieved sequentially in specific time windows. Similarly, the early gut microbiome maturation can be characterized by specific temporal microorganism acquisition, colonization and selection with differential functional features over time. This orchestrated microbial sequence occurs from birth during the first years of age before the microbiome reaches an adult-like composition and function between 3 and 5 years of age. Increasingly, these different steps of microbiome development are recognized as crucial windows of opportunity for long term health, primarily linked to appropriate immune and metabolic development. For instance, microbiome disruptors such as preterm and Cesarean-section birth, malnutrition and antibiotic use are associated with increased risk to negatively affect long-term immune and metabolic health. Different age discriminant microbiome taxa and functionalities are used to describe age-appropriate microbiome development, and advanced modelling techniques enable an understanding and visualization of an optimal microbiome maturation trajectory. Specific microbiome features can be related to later health conditions, however, whether such features have a causal relationship is the topic of intense research. Early life nutrition is an important microbiome modulator, and 'Mother Nature' provides the model with breast milk as the sole source of nutrition for the early postnatal period, while dietary choices during the prenatal and weaning period are to a large extent guided by tradition and culture. Increasing evidence suggests prenatal maternal diet and infant and child nutrition impact the infant microbiome trajectory and immune competence development. The lack of a universal feeding reference for such phases represents a knowledge gap, but also a great opportunity to provide adequate nutritional guidance to maintain an age-appropriate microbiome for long term health. Here, we provide a narrative review and perspective on our current understanding of age-appropriate microbiome maturation, its relation to long term health and how nutrition shapes and influences this relationship.
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Affiliation(s)
| | | | | | | | | | - Norbert Sprenger
- Nestlé Institute of Health Sciences, Société des Produits Nestlé S.A., 1000 Lausanne 26, Switzerland; (S.K.D.); (K.C.C.); (D.W.); (O.S.); (S.C.M.)
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Jia Y, Zhang L, Liu X, Zhang S, Dai J, Huang J, Chen J, Wang Y, Zhou J, Zeng Z. Selenium can regulate the differentiation and immune function of human dendritic cells. Biometals 2021; 34:1365-1379. [PMID: 34599706 DOI: 10.1007/s10534-021-00347-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/26/2021] [Indexed: 01/30/2023]
Abstract
Selenium is an essential trace element that can regulate the function of immnue cells via selenoproteins. However, the effects of selenium on human dendritic cell (DCs) remain unclear. Thus, selenoprotein levels in monocytes, immature DCs (imDCs) and mature DCs (mDCs) treated with or without Na2SeO3 were evaluated using RT-PCR, and then the immune function of imDCs and mDCs was detected by flow cytometry, cell counting and the CCK8 assay. In addition, the effects of Se on cytokine and surface marker expression were investigated by RT-PCR. The results revealed different expression levels of selenoprotein in monocytes, imDCs and mDCs, and selenoproeins could be regulated by Se. Moreover, it was indicated that anti-phagocytic activity was improved by 0.1 µM Se, whereas it was suppressed by 0.2 µM Se in imDCs; The migration of imDCs and mDCs was improved by 0.1 µM Se, whereas their migration was inhibited by treatment with 0.05 or 0.2 µM Se; The mixed lymphocyte reaction of mDCs was improved by 0.1 µM Se, and it was inhibited by 0.05 and 0.2 µM Se. In addition, 0.1 µM Se improved the immune function of DCs through the regulation of CD80, CD86, IL12-p35 and IL12-p40. Wheres 0.05 and 0.2 µM Se impaired immune function of DCs by up-regulation of interleukin (IL-10) in imDCs and down-regulation of CD80, CD86, IL12-p35 and IL12-p40 in mDCs. In conclusion, 0.1 µM Se might improve the immune function of human DCs through selenoproteins.
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Affiliation(s)
- Yi Jia
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
| | - Liangliang Zhang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Xianmei Liu
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Shichao Zhang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Jie Dai
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Jiangtao Huang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Jin Chen
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Yun Wang
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Basic Medical Science, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Jing Zhou
- Immune Cells and Antibody Engineering Research Center of Guizhou Province/Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China
| | - Zhu Zeng
- School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
- School of Basic Medical Science, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
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Pakfetrat Z, Janfeshan S, Masjedi F, Rafiei M, Karimi Z. Involvement of oxidative stress and toll-like receptor-4 signaling pathways in gentamicin-induced nephrotoxicity in male Sprague Dawley rats. Drug Chem Toxicol 2021; 45:2568-2575. [PMID: 34538191 DOI: 10.1080/01480545.2021.1977024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Gentamicin (GM) is an antibiotic belonging to an aminoglycoside family that might induce nephrotoxicity in human and animal models via oxidative stress. Toll-like receptors (TLRs) are part of innate immune systems that participate in inflammatory responses. In this regard, we investigated the effect of GM on kidney functional and structural parameters, enzymatic antioxidant levels, and mRNA expression of TLR4 and IL6 in the rat kidney. Adult male Sprague Dawley rats were randomly divided into two groups (n = 10): Control and Gentamicin (100 mg/kg, i.p.). After ten days of GM administration, a blood sample was taken, and the kidneys were removed. The serum levels of creatinine (Cr) and blood urea nitrogen (BUN) were measured. Furthermore, the right kidney was preserved in formalin 10% for hematoxylin and eosin (H&E) staining, and the left kidney was kept at -80 °C for molecular and oxidative indexes analysis. Administration of GM caused tubular damages and functional disturbance. So that, Cr and BUN values in the GM group were higher than Control group. Furthermore, molecular findings showed upregulation of TLR4 and IL-6 mRNA expression in renal tissue of the GM-received group. In this study, superoxide dismutase (SOD) activity was slightly increased as a compensatory mechanism in response to elevated malondialdehyde (MDA) levels in the GM-treated group. On the other hand, the activity of catalase (CAT) and glutathione peroxidase (GPx) were significantly declined. Our results demonstrated that oxidative stress and subsequent TLR4 upregulation signaling pathways are involved in GM-induced nephrotoxicity.
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Affiliation(s)
- Zahra Pakfetrat
- Department of Biology, Arsanjan Branch, Islamic Azad University, Arsanjan, Iran
| | - Sahar Janfeshan
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Masjedi
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Rafiei
- Department of Biology, Arsanjan Branch, Islamic Azad University, Arsanjan, Iran
| | - Zeinab Karimi
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Proskocil BJ, Wai K, Lebold KM, Norgard MA, Michaelis KA, De La Torre U, Cook M, Marks DL, Fryer AD, Jacoby DB, Drake MG. TLR7 is expressed by support cells, but not sensory neurons, in ganglia. J Neuroinflammation 2021; 18:209. [PMID: 34530852 PMCID: PMC8447680 DOI: 10.1186/s12974-021-02269-x] [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: 12/24/2020] [Accepted: 08/31/2021] [Indexed: 11/10/2022] Open
Abstract
Background Toll-like receptor 7 (TLR7) is an innate immune receptor that detects viral single-stranded RNA and triggers the production of proinflammatory cytokines and type 1 interferons in immune cells. TLR7 agonists also modulate sensory nerve function by increasing neuronal excitability, although studies are conflicting whether sensory neurons specifically express TLR7. This uncertainty has confounded the development of a mechanistic understanding of TLR7 function in nervous tissues. Methods TLR7 expression was tested using in situ hybridization with species-specific RNA probes in vagal and dorsal root sensory ganglia in wild-type and TLR7 knockout (KO) mice and in guinea pigs. Since TLR7 KO mice were generated by inserting an Escherichia coli lacZ gene in exon 3 of the mouse TLR7 gene, wild-type and TLR7 (KO) mouse vagal ganglia were also labeled for lacZ. In situ labeling was compared to immunohistochemistry using TLR7 antibody probes. The effects of influenza A infection on TLR7 expression in sensory ganglia and in the spleen were also assessed. Results In situ probes detected TLR7 in the spleen and in small support cells adjacent to sensory neurons in the dorsal root and vagal ganglia in wild-type mice and guinea pigs, but not in TLR7 KO mice. TLR7 was co-expressed with the macrophage marker Iba1 and the satellite glial cell marker GFAP, but not with the neuronal marker PGP9.5, indicating that TLR7 is not expressed by sensory nerves in either vagal or dorsal root ganglia in mice or guinea pigs. In contrast, TLR7 antibodies labeled small- and medium-sized neurons in wild-type and TLR7 KO mice in a TLR7-independent manner. Influenza A infection caused significant weight loss and upregulation of TLR7 in the spleens, but not in vagal ganglia, in mice. Conclusion TLR7 is expressed by macrophages and satellite glial cells, but not neurons in sensory ganglia suggesting TLR7’s neuromodulatory effects are mediated indirectly via activation of neuronally-associated support cells, not through activation of neurons directly. Our data also suggest TLR7’s primary role in neuronal tissues is not related to antiviral immunity. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02269-x.
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Affiliation(s)
- Becky J Proskocil
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Karol Wai
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Katherine M Lebold
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Mason A Norgard
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Katherine A Michaelis
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Ubaldo De La Torre
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Madeline Cook
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Allison D Fryer
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - David B Jacoby
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA
| | - Matthew G Drake
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR, 97239, USA.
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Hennessy C, McKernan DP. Anti-Viral Pattern Recognition Receptors as Therapeutic Targets. Cells 2021; 10:cells10092258. [PMID: 34571909 PMCID: PMC8466445 DOI: 10.3390/cells10092258] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 12/11/2022] Open
Abstract
Pattern recognition receptors (PRRs) play a central role in the inflammation that ensues following microbial infection by their recognition of molecular patterns present in invading microorganisms but also following tissue damage by recognising molecules released during disease states. Such receptors are expressed in a variety of cells and in various compartments of these cells. PRR binding of molecular patterns results in an intracellular signalling cascade and the eventual activation of transcription factors and the release of cytokines, chemokines, and vasoactive molecules. PRRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. They are also key to reacting to infection and in stimulating the immune system when needed. Therefore, targeting PRRs offers a potential therapeutic approach for chronic inflammatory disease, infections and as vaccine adjuvants. In this review, the current knowledge on anti-viral PRRs and their signalling pathways is reviewed. Finally, compounds that target PRRs and that have been tested in clinical trials for chronic infections and as adjuvants in vaccine trials are discussed.
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Kapelouzou A, Katsimpoulas M, Kontogiannis C, Lidoriki I, Georgiopoulos G, Kourek C, Papageorgiou C, Mylonas KS, Dritsas S, Charalabopoulos A, Cokkinos DV. A High-Cholesterol Diet Increases Toll-like Receptors and Other Harmful Factors in the Rabbit Myocardium: The Beneficial Effect of Statins. Curr Issues Mol Biol 2021; 43:818-830. [PMID: 34449561 PMCID: PMC8928938 DOI: 10.3390/cimb43020059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.
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Affiliation(s)
- Alkistis Kapelouzou
- Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; (A.K.); (M.K.)
| | - Michalis Katsimpoulas
- Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; (A.K.); (M.K.)
- Attiko Hospital Animal, 19002 Athens, Greece
| | - Christos Kontogiannis
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.K.); (G.G.); (C.K.); (C.P.)
| | - Irene Lidoriki
- Vascular Unit, First Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece; (I.L.); (K.S.M.); (A.C.)
| | - Georgios Georgiopoulos
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.K.); (G.G.); (C.K.); (C.P.)
| | - Christos Kourek
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.K.); (G.G.); (C.K.); (C.P.)
| | - Christos Papageorgiou
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.K.); (G.G.); (C.K.); (C.P.)
| | - Konstantinos S. Mylonas
- Vascular Unit, First Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece; (I.L.); (K.S.M.); (A.C.)
| | - Spyridon Dritsas
- Second Department of Surgery, Aretaieio Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Alexandros Charalabopoulos
- Vascular Unit, First Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, 11527 Athens, Greece; (I.L.); (K.S.M.); (A.C.)
| | - Dennis V. Cokkinos
- Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; (A.K.); (M.K.)
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ω-3 fatty acid alleviates virus-induced myocardial injury by regulating TLR4 and TLR3 expression. Int Immunopharmacol 2021; 99:107973. [PMID: 34298398 DOI: 10.1016/j.intimp.2021.107973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/08/2021] [Accepted: 07/08/2021] [Indexed: 11/23/2022]
Abstract
The specific pathogenesis of viral-induced myocardial injury is unclear. TLR regulation plays an important role in virus-induced myocardial injury. The therapeutic effect and possible mechanism of omega-3 fatty acids in patients with viral-induced myocardial injury must be investigated. The study population was randomly divided into three groups: a healthy control group (n = 50); general treatment group (n = 40); and general treatment with ω-3 polyunsaturated fatty acid group (n = 36). We detected the mRNA levels of TLR3 and TLR4, downstream signal pathway proteins, inflammatory factors, oxidative stress markers, and myocardial enzymes in patients and healthy controls. ω-3 fatty acid therapy in patients with virus-induced myocardial injury significantly regulates the expression of TLR3 and TLR4 and their downstream signal protein, increases antioxidant expression, reduces the secretion of inflammatory factors, alleviates myocardial injury, and improves cardiac function. This provides a new strategy to treat virus-induced myocardial injury.
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Mohanty A, Sadangi S, Paichha M, Saha A, Das S, Samanta M. Toll-interacting protein in the freshwater fish Labeo rohita exhibits conserved structural motifs of higher eukaryotes and is distinctly expressed in pathogen-associated molecular pattern stimulations and bacterial infections. Microbiol Immunol 2021; 65:281-289. [PMID: 32237168 DOI: 10.1111/1348-0421.12792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/18/2020] [Accepted: 03/27/2020] [Indexed: 11/30/2022]
Abstract
Toll-interacting protein (Tollip) is a critical regulator of TOLL- like receptor (TLR)-signaling pathway. It is predominantly associated with TLR2 and TLR4 during acute inflammatory conditions and inhibits the TLR-mediated nuclear factor-kappa activation by suppressing the autophosphorylation of interleukin-1 receptor-associated kinase and its kinase activity. This article describes the Tollip of Labeo rohita (LrTollip), a highly valuable freshwater fish from the Indian subcontinent. The full-length LrTollip complementary DNA (1412 nucleotides) encodes a 276-amino acid (aa) protein, depicting a highly conserved target of the Myb1 (Tom1)-binding domain (TBD; 1-53 aa), conserved core domain 2 (C2; 54-151 aa), and coupling of ubiquitin to endoplasmic reticulum degradation (CUE; 231-273 aa) domains of mouse and human counterparts. The key amino acids exerting the critical functions of Tollip, such as phospholipids recognition and ubiquitination, are present in the C2 and CUE domains of LrTollip, respectively. LrTollip is widely expressed in the kidneys, gills, spleen, liver, and blood, and among these tested tissues, the highest expression is observed in blood. In response to TLR ligands and NOD-like receptor (NLR) ligands stimulations and Aeromonas hydrophila, Edwardsiella tarda, and Bacillus subtilis infections, LrTollip gene expression is induced in various organs/tissues with remarkable difference in their kinetics. These data together suggest the important role of LrTollip in TLR- and NLR-signal transduction pathways and immune-related diseases in fish.
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Affiliation(s)
- Arpita Mohanty
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, 751002, India
| | - Sushmita Sadangi
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, 751002, India
| | - Mahismita Paichha
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, 751002, India
| | - Ashis Saha
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, 751002, India
| | - Surajit Das
- Laboratory of Environmental Microbiology and Ecology (LEnME), Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Mrinal Samanta
- Fish Health Management Division, ICAR-Central Institute of Freshwater Aquaculture, Bhubaneswar, Odisha, 751002, India
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48
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Kilian LS, Frank D, Rangrez AY. RhoA Signaling in Immune Cell Response and Cardiac Disease. Cells 2021; 10:1681. [PMID: 34359851 PMCID: PMC8306393 DOI: 10.3390/cells10071681] [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: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/01/2021] [Indexed: 11/25/2022] Open
Abstract
Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.
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Affiliation(s)
- Lucia Sophie Kilian
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Derk Frank
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
| | - Ashraf Yusuf Rangrez
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care, University Medical Center Kiel, 24105 Kiel, Germany;
- DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany
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A bioinformatics approach for identifying potential molecular mechanisms and key genes involved in COVID-19 associated cardiac remodeling. GENE REPORTS 2021; 24:101246. [PMID: 34131597 PMCID: PMC8192842 DOI: 10.1016/j.genrep.2021.101246] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023]
Abstract
In 2019 coronavirus disease (COVID-19), whose main complication is respiratory involvement, different organs may also be affected in severe cases. However, COVID-19 associated cardiovascular manifestations are limited at present. The main purpose of this study was to identify potential candidate genes involved in COVID-19-associated heart damage by bioinformatics analysis. Differently expressed genes (DEGs) were identified using transcriptome profiles (GSE150392 and GSE4172) downloaded from the GEO database. After gene and pathway enrichment analyses, PPI network visualization, module analyses, and hub gene extraction were performed using Cytoscape software. A total of 228 (136 up and 92 downregulated) overlapping DEGs were identified at these two microarray datasets. Finally, the top hub genes (FGF2, JUN, TLR4, and VEGFA) were screened out as the critical genes among the DEGs from the PPI network. Identification of critical genes and mechanisms in any disease can lead us to better diagnosis and targeted therapy. Our findings identified core genes shared by inflammatory cardiomyopathy and SARS-CoV-2. The findings of the current study support the idea that these key genes can be used in understanding and managing the long-term cardiovascular effects of COVID-19.
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50
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Sanami S, Azadegan-Dehkordi F, Rafieian-Kopaei M, Salehi M, Ghasemi-Dehnoo M, Mahooti M, Alizadeh M, Bagheri N. Design of a multi-epitope vaccine against cervical cancer using immunoinformatics approaches. Sci Rep 2021; 11:12397. [PMID: 34117331 PMCID: PMC8196015 DOI: 10.1038/s41598-021-91997-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/03/2021] [Indexed: 02/05/2023] Open
Abstract
Cervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.
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Affiliation(s)
- Samira Sanami
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fatemeh Azadegan-Dehkordi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Maryam Ghasemi-Dehnoo
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mehran Mahooti
- Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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