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Wang C, Fan X, Shi Y, Tang F. Radiation-Induced Brain Injury with Special Reference to Astrocytes as a Therapeutic Target. J Integr Neurosci 2025; 24:25907. [PMID: 40152565 DOI: 10.31083/jin25907] [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: 07/30/2024] [Revised: 10/22/2024] [Accepted: 11/06/2024] [Indexed: 03/29/2025] Open
Abstract
Radiotherapy is one of the primary modalities for oncologic treatment and has been utilized at least once in over half of newly diagnosed cancer patients. Cranial radiotherapy has significantly enhanced the long-term survival rates of patients with brain tumors. However, radiation-induced brain injury, particularly hippocampal neuronal damage along with impairment of neurogenesis, inflammation, and gliosis, adversely affects the quality of life for these patients. Astrocytes, a type of glial cell that are abundant in the brain, play essential roles in maintaining brain homeostasis and function. Despite their importance, the pathophysiological changes in astrocytes induced by radiation have not been thoroughly investigated, and no systematic or comprehensive review addressing the effects of radiation on astrocytes and related diseases has been conducted. In this paper, we review current studies on the neurophysiological roles of astrocytes following radiation exposure. We describe the pathophysiological changes in astrocytes, including astrogliosis, astrosenescence, and the associated cellular and molecular mechanisms. Additionally, we summarize the roles of astrocytes in radiation-induced impairments of neurogenesis and the blood-brain barrier (BBB). Based on current research, we propose that brain astrocytes may serve as potential therapeutic targets for treating radiation-induced brain injury (RIBI) and subsequent neurological and neuropsychiatric disorders.
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Affiliation(s)
- Caiping Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 226001 Nantong, Jiangsu, China
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
| | - Xingjuan Fan
- Department of Neurology, Affiliated Hospital of Nantong University, 226001 Nantong, Jiangsu, China
| | - Yunwei Shi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 226001 Nantong, Jiangsu, China
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
| | - Fengru Tang
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
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Abe K, Yokota S, Matsumoto S, Ujiie H, Kikuchi E, Satoh K, Ishisaki A, Chosa N. Proinflammatory cytokine-induced matrix metalloproteinase-9 expression in temporomandibular joint osteoarthritis is regulated by multiple intracellular mitogen-activated protein kinase pathways. J Oral Biosci 2025; 67:100609. [PMID: 39755166 DOI: 10.1016/j.job.2024.100609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/06/2025]
Abstract
OBJECTIVES Temporomandibular joint (TMJ) osteoarthritis (OA) is an inflammatory disease that involves periarthritis of the TMJ and destruction of cartilage tissue in the mandibular condyle. However, the role of proinflammatory cytokines in the expression levels of matrix metalloproteinase (MMP) remains inconclusive. Thus, in this study, we aimed to investigate the effect of proinflammatory cytokines on the expression of MMPs. METHODS FLS1 cells (mouse TMJ-derived synovial cell line) were treated with tumor necrosis factor alpha (TNF-α) or interleukin (IL)-1β in the presence or absence of mitogen-activated protein kinase (MAPK) inhibitors. The mRNA expression levels of MMP-2 and MMP-9 were examined by reverse transcription-quantitative polymerase chain reaction. Additionally, the phosphorylation status of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK in the FLS1 cells treated with TNF-α or IL-1β was evaluated by performing western blotting analysis. RESULTS TNF-α and IL-1β significantly increased the expression of MMP-9 in the FLS1 cells; however, MMP-2 expression remained unaffected. Mitogen-activated protein kinase kinase (MEK) and p38 MAPK inhibitors significantly suppressed cytokine-induced MMP-9 upregulation. Conversely, Jun amino-terminal kinase (JNK) inhibitors further increased MMP-9 expression in the cells treated with TNF-α or IL-1β. Moreover, TNF-α and IL-1β enhanced ERK1/2 and p38 MAPK phosphorylation in the FLS1 cells. CONCLUSIONS TNF-α and IL-1β induced MMP-9 expression in the FLS1 cells via the MEK/ERK and p38 MAPK pathways and suppressed it via the JNK pathway. Thus, proinflammatory cytokines control MMP-9 expression in TMJ-OA by regulating multiple MAPK pathways.
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Affiliation(s)
- Karen Abe
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan; Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University School of Dentistry, Morioka, Iwate, 020-8505, Japan
| | - Seiji Yokota
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan
| | - Shikino Matsumoto
- Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University School of Dentistry, Morioka, Iwate, 020-8505, Japan
| | - Hayato Ujiie
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan
| | - Emiko Kikuchi
- Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University School of Dentistry, Morioka, Iwate, 020-8505, Japan
| | - Kazuro Satoh
- Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University School of Dentistry, Morioka, Iwate, 020-8505, Japan
| | - Akira Ishisaki
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan
| | - Naoyuki Chosa
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate, 028-3694, Japan.
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Schoenherr C, Pietzsch S, Barca C, Müller FE, Bahr FS, Kasten M, Zeug A, Erschow S, Falk CS, Ponimaskin E, Thackeray JT, Hilfiker-Kleiner D, Ricke-Hoch M. Immune-checkpoint-inhibitor therapy directed against PD-L1 is tolerated in the heart without manifestation of cardiac inflammation in a preclinical reversible melanoma mouse model. FRONTIERS IN MOLECULAR MEDICINE 2025; 4:1487526. [PMID: 39834851 PMCID: PMC11743445 DOI: 10.3389/fmmed.2024.1487526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025]
Abstract
Immune-checkpoint-inhibitors (ICI) target key regulators of the immune system expressed by cancer cells that mask those from recognition by the immune system. They have improved the outcome for patients with various cancer types, such as melanoma. ICI-based therapy is frequently accompanied by immune-related adverse side effects (IRAEs). The reversible melanoma cancer mouse model (B16F10 cells stably expressing a ganciclovir (GCV)-inducible suicide gene in C57BL/6N mice: B16F10-GCV) allows chemotherapy-free tumor elimination in advanced disease stage and demonstrates almost complete recovery of the mouse heart from cancer-induced atrophy, molecular impairment and heart failure. Thus, enabling the study of anti-cancer-therapy effects. Here, we analyzed potential cardiac side effects of antibody-mediated PD-L1 inhibition in the preclinical B16F10-GCV mouse model after tumor elimination and 2 weeks recovery (50 days after tumor inoculation). Anti-PD-L1 treatment was associated with improved survival as compared to isotype control (Ctrl) treated mice. Surviving anti-PD-L1 and Ctrl mice showed similar cardiac function, dimensions and the expression of cardiac stress and hypertrophy markers. Although anti-PD-L1 treatment was associated with increased troponin I type 3 cardiac (TNNI3) blood levels, cardiac mRNA expression of macrophage markers and elevated cardiac levels of secreted inflammatory factors compared to Ctrl treatment, both groups showed a comparable density of inflammatory cells in the heart (using CXCR4-ligand 68Ga-Pentixafor in PET-CT and immunohistochemistry). Thus, anti-PD-L1 therapy improved survival in mice with advanced melanoma cancer with no major cardiac phenotype or inflammation 50 days after tumor inoculation. Without a second hit that triggers the inflammatory response, anti-PD-L1 treatment appears to be safe for the heart in the preclinical melanoma mouse model.
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Affiliation(s)
- Caroline Schoenherr
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Stefan Pietzsch
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Cristina Barca
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Franziska E. Müller
- Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
| | - Frauke S. Bahr
- Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
| | - Martina Kasten
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Andre Zeug
- Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
| | - Sergej Erschow
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Christine S. Falk
- Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany
| | - Evgeni Ponimaskin
- Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany
| | - James T. Thackeray
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Denise Hilfiker-Kleiner
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- Department of Cardiovascular Complications of Oncologic Therapies, Medical Faculty of the Philipps University Marburg, Marburg, Germany
| | - Melanie Ricke-Hoch
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
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Liu G, Wang H, Zhang C, Li X, Mi Y, Chen Y, Xu L, Miao L, Long H, Liu Y. Tumor Necrosis Factor Receptor 1 Is Required for Human Umbilical Cord-Derived Mesenchymal Stem Cell-Mediated Rheumatoid Arthritis Therapy. Cell Transplant 2025; 34:9636897241301703. [PMID: 39831589 PMCID: PMC11748158 DOI: 10.1177/09636897241301703] [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: 05/12/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 01/22/2025] Open
Abstract
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease characterized by altered levels of inflammatory cytokines. One of the key cytokines involved in the pathogenesis of RA is tumor necrosis factor α (TNF-α), which plays a crucial role in the differentiation of T cells and B cells and serves as a primary trigger of inflammation and joint damage in RA. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have shown potential in alleviating the symptoms of RA. Previous in vitro studies indicate that TNF-α secreted by T cells can activate NF-κB in human MSCs, thereby triggering the immunoregulatory capacity of MSCs in a manner dependent on tumor necrosis factor receptor 1 (TNFR1). Inspired by these findings, we aimed to evaluate whether TNFR1 determine the therapeutic effects of hUC-MSCs on RA. First, we investigated whether TNFR1 is necessary for hUC-MSCs to inhibit TNF-α production of PBMCs, a source of elevated TNF-α in patients. Through coculture experiment, we confirmed that this inhibition was dependent on TNFR1. Subsequently, we administered hUC-MSCs or siTNFR1-MSCs to DBA/1J male mice with collagen-induced arthritis. The results indicated that hUC-MSCs significantly alleviated the pathological features of RA and suppressed the inflammatory cytokines IFN-γ, TNF-α, and IL-6 in peripheral blood, also in a manner dependent on TNFR1 either. Given the dramatic pathologic differences between hUC-MSCs and siTNFR1-MSCs treatments, we questioned whether production of growth factors and chemokines was significantly influenced by TNFR1. Consequently, we stimulated hUC-MSCs or siTNFR1-MSCs through IFN-γ, TNF-α, and IL-6, and profiled growth factors and chemokines in serum, which revealed significant changes of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), as well as chemokines CXCL9, CXCL10, IL-8, and RANTES. In summary, our findings suggest that TNFR1 may determine whether hUC-MSCs will gain abilities of anti-inflammation and tissue regeneration.
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Affiliation(s)
- Guangyang Liu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Herui Wang
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Chenliang Zhang
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Xin Li
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yi Mi
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yaoyao Chen
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Liqiang Xu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Li Miao
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Haomiao Long
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yongjun Liu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
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Javaid N, Ahmad B, Patra MC, Choi S. Decoy peptides that inhibit TNF signaling by disrupting the TNF homotrimeric oligomer. FEBS J 2024; 291:4372-4391. [PMID: 39003565 DOI: 10.1111/febs.17220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/18/2024] [Accepted: 06/24/2024] [Indexed: 07/15/2024]
Abstract
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine and its functional homotrimeric form interacts with the TNF receptor (TNFR) to activate downstream apoptotic, necroptotic, and inflammatory signaling pathways. Excessive activation of these pathways leads to various inflammatory diseases, which makes TNF a promising therapeutic target. Here, 12-mer peptides were selected from the interface of TNF-TNFR based upon their relative binding energies and were named 'TNF-inhibiting decoys' (TIDs). These decoy peptides inhibited TNF-mediated secretion of cytokines and cell death, as well as activation of downstream signaling effectors. Effective TIDs inhibited TNF signaling by disrupting the formation of TNF's functional homotrimeric form. Among derivatives of TIDs, TID3c showed slightly better efficacy in cell-based assays by disrupting TNF trimer formation. Moreover, TID3c oligomerized TNF to a high molecular weight configuration. In silico modeling and simulations revealed that TID3c and its parent peptide, TID3, form a stable complex with TNF through hydrogen bonds and electrostatic interactions, which makes them the promising lead to develop peptide-based anti-TNF therapeutics.
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Affiliation(s)
- Nasir Javaid
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
| | - Bilal Ahmad
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
| | | | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
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Lopalco G, Cito A, Venerito V, Iannone F, Proft F. The management of axial spondyloarthritis with cutting-edge therapies: advancements and innovations. Expert Opin Biol Ther 2024; 24:835-853. [PMID: 39109494 DOI: 10.1080/14712598.2024.2389987] [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: 05/28/2024] [Accepted: 08/05/2024] [Indexed: 08/28/2024]
Abstract
INTRODUCTION Axial involvement in spondyloarthritis has significantly evolved from the original 1984 New York criteria for ankylosing spondylitis, leading to an improved understanding of axial spondyloarthritis (axSpA) as a disease continuum encompassing non- radiographic axSpA (nr-axSpA) and radiographic axSpA (r-axSpA). A clear definition for early axSpA has been established, underscoring the need for early intervention with biological and targeted synthetic drugs to mitigate pain, reduce functional impairment, and prevent radiographic progression. AREAS COVERED This review explores therapeutic strategies in axSpA management, focusing on biological and targeted synthetic therapies and recent advancements. Biologics targeting TNFα or IL-17 and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) are primary treatment options. These therapies significantly impact clinical outcomes, radiographic progression, and patient-reported functional improvement. EXPERT OPINION AxSpA treatment has evolved significantly, offering various therapeutic options. Biological DMARDs, particularly TNFα inhibitors, have transformed treatment, significantly enhancing patient outcomes. However, challenges persist for patients unresponsive or intolerant to existing therapies. Emerging therapeutic targets promise to address these challenges. Comprehensive management strategies and personalized approaches, considering extra-articular manifestations and individual patient factors, are crucial for achieving optimal outcomes in axSpA management.
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Affiliation(s)
- Giuseppe Lopalco
- Department of Precision Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Bari, Italy
| | - Andrea Cito
- Department of Precision Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Bari, Italy
| | - Vincenzo Venerito
- Department of Precision Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Bari, Italy
| | - Florenzo Iannone
- Department of Precision Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, Bari, Italy
| | - Fabian Proft
- Department of Gastroenterology, Infectiology and Rheumatology (including Nutrition Medicine), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Papadakos SP, Chatzikalil E, Vakadaris G, Reppas L, Arvanitakis K, Koufakis T, Siakavellas SI, Manolakopoulos S, Germanidis G, Theocharis S. Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2609. [PMID: 39061246 PMCID: PMC11275207 DOI: 10.3390/cancers16142609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Elena Chatzikalil
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Georgios Vakadaris
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Lampros Reppas
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece;
| | - Spyros I. Siakavellas
- 2nd Academic Department of Internal Medicine, Liver-GI Unit, General Hospital of Athens “Hippocration”, National and Kapodistrian University of Athens, 114 Vas. Sofias str, 11527 Athens, Greece; (S.I.S.); (S.M.)
| | - Spilios Manolakopoulos
- 2nd Academic Department of Internal Medicine, Liver-GI Unit, General Hospital of Athens “Hippocration”, National and Kapodistrian University of Athens, 114 Vas. Sofias str, 11527 Athens, Greece; (S.I.S.); (S.M.)
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.V.); (K.A.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
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Hsieh HL, Yu MC, Chang YC, Wu YH, Huang KH, Tsai MM. Lonicera japonica Thunb. Ethanol Extract Exerts a Protective Effect on Normal Human Gastric Epithelial Cells by Modulating the Activity of Tumor-Necrosis-Factor-α-Induced Inflammatory Cyclooxygenase 2/Prostaglandin E2 and Matrix Metalloproteinase 9. Curr Issues Mol Biol 2024; 46:7303-7323. [PMID: 39057074 PMCID: PMC11276375 DOI: 10.3390/cimb46070433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.
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Affiliation(s)
- Hsi-Lung Hsieh
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; (H.-L.H.); (Y.-C.C.); (Y.-H.W.)
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Chemical Engineering, R&D Center of Biochemical Engineering Technology, Ming Chi University of Technology, New Taipei City 301, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Yu-Chia Chang
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; (H.-L.H.); (Y.-C.C.); (Y.-H.W.)
| | - Yi-Hsuan Wu
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; (H.-L.H.); (Y.-C.C.); (Y.-H.W.)
| | - Kuo-Hsiung Huang
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan;
- Department of Laboratory Medicine, Section of Clinical Serology and Immunology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; (H.-L.H.); (Y.-C.C.); (Y.-H.W.)
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan;
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan;
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Pérez-Pons A, Teodosio C, Jara-Acevedo M, Henriques A, Navarro-Navarro P, García-Montero AC, Álvarez-Twose I, Lecrevisse Q, Fluxa R, Sánchez-Muñoz L, Caldas C, Pozo J, Martín S, Sanfeliciano TC, Pedreira CE, Botafogo V, González-López O, Mayado A, Orfao A. T-cell immune profile in blood of systemic mastocytosis: Association with disease features. Allergy 2024; 79:1921-1937. [PMID: 38299742 DOI: 10.1111/all.16043] [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: 07/28/2023] [Revised: 01/02/2024] [Accepted: 01/16/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Systemic mastocytosis (SM) is a heterogeneous disease characterized by an expansion of KIT-mutated mast cells (MC). KIT-mutated MC display activated features and release MC mediators that might act on the tumour microenvironment and other immune cells. Here, we investigated the distribution of lymphocyte subsets in blood of patients with distinct subtypes of SM and determined its association with other disease features. METHODS We studied the distribution of TCD4+ and TCD4- cytotoxic cells and their subsets, as well as total NK- and B cells, in blood of 115 SM patients-38 bone marrow mastocytosis (BMM), 67 indolent SM (ISM), 10 aggressive SM (ASM)- and 83 age-matched healthy donors (HD), using spectral flow cytometry and the EuroFlow Immunomonitoring panel, and correlated it with multilineage KITD816V, the alpha-tryptasemia genotype (HαT) and the clinical manifestations of the disease. RESULTS SM patients showed decreased counts (vs. HD) of TCD4- cytotoxic cells, NK cells and several functional subsets of TCD4+ cells (total Th1, Th2-effector memory, Th22-terminal effector and Th1-like Tregs), together with increased T-follicular-helper and Th1/Th17-like Treg counts, associated with different immune profiles per diagnostic subtype of SM, in multilineal versus MC-restricted KITD816V and in cases with a HαT+ versus HαT- genotype. Unique immune profiles were found among BMM and ISM patients with MC-restricted KITD816V who displayed HαT, anaphylaxis, hymenoptera venom allergy, bone disease, pruritus, flushing and GI symptoms. CONCLUSION Our results reveal altered T- and NK-cell immune profiles in blood of SM, which vary per disease subtype, the pattern of involvement of haematopoiesis by KITD816V, the HαT genotype and specific clinical manifestations of the disease.
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Affiliation(s)
- Alba Pérez-Pons
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
| | - Cristina Teodosio
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - María Jara-Acevedo
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
- Sequencing Service (NUCLEUS), Universidad de Salamanca, Salamanca, Spain
| | - Ana Henriques
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Virgen del Valle Hospital, CIBERONC, Toledo, Madrid, Spain
- Cytognos SL, Salamanca, Spain
| | - Paula Navarro-Navarro
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
- Sequencing Service (NUCLEUS), Universidad de Salamanca, Salamanca, Spain
| | - Andrés C García-Montero
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
| | - Iván Álvarez-Twose
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Virgen del Valle Hospital, CIBERONC, Toledo, Madrid, Spain
| | - Quentin Lecrevisse
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | | | - Laura Sánchez-Muñoz
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
- Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Virgen del Valle Hospital, CIBERONC, Toledo, Madrid, Spain
| | - Carolina Caldas
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
| | - Julio Pozo
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Silvia Martín
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | | | - Carlos E Pedreira
- Systems and Computing Department (PESC), COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Vitor Botafogo
- Department of Hematology and Hemotherapy, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Oscar González-López
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
| | - Andrea Mayado
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
| | - Alberto Orfao
- Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Universidad de Salamanca, Salamanca, Spain
- Biomedical Research Networking Center Consortium (CIBERONC; CB16/12/00400), Madrid, Spain
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Spanish Network on Mastocytosis (REMA), Toledo, Salamanca, Spain
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10
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Tittes J, Brell J, Fritz P, Jonak C, Stary G, Ressler JM, Künig S, Weninger W, Stöckl J. Regulation of the Immune Cell Repertoire in Psoriasis Patients Upon Blockade of IL-17A or TNFα. Dermatol Ther (Heidelb) 2024; 14:613-626. [PMID: 38459237 PMCID: PMC10965886 DOI: 10.1007/s13555-024-01112-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 02/08/2024] [Indexed: 03/10/2024] Open
Abstract
INTRODUCTION Targeting of the proinflammatory cytokine interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with the monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, is a successful therapy for chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. METHODS In this study, we compared the composition of cutaneous, lesional and non-lesional immune cells and blood immune cells in ixekizumab- or adalimumab-treated patients with psoriasis. RESULTS Our data reveal that both treatments efficiently downregulate T cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to the skin of healthy subjects. Treatment with neither ixekizumab nor adalimumab reversed this DC imbalance in non-lesional skin of psoriatic patients. CONCLUSION Our study shows that anti-IL-17A and anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients but fails to restore the disturbed immune cell repertoire in non-lesional skin.
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Affiliation(s)
- Julia Tittes
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
| | - Jennifer Brell
- Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090, Vienna, Austria
| | - Pia Fritz
- Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090, Vienna, Austria
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Julia M Ressler
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Sarojinidevi Künig
- Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090, Vienna, Austria
| | - Wolfgang Weninger
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Johannes Stöckl
- Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090, Vienna, Austria
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11
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Nelson NC, Kogan R, Condos R, Hena KM. Emerging Therapeutic Options for Refractory Pulmonary Sarcoidosis: The Evidence and Proposed Mechanisms of Action. J Clin Med 2023; 13:15. [PMID: 38202021 PMCID: PMC10779381 DOI: 10.3390/jcm13010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 01/12/2024] Open
Abstract
Sarcoidosis is a systemic disease with heterogenous clinical phenotypes characterized by non-necrotizing granuloma formation in affected organs. Most disease either remits spontaneously or responds to corticosteroids and second-line disease-modifying therapies. These medications are associated with numerous toxicities that can significantly impact patient quality-of-life and often limit their long-term use. Additionally, a minority of patients experience chronic, progressive disease that proves refractory to standard treatments. To date, there are limited data to guide the selection of alternative third-line medications for these patients. This review will outline the pathobiological rationale behind current and emerging therapeutic agents for refractory or drug-intolerant sarcoidosis and summarize the existing clinical evidence in support of their use.
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Affiliation(s)
| | | | | | - Kerry M. Hena
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University, 301 E 17th St Suite 550, New York, NY 10003, USA
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12
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Prasad R, Patel RS, Mishra SP, Singh A, Abhinay A, Singh TB. Cerebrospinal fluid tumor necrosis factor-alpha (TNF-α) levels in children with cerebral malaria. J Trop Pediatr 2023; 69:fmad032. [PMID: 37805828 DOI: 10.1093/tropej/fmad032] [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] [Indexed: 10/09/2023]
Abstract
This prospective cross-sectional study evaluated the diagnostic and prognostic role of cerebrospinal fluid (CSF) tumor necrosis factor-alpha (TNF-α) in children with cerebral malaria (CM) and its role in the differentiation of CM from non-cerebral severe malaria. CSF TNF-α was measured using a human TNF-α enzyme-linked immunosorbent assay kit of 39 cases of CM and 19 cases of non-cerebral severe malaria. CSF TNF-α levels were significantly higher in CM (p < 0.001). Based on the receiver operating characteristics curve, a cutoff value of CSF TNF-α was 5.7 pg/ml for diagnosis of CM with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 87.2%, 94.7%, 97.1% and 78.3% respectively. The cutoff value of CSF TNF-α was 13.7 pg/ml for predicting adverse outcomes in CM with sensitivity, specificity, PPV and NPV of 100%, 96.8%, 88.9% and 100%, respectively. However, the cutoff value of CSF TNF-α was 4.96 pg/ml for predicting adverse outcomes in non-cerebral severe malaria with a sensitivity, specificity, PPV and NPV of 100%, 94.1%, 88.9% and 100% respectively. So, CSF TNF-α is an excellent biomarker and can be used as a diagnostic and prognostic tool. More studies are needed to establish CSF TNF-α as a predictor of neurological sequelae.
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Affiliation(s)
- Rajniti Prasad
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Raghvendra Singh Patel
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - S P Mishra
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Ankur Singh
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Abhishek Abhinay
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Tej Bali Singh
- Department of Biostatistics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
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13
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Santolaya JL, Schweer DS, Cardenas-Goicoechea J, Bukowski R, Santolaya-Forgas J. Bioavailability of the tumor necrosis factor alpha/regulated on activation, normal T cell expressed and secreted (RANTES) biosystem inside the gestational sac during the pre-immune stages of embryo development. J Perinat Med 2023; 51:891-895. [PMID: 37067543 DOI: 10.1515/jpm-2022-0542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/06/2023] [Indexed: 04/18/2023]
Abstract
OBJECTIVES In-vivo studies of the bioavailability of major components of the tumor necrosis factor alpha (TNFα) biosystem inside the gestational sac during embryogenesis have not been reported. We sought to determine the concentration of TNFα, soluble (s) TNFα receptors (sTNFR1, sTNFR2), and RANTES in the primate extraembryonic celomic fluid (ECF). METHODS A validated timed-pregnant baboon animal model (N: 10) for experimental research in pregnancy was used to collect paired maternal blood and ECF samples in ongoing pregnancies. The concentrations (pg/dL) of TNFα, sTNFR1, sTNFR2, and RANTES were then determined by ELISA immunoassays. RESULTS All animals delivered at term healthy newborns. The differential concentration of TNFα, sTNFR1, sTNFR2, and RANTES between the maternal plasma and the ECF could be determined with ratios for TNFα (5.4), sTNFR2 (1.85) and RANTES (3.59) that contrasted with that of sTNFR1 (0.07), which favored the gestational sac compartment. No significant correlations were noted between maternal plasma and ECF TNFR1, sTNFR2 and RANTES. There was a trend for a correlation between TNFα in maternal plasma and ECF (R=0.74; p=0.07). CONCLUSIONS We report the physiological concentrations of TNFα, sTNFR1, sTNFR2, and RANTES in extraembryonic celomic fluid during embryogenesis in primates.
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Affiliation(s)
- Jacobo L Santolaya
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - David S Schweer
- Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA
| | | | - Radek Bukowski
- Department of Obstetrics and Gynecology, University of Texas, Austin, TX, USA
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Baranasic J, Niazi Y, Chattopadhyay S, Rumora L, Ćorak L, Dugac AV, Jakopović M, Samaržija M, Försti A, Knežević J. Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2023; 73:243-256. [PMID: 37307368 DOI: 10.2478/acph-2023-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 06/14/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are closely related diseases associated with smoking history and dysregulated immune response. However, not all smokers develop the disease, indicating that genetic susceptibility could be important. Therefore, the aim of this study was to search for the potential overlapping genetic biomarkers, with a focus on single nucleotide polymorphisms (SNPs) located in the regulatory regions of immune-related genes. Additionally, the aim was to see if an identified SNP has potentially an effect on proinflamma-tory cytokine concentration in the serum of COPD patients. We extracted summary data of variants in 1511 immune-related genes from COPD and LC genome-wide association studies (GWAS) from the UK Biobank. The LC data had 203 cases, patients diagnosed with LC, and 360 938 controls, while COPD data had 1 897 cases and 359 297 controls. Assuming 1 association/gene, SNPs with a p-value < 3.3 × 10-5 were considered statistically significantly associated with the disease. We identified seven SNPs located in different genes (BAG6, BTNL2, TNF, HCP5, MICB, NCR3, ABCF1, TCF7L1) to be associated with the COPD risk and two with the LC risk (HLA-C, HLA-B), with statistical significance. We also identified two SNPs located in the IL2RA gene associated with LC (rs2386841; p = 1.86 × 10-4) and COPD (rs11256442; p = 9.79 × 10-3) but with lower significance. Functional studies conducted on COPD patients showed that RNA expression of IL2RA, IFNγ and related proinflammatory cytokines in blood serum did not correlate with a specific genotype. Although results presented in this study do not fully support our hypothesis, it is worth to mention that the identified genes/SNPs that were associated with either COPD or LC risk, all were involved in the activation of the NF-κB transcription factor which is closely related to the regulation of the inflammatory response, a condition associated with both pathologies.
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Affiliation(s)
- Jurica Baranasic
- 1Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Yasmeen Niazi
- 2Hopp Children's Cancer Center (KiTZ) Heidelberg, Germany
- 3Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) German Cancer Consortium (DKTK) Heidelberg, Germany
| | - Subhayan Chattopadhyay
- 3Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) German Cancer Consortium (DKTK) Heidelberg, Germany
- 4Departments of Clinical Genetics, Lund University, Lund, Sweden
| | - Lada Rumora
- 5Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb Zagreb, Croatia
| | - Lorna Ćorak
- 6Clinical Department for Respiratory Diseases Jordanovac, University Hospital Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Andrea Vukić Dugac
- 6Clinical Department for Respiratory Diseases Jordanovac, University Hospital Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Marko Jakopović
- 6Clinical Department for Respiratory Diseases Jordanovac, University Hospital Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Miroslav Samaržija
- 6Clinical Department for Respiratory Diseases Jordanovac, University Hospital Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Asta Försti
- 2Hopp Children's Cancer Center (KiTZ) Heidelberg, Germany
- 3Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) German Cancer Consortium (DKTK) Heidelberg, Germany
| | - Jelena Knežević
- 1Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
- 7Faculty of Dental Medicine and Health University of Osijek, Osijek, Croatia
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Wang DY, Ohnuma S, Suzuki H, Ishida M, Ishii K, Hirosawa T, Hirashima T, Murakami M, Kobayashi M, Kudoh K, Haneda S, Musha H, Naitoh T, Unno M. Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation. Curr Issues Mol Biol 2023; 45:2895-2907. [PMID: 37185713 PMCID: PMC10136890 DOI: 10.3390/cimb45040189] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), such as Crohn’s disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.
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Affiliation(s)
- Dan-Yang Wang
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Shinobu Ohnuma
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Hideyuki Suzuki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Masaharu Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Kentaro Ishii
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Takashi Hirosawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Tomoaki Hirashima
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Megumi Murakami
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Minoru Kobayashi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Katsuyoshi Kudoh
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Sho Haneda
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Hiroaki Musha
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Takeshi Naitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
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Rezaee M, Zangiabadian M, Soheili A, Calcagno TM, Rahmannia M, Dinparastisaleh R, Nasiri MJ, Mirsaeidi M. Role of anti-tumor necrosis factor-alpha agents in treatment of sarcoidosis: A meta-analysis. Eur J Intern Med 2023; 109:42-49. [PMID: 36526497 DOI: 10.1016/j.ejim.2022.12.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022]
Abstract
IMPORTANCE Anti-tumor necrosis factor-alpha agent (anti-TNF-α) is considered an effective third-line therapy for refractory sarcoidosis,studies observing the efficacy of anti-TNF-α agents show conflicting results. OBJECTIVE We performed an up-to-date systemic meta-analysis to determine effectiveness and further elucidate the role of anti-TNF-α in the treatment of sarcoidosis. DATA SOURCES A systematic search was carried out in PubMed/Medline, EMBASE, and Cochrane Library for studies reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis, published up to April 10, 2022. The study was registered in the international prospective register of systematic reviews (PROSPERO) under ID: CRD42022364614. STUDY SELECTION Clinical trials written reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis were included. DATA EXTRACTION AND SYNTHESIS Statistical analyses were performed with Comprehensive Meta-Analysis software, and the random-effects model was used. The combined overall treatment success was determined for patients with pulmonary and extrapulmonary sarcoidosis. MAIN OUTCOMES AND MEASURES Overall treatment success rate wasdefined as no disease progression or improvement in symptoms. RESULTS Eight clinical trial articles were included in the meta-analysis; four used Infliximab, two Etanercept, one Adalimumab, and one Ustekinumab and Golimumab. The mean age of participants was 48.5 years. The duration of drug therapy ranged from 14 to 45 weeks. We found a combined overall treatment success rate, defined as no disease progression or improvement in symptoms, of 69.9% (95% CI 35.0-90.9, I2: 70%) in the pulmonary sarcoidosis group and 74.5% (95% CI 36.3-93.7, I2: 90%) in the extrapulmonary sarcoidosis group. There was no evidence of publication bias in either group. CONCLUSION AND RELEVANCE Treatment of refractory sarcoidosis with anti-TNF-α agents was effective in both pulmonary and extrapulmonary sarcoidosis, with a slightly higher efficacy seen in extrapulmonary sarcoidosis. Further randomized controlled trials should be conducted to determine the effects of anti-TNF-α agents as a part of the management strategy of sarcoidosis. Patients with pulmonary sarcoidosis should be studied separately from patients with extrapulmonary sarcoidosis to adjust for confounding results.
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Affiliation(s)
- Malihe Rezaee
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moein Zangiabadian
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirali Soheili
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Maryam Rahmannia
- Department of Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roshan Dinparastisaleh
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Jacksonville, FL, USA
| | - Mohammad J Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehdi Mirsaeidi
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Jacksonville, FL, USA.
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El-Ghamrawy M, El-Gharbawi N, Shahin G, Abdelhady A, Sayed R, Diaa N, Bishai I. Combined tumor necrosis factor-α (-308 G/A) and tumor necrosis factor-β (+ 252 A/G) nucleotide polymorphisms and chronicity in Egyptian children with immune thrombocytopenia. Int J Hematol 2023; 117:856-862. [PMID: 36802017 DOI: 10.1007/s12185-023-03551-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/25/2023] [Accepted: 01/25/2023] [Indexed: 02/21/2023]
Abstract
BACKGROUND Primary immune thrombocytopenia (ITP) is a common autoimmune disorder. Secretion of TNF-α, TNF-β and IFN-γ plays a major role in the pathogenesis of ITP. OBJECTIVE This cross-sectional study aimed to detect TNF-α (-308 G/A) and TNF-β (+ 252 A/G) gene polymorphism in a cohort of Egyptian children with chronic ITP (cITP) to clarify their possible association with progression to chronic disease. METHODS The study included 80 Egyptian cITP patients and 100 unrelated age- and sex-matched controls. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS Patients with TNF-α homozygous (A/A) genotype had significantly higher mean age, longer disease duration and lower platelet counts (p values 0.005, 0.024 and 0.008, respectively). TNF-α wild (G/G) genotype was significantly more frequent among responders (p = 0.049). Complete response was more frequent among wild (A/A) TNF-β genotype patients (p = 0.011), and platelet count was significantly lower among homozygous (G/G) genotype (p = 0.018) patients. Combined polymorphisms were strongly associated with susceptibility to chronic ITP. CONCLUSION Homozygosity in either gene might contribute to a worse course of disease, increased severity and poor response to therapy. Patients expressing combined polymorphisms are more prone to progression to chronic disease, severe thrombocytopenia and longer disease duration.
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Affiliation(s)
- Mona El-Ghamrawy
- Pediatric Hematology & BMT Unit, Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Nesrine El-Gharbawi
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Gehan Shahin
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alaa Abdelhady
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rasha Sayed
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nehal Diaa
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Irene Bishai
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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18
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Xia Y, Wang H, Yang R, Hou Y, Li Y, Zhu J, Fu C. Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment. Front Immunol 2023; 14:1051606. [PMID: 36756124 PMCID: PMC9900107 DOI: 10.3389/fimmu.2023.1051606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.
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Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ruohan Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yulin Hou
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China,*Correspondence: Changfeng Fu,
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19
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Chen J, Xiang X, Nie L, Guo X, Zhang F, Wen C, Xia Y, Mao L. The emerging role of Th1 cells in atherosclerosis and its implications for therapy. Front Immunol 2023; 13:1079668. [PMID: 36685487 PMCID: PMC9849744 DOI: 10.3389/fimmu.2022.1079668] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Atherosclerosis is a chronic progressive inflammatory disease of the large and medium-sized artery walls. The molecular mechanisms regulating the onset and progression of atherosclerosis remain unclear. T cells, one of the most common immune cell types in atherosclerotic plaques, are increasingly recognized as a key mediator in the pathogenesis of atherosclerosis. Th1 cells are a subset of CD4+ T helper cells of the adaptive immune system, characterized by the expression of the transcription factor T-bet and secretion of cytokines such as IFN-γ. Converging evidence shows that Th1 cells play a key role in the onset and progression of atherosclerosis. Besides, Th1 is the central mediator to orchestrate the adaptive immune system. In this review, we aim to summarize the complex role of Th1 cells in atherosclerosis and propose novel preventative and therapeutic approaches targeting Th1 cell-associated specific cytokines and receptors to prevent atherogenesis.
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Affiliation(s)
| | | | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqing Guo
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Wen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanpeng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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20
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The complex role of inflammation and gliotransmitters in Parkinson's disease. Neurobiol Dis 2023; 176:105940. [PMID: 36470499 PMCID: PMC10372760 DOI: 10.1016/j.nbd.2022.105940] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Our understanding of the role of innate and adaptive immune cell function in brain health and how it goes awry during aging and neurodegenerative diseases is still in its infancy. Inflammation and immunological dysfunction are common components of Parkinson's disease (PD), both in terms of motor and non-motor components of PD. In recent decades, the antiquated notion that the central nervous system (CNS) in disease states is an immune-privileged organ, has been debunked. The immune landscape in the CNS influences peripheral systems, and peripheral immunological changes can alter the CNS in health and disease. Identifying immune and inflammatory pathways that compromise neuronal health and survival is critical in designing innovative and effective strategies to limit their untoward effects on neuronal health.
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21
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Yu K, Yu C, Jiao L, Miao K, Ni L, Rao X, Zhou L, Zhao C. The Function and Therapeutic Implications of TNF Signaling in MDSCs. Biomolecules 2022; 12:1627. [PMID: 36358977 PMCID: PMC9687347 DOI: 10.3390/biom12111627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 09/27/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of immature and heterogeneous myeloid cells with immunosuppressive functions. MDSCs play important roles in the pathogenesis of cancer, chronic inflammatory diseases, and many autoimmune disorders. The accumulation and activation of MDSCs can be regulated by tumor necrosis factor α (TNF-α). In this review, we summarize the roles played by TNF-α in the recruitment, immunosuppressive functions, and chemotaxis of MDSCs, and discuss the potential therapeutic effects of TNF-α upon these cells in tumor growth and some inflammatory disorders.
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Affiliation(s)
- Kun Yu
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chengxin Yu
- GI Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liping Jiao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Kun Miao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Ni
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoquan Rao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ling Zhou
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chunxia Zhao
- Division of Cardiology, Departments of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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22
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Advancing Biologic Therapy for Refractory Autoimmune Hepatitis. Dig Dis Sci 2022; 67:4979-5005. [PMID: 35147819 DOI: 10.1007/s10620-021-07378-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
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23
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Comparison of the inhibitory effect of tocilizumab and etanercept on the progression of joint erosion in rheumatoid arthritis treatment. Sci Rep 2022; 12:17524. [PMID: 36266430 PMCID: PMC9585052 DOI: 10.1038/s41598-022-22152-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 10/10/2022] [Indexed: 01/13/2023] Open
Abstract
We compared the efficacy of tocilizumab and etanercept in inhibiting radiographic progression of joint destruction in rheumatoid arthritis. Overall, 187 patients treated with etanercept or tocilizumab were selected. To adjust for baseline patient characteristics between the tocilizumab and etanercept treatment groups, a propensity score matching was performed. Radiographic progression of joint destruction was compared between patients treated with tocilizumab or etanercept. Clinical disease activity index (CDAI) and modified health assessment questionnaire (mHAQ) scores at the administration of biologic treatment and after 12 months of tocilizumab and etanercept therapy were measured and compared to radiographical parameters between the groups. Levels of C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), CDAI, and mHAQ scores improved after 12 months of treatment in the two groups. Proportion of patients with no Sharp erosion score progression was significantly higher with tocilizumab treatment than with etanercept treatment (p = 0.032). Multivariate analysis demonstrated that Sharp erosion score was significantly associated with baseline CDAI (odds ratio, 1.05; 95% confidence interval, 1.003-1.099, p = 0.037). Tocilizumab treatment suppressed joint erosion progression compared to etanercept, and the progression correlated with baseline CDAI.
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24
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Arman Y, Atici A, Altun O, Sarikaya R, Yoldemir SA, Akarsu M, Kutlu O, Ozturk GZ, Demir P, Ozcan M, Bayraktarli RY, Tukek T. Can the Serum Endocan Level Be Used as a Biomarker to Predict Subclinical Atherosclerosis in Patients with Prediabetes? Arq Bras Cardiol 2022; 119:544-550. [PMID: 35946756 PMCID: PMC9563878 DOI: 10.36660/abc.20210797] [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: 09/20/2021] [Accepted: 04/06/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Patients with prediabetes have an increased risk of atherosclerotic cardiovascular disease; therefore, early detection is important. OBJECTIVE The present study aimed to reveal the usability of serum endocan levels as a biomarker in the diagnosis of subclinical atherosclerosis in patients with prediabetes, based on CIMT measurements. METHODS Participants were classified according to the presence (n=42) or absence (n=42) of prediabetes. Serum endocan, fasting blood sugar, fasting insulin, and glycated hemoglobin (HbA1c) values of patients were examined, and CIMT was measured. The level of significance for statistical analysis was 0.05. RESULTS While serum endocan levels were found to be lower in patients with prediabetes, when compared to the control group (p=0.042), CIMT values were found to be higher (p=0.046). When evaluated by multivariate regression analysis, the serum endocan level was found to be associated with CIMT, regardless of other parameters (p=0.007). A negative correlation was found between plasma fasting insulin and endocan levels (r=-0.320, p=0.001). CONCLUSIONS Carotid intima media thickness was found to be high and the serum endocan level was low in patients with prediabetes. Decreased serum endocan levels in patients with prediabetes may be a contributing factor to atherosclerosis formation mechanisms.
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Affiliation(s)
- Yucel Arman
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Internal Medicine, Istanbul - Turquia
| | - Adem Atici
- Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Department of Cardiology, Istanbul - Turquia
| | - Ozgur Altun
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Internal Medicine, Istanbul - Turquia
| | - Remzi Sarikaya
- University of Health Sciences, Van Education and Research Hospital, Department of Cardiology, Van - Turquia
| | - Sengül Aydin Yoldemir
- University of Health Sciences, Istanbul Bakirkoy Dr Sadi Konuk Training and Research Hospital, Department of İnternal Medicine, Istanbul - Turquia
| | - Murat Akarsu
- University of Health Sciences, Kanunİ Sultan Suleiman Traİnİng and Research Hospİtal, Department of İnternal Medicine, Istanbul - Turquia
| | - Orkide Kutlu
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Internal Medicine, Istanbul - Turquia
| | - Guzin Zeren Ozturk
- University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Department of Family Medicine, Istanbul - Turquia
| | - Pinar Demir
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Internal Medicine, Istanbul - Turquia
| | - Mustafa Ozcan
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Internal Medicine, Istanbul - Turquia
| | - Recep Yilmaz Bayraktarli
- University of Health Sciences, Prof Dr Cemil Tascioglu City Hospital, Department of Radiology, Istanbul - Turquia
| | - Tufan Tukek
- Istanbul University, Istanbul Faculty of Medicine, Department of İnternal Medicine, Istanbul - Turquia
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25
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Use of Generalized Weighted Quantile Sum Regressions of Tumor Necrosis Factor Alpha and Kidney Function to Explore Joint Effects of Multiple Metals in Blood. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19127399. [PMID: 35742647 PMCID: PMC9223707 DOI: 10.3390/ijerph19127399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 02/04/2023]
Abstract
Exposure to heavy metals could lead to adverse health effects by oxidative reactions or inflammation. Some essential elements are known as reactors of anti-inflammatory enzymes or coenzymes. The relationship between tumor necrosis factor alpha (TNF-α) and heavy metal exposures was reported. However, the interaction between toxic metals and essential elements in the inflammatory response remains unclear. This study aimed to explore the association between arsenic (As), cadmium (Cd), lead (Pb), cobalt (Co), copper (Cu), selenium (Se), and zinc (Zn) in blood and TNF-α as well as kidney function. We enrolled 421 workers and measured the levels of these seven metals/metalloids and TNF-α in blood; kidney function was calculated by CKD-EPI equation. We applied weighted quantile sum (WQS) regression and group WQS regression to assess the effects of metal/metalloid mixtures to TNF-α and kidney function. We also approached the relationship between metals/metalloids and TNF-α by generalized additive models (GAM). The relationship of the exposure−response curve between Pb level and TNF-α in serum was found significantly non-linear after adjusting covariates (p < 0.001). Within the multiple-metal model, Pb, As, and Zn were associated with increased TNF-α levels with effects dedicated to the mixture of 50%, 31%, and 15%, respectively. Grouped WQS revealed that the essential metal group showed a significantly negative association with TNF-α and kidney function. The toxic metal group found significantly positive associations with TNF-α, serum creatinine, and WBC but not for eGFR. These results suggested Pb, As, Zn, Se, and mixtures may act on TNF-α even through interactive mechanisms. Our findings offer insights into what primary components of metal mixtures affect inflammation and kidney function during co-exposure to metals; however, the mechanisms still need further research.
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26
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Rahimian R, Belliveau C, Chen R, Mechawar N. Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder. Front Psychiatry 2022; 13:871997. [PMID: 35782423 PMCID: PMC9245023 DOI: 10.3389/fpsyt.2022.871997] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/23/2022] [Indexed: 12/19/2022] Open
Abstract
Increasing evidence supports the notion that neuroinflammation plays a critical role in the etiology of major depressive disorder (MDD), at least in a subset of patients. By virtue of their capacity to transform into reactive states in response to inflammatory insults, microglia, the brain's resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have demonstrated the ability of microglia to recognize pathogens or damaged cells, leading to the activation of a cytotoxic response that exacerbates damage to brain cells. However, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. MDD has been associated with chronic priming of microglia. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to depression and associated impairments in neuroplasticity. In this context, modifying microglia phenotype by tuning inflammatory pathways might have important translational relevance to harness neuroinflammation in MDD. Interestingly, it was recently shown that different microglial phenotypes are associated with distinct metabolic pathways and analysis of the underlying molecular mechanisms points to an instrumental role for energy metabolism in shaping microglial functions. Here, we review various canonical pro-inflammatory, anti-inflammatory and metabolic pathways in microglia that may provide new therapeutic opportunities to control neuroinflammation in brain disorders, with a strong focus on MDD.
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Affiliation(s)
- Reza Rahimian
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
| | - Claudia Belliveau
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Rebecca Chen
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Naguib Mechawar
- Douglas Mental Health University Institute, McGill Group for Suicide Studies, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Department of Psychiatry, McGill University, Montreal, QC, Canada
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27
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Sylvester M, Son A, Schwartz DM. The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations. Front Immunol 2022; 13:818039. [PMID: 35281022 PMCID: PMC8907424 DOI: 10.3389/fimmu.2022.818039] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/02/2022] [Indexed: 12/30/2022] Open
Abstract
Autoinflammatory diseases are a group of clinical syndromes characterized by constitutive overactivation of innate immune pathways. This results in increased production of or responses to monocyte- and neutrophil-derived cytokines such as interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Type 1 interferon (IFN). By contrast, clinical allergy is caused by dysregulated type 2 immunity, which is characterized by expansion of T helper 2 (Th2) cells and eosinophils, as well as overproduction of the associated cytokines IL-4, IL-5, IL-9, and IL-13. Traditionally, type 2 immune cells and autoinflammatory effectors were thought to counter-regulate each other. However, an expanding body of evidence suggests that, in some contexts, autoinflammatory pathways and cytokines may potentiate type 2 immune responses. Conversely, type 2 immune cells and cytokines can regulate autoinflammatory responses in complex and context-dependent manners. Here, we introduce the concepts of autoinflammation and type 2 immunity. We proceed to review the mechanisms by which autoinflammatory and type 2 immune responses can modulate each other. Finally, we discuss the epidemiology of type 2 immunity and clinical allergy in several monogenic and complex autoinflammatory diseases. In the future, these interactions between type 2 immunity and autoinflammation may help to expand the spectrum of autoinflammation and to guide the management of patients with various autoinflammatory and allergic diseases.
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Affiliation(s)
- McKella Sylvester
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Aran Son
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Daniella M Schwartz
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
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28
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Xie G, Tang L, Xie Y, Xie L. Secondary Metabolites from Hericium erinaceus and Their Anti-Inflammatory Activities. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072157. [PMID: 35408555 PMCID: PMC9000484 DOI: 10.3390/molecules27072157] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 11/23/2022]
Abstract
Hericium erinaceus, a culinary and medicinal mushroom, is widely consumed in Asian countries. Chemical investigation on the fruiting bodies of Hericium erinaceus led to the isolation of one new ergostane-type sterol fatty acid ester, erinarol K (1); and eleven known compounds: 5α,8α -epidioxyergosta-6,22-dien-3β-yl linoleate (2); ethyl linoleate (3); linoleic acid (4); hericene A (5); hericene D (6); hericene E (7); ergosta-4,6,8(14),22-tetraen-3-one (8); hericenone F (9); ergosterol (10); ergosterol peroxide (11); 3β,5α,6α,22E-ergosta-7,22-diene-3,5,6-triol 6-oleate (12). The chemical structures of the compounds were determined by 1D and 2D NMR (nuclear magnetic resonance) spectroscopy, mass spectra, etc. Anti-inflammatory effects of the isolated aromatic compounds (5–7, 9) were evaluated in terms of inhibition of pro-inflammatory mediator (TNF-α, IL-6 and NO) production in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophage cells. The results showed that compounds 5 and 9 exhibited moderate activity against TNF-α (IC50: 78.50 μM and 62.46 μM), IL-6 (IC50: 56.33 μM and 48.50 μM) and NO (IC50: 87.31 μM and 76.16 μM) secretion. These results supply new information about the secondary metabolites of Hericium erinaceus and their anti-inflammatory effects.
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Affiliation(s)
- Guangbo Xie
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China; (L.T.); (Y.X.)
- Correspondence: (G.X.); (L.X.)
| | - Lan Tang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China; (L.T.); (Y.X.)
| | - Yu Xie
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China; (L.T.); (Y.X.)
| | - Liyuan Xie
- Sichuan Institute of Edible Fungi, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China
- Correspondence: (G.X.); (L.X.)
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Hsieh HL, Yu MC, Cheng LC, Chu MY, Huang TH, Yeh TS, Tsai MM. Quercetin exerts anti-inflammatory effects via inhibiting tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in normal human gastric epithelial cells. World J Gastroenterol 2022; 28:1139-1158. [PMID: 35431500 PMCID: PMC8985486 DOI: 10.3748/wjg.v28.i11.1139] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/23/2021] [Accepted: 02/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric injury is the most common digestive system disease worldwide and involves inflammation, which can lead to gastric ulcer or gastric cancer (GC). Matrix metallopeptidase-9 [MMP-9 (gelatinase-B)] plays an important role in inflammation and GC progression. Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities. However, the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear.
AIM To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells.
METHODS The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the anti-inflammatory effects of quercetin. The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line. Cell migration was measured using Transwell assay. The expression of proto-oncogene tyrosine-protein kinase Src (c-Src), phospho (p)-c-Src, extracellular-signal-regulated kinase 2 (ERK2), p-ERK1/2, c-Fos, p-c-Fos, nuclear factor kappa B (NF-κB/p65), and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction (qRT–PCR) and gelatin zymography, respectively.
RESULTS qRT-PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-α antagonist (TNFR inhibitor) in a dose- and time-dependent manner. Quercetin and TNF-α antagonists decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, TNF-α antagonist, PP1, U0126, and tanshinone IIA (TSIIA) reduced TNF-α-induced c-Fos phosphorylation and AP-1–Luciferase (Luc) activity in a dose- and time-dependent manner. Pretreatment with quercetin, TNF-α antagonist, PP1, U0126, or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65–Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and these results were reduced by pretreatment with quercetin or a TNF-α antagonist.
CONCLUSION Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src–ERK1/2 and c-Fos or NF-κB pathways.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Mei-Yi Chu
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Tzu-Hao Huang
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Chang CC, Peng SY, Tsao HH, Huang HT, Lai XY, Hsu HJ, Jiang SJ. A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation. Front Pharmacol 2022; 13:853818. [PMID: 35370629 PMCID: PMC8965626 DOI: 10.3389/fphar.2022.853818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/18/2022] [Indexed: 11/13/2022] Open
Abstract
Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-α, IL-1β, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-α, IL-1β, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.
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Affiliation(s)
- Chun-Chun Chang
- Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shih-Yi Peng
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hao-Hsiang Tsao
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hsin-Ting Huang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Xing-Yan Lai
- Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hao-Jen Hsu
- Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
- *Correspondence: Hao-Jen Hsu, ; Shinn-Jong Jiang,
| | - Shinn-Jong Jiang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
- *Correspondence: Hao-Jen Hsu, ; Shinn-Jong Jiang,
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31
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Gayer FA, Fichtner A, Legler TJ, Reichardt HM. A Coculture Model Mimicking the Tumor Microenvironment Unveils Mutual Interactions between Immune Cell Subtypes and the Human Seminoma Cell Line TCam-2. Cells 2022; 11:cells11050885. [PMID: 35269507 PMCID: PMC8909655 DOI: 10.3390/cells11050885] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/24/2022] [Accepted: 03/02/2022] [Indexed: 11/24/2022] Open
Abstract
Testicular germ cell cancer (TGCC) is the most common type of cancer in young men. Seminomas account for around half of them and are characterized by a pronounced infiltration of immune cells. So far, the impact of the tumor microenvironment (TME) on disease progression, especially the interaction of individual immune cell subtypes with the tumor cells, remains unclear. To address this question, we used an in vitro TME model involving the seminoma-derived cell line Tcam-2 and immune cell subsets purified from human peripheral blood. T cells and monocytes were strongly activated when individually cocultured with Tcam-2 cells as revealed by increased expression of activation markers and pro-inflammatory cytokines both on the mRNA and protein level. Importantly, the interaction between tumor and immune cells was mutual. Gene expression of pluripotency markers as well as markers of proliferation and cell cycle activity were upregulated in Tcam-2 cells in cocultures with T cells, whereas gene expression of SOX17, a marker for seminomas, was unaltered. Interestingly, the impact of monocytes on gene expression of Tcam-2 cells was less pronounced, indicating that the effects of individual immune cell subsets on tumor cells in the TME are highly specific. Collectively, our data indicate that seminoma cells induce immune cell activation and thereby generate a strong pro-inflammatory milieu, whereas T cells conversely increase the proliferation, metastatic potential, and stemness of tumor cells. Although the employed model does not fully mimic the physiological situation found in TGCC in vivo, it provides new insights potentially explaining the connection between inflammatory infiltrates in seminomas and their tendency to burn out and metastasize.
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Affiliation(s)
- Fabian A. Gayer
- Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany;
- Clinic of Urology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Alexander Fichtner
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Tobias J. Legler
- Department of Transfusion Medicine, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Holger M. Reichardt
- Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany;
- Correspondence: ; Tel.: +49-551-39-63365
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32
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Zacks DN, Kocab AJ, Choi JJ, Gregory-Ksander MS, Cano M, Handa JT. Cell Death in AMD: The Rationale for Targeting Fas. J Clin Med 2022; 11:jcm11030592. [PMID: 35160044 PMCID: PMC8836408 DOI: 10.3390/jcm11030592] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/18/2022] [Accepted: 01/21/2022] [Indexed: 11/21/2022] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the developed world. While great advances have been made in the treatment of the neovascular (“wet”) form of the disease, there is still a significant need for therapies that prevent the vision loss associated with the advanced forms of dry, atrophic AMD. In this atrophic form, retinal pigment epithelial (RPE) and photoreceptor cell death is the ultimate cause of vision loss. In this review, we summarize the cell death pathways and their relation to RPE and retinal cell death in AMD. We review the data that support targeting programmed cell death through inhibition of the Fas receptor as a novel approach to preserve these structures and that this effect results from inhibiting both canonical death pathway activation and reducing the associated inflammatory response. These data lay the groundwork for current clinical strategies targeting the Fas pathway in this devastating disease.
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Affiliation(s)
- David N. Zacks
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA;
- Correspondence: ; Tel.: +1-734-936-0871
| | | | - Joanne J. Choi
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Meredith S. Gregory-Ksander
- Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA;
| | - Marisol Cano
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA; (M.C.); (J.T.H.)
| | - James T. Handa
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA; (M.C.); (J.T.H.)
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33
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Posadas N, Baquiran JIP, Nada MAL, Kelly M, Conaco C. Microbiome diversity and host immune functions influence survivorship of sponge holobionts under future ocean conditions. THE ISME JOURNAL 2022; 16:58-67. [PMID: 34218251 PMCID: PMC8692459 DOI: 10.1038/s41396-021-01050-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 06/20/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023]
Abstract
The sponge-associated microbial community contributes to the overall health and adaptive capacity of the sponge holobiont. This community is regulated by the environment and the immune system of the host. However, little is known about the effect of environmental stress on the regulation of host immune functions and how this may, in turn, affect sponge-microbe interactions. In this study, we compared the bacterial diversity and immune repertoire of the demosponge, Neopetrosia compacta, and the calcareous sponge, Leucetta chagosensis, under varying levels of acidification and warming stress based on climate scenarios predicted for 2100. Neopetrosia compacta harbors a diverse microbial community and possesses a rich repertoire of scavenger receptors while L. chagosensis has a less diverse microbiome and an expanded range of pattern recognition receptors and immune response-related genes. Upon exposure to RCP 8.5 conditions, the microbiome composition and host transcriptome of N. compacta remained stable, which correlated with high survival (75%). In contrast, tissue necrosis and low survival (25%) of L. chagosensis was accompanied by microbial community shifts and downregulation of host immune-related pathways. Meta-analysis of microbiome diversity and immunological repertoire across poriferan classes further highlights the importance of host-microbe interactions in predicting the fate of sponges under future ocean conditions.
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Affiliation(s)
- Niño Posadas
- grid.11134.360000 0004 0636 6193Marine Science Institute, University of the Philippines Diliman, Quezon City, Philippines
| | - Jake Ivan P. Baquiran
- grid.11134.360000 0004 0636 6193Marine Science Institute, University of the Philippines Diliman, Quezon City, Philippines
| | - Michael Angelou L. Nada
- grid.11134.360000 0004 0636 6193Marine Science Institute, University of the Philippines Diliman, Quezon City, Philippines
| | - Michelle Kelly
- grid.419676.b0000 0000 9252 5808National Institute of Water and Atmospheric Research, Ltd., Auckland, New Zealand
| | - Cecilia Conaco
- grid.11134.360000 0004 0636 6193Marine Science Institute, University of the Philippines Diliman, Quezon City, Philippines
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Saalfeld W, Mixon AM, Zelie J, Lydon EJ. Differentiating Psoriatic Arthritis from Osteoarthritis and Rheumatoid Arthritis: A Narrative Review and Guide for Advanced Practice Providers. Rheumatol Ther 2021; 8:1493-1517. [PMID: 34519965 PMCID: PMC8572231 DOI: 10.1007/s40744-021-00365-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/24/2021] [Indexed: 12/18/2022] Open
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects multiple organ systems and is characterized by skin and joint manifestations. PsA is frequently undiagnosed and/or misdiagnosed, especially because of the similarities in clinical presentation shared with other arthritic diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). An accurate and timely diagnosis of PsA is crucial to prevent delays in optimal treatment, which can lead to irreversible joint damage and increased functional disability. Patients are usually seen by a number of different healthcare providers on their path to a diagnosis of PsA, including advanced practice providers (APPs). This review provides a comprehensive overview of the characteristic features that can be used to facilitate the differentiation of PsA from RA and OA. Detailed information on clinical manifestations, biomarkers, radiologic features, and therapeutic recommendations for PsA included here can be applied in routine clinical settings to provide APPs with the confidence and knowledge to recognize and refer patients more accurately to rheumatologists for management of patients with PsA.
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Affiliation(s)
- William Saalfeld
- Arthritis Center of Nebraska, 3901 Pine Lake Road, Suite 120, Lincoln, NE, 68516, USA.
| | - Amanda M Mixon
- Arthritis and Rheumatology Clinic of Northern Colorado, Fort Collins, CO, USA
| | - Jonna Zelie
- URMC Division of Rheumatology, Rochester, NY, USA
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35
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Upregulation of Bax, TNF-α and down-regulation of Bcl-2 in liver cancer cells treated with HL-7 and HL-10 peptides. Biologia (Bratisl) 2021. [DOI: 10.1007/s11756-021-00800-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Adverse effects of biologic anti-inflammatory agents on the respiratory system: A review. Afr J Thorac Crit Care Med 2021; 27. [PMID: 34430870 PMCID: PMC8327682 DOI: 10.7196/ajtccm.2021.v27i2.117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 12/12/2022] Open
Abstract
The therapy of autoimmune rheumatological conditions has undergone significant changes with the introduction of biologic antiinflammatory agents including cytokine antagonists and agents that interfere with the function of T and B cells or those that inhibit
intracellular enzymes such as Janus kinase (JAK). Although useful to control inflammation, these agents may be associated with druginduced lung disease, which may be difficult to differentiate from pulmonary disorders caused by the underlying autoimmune diseases.
This review aims to provide a description of lung disease, both infectious and non-infectious, that may be induced by the administration of
biologic anti-inflammatory agents with emphasis on inhibitors of tumour necrosis factor, interleukin-1, interleukin-6 and JAK.
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Lidington D, Wan H, Bolz SS. Cerebral Autoregulation in Subarachnoid Hemorrhage. Front Neurol 2021; 12:688362. [PMID: 34367053 PMCID: PMC8342764 DOI: 10.3389/fneur.2021.688362] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/25/2021] [Indexed: 12/28/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with a high rate of mortality and morbidity. The poor clinical outcome can be attributed to the biphasic course of the disease: even if the patient survives the initial bleeding emergency, delayed cerebral ischemia (DCI) frequently follows within 2 weeks time and levies additional serious brain injury. Current therapeutic interventions do not specifically target the microvascular dysfunction underlying the ischemic event and as a consequence, provide only modest improvement in clinical outcome. SAH perturbs an extensive number of microvascular processes, including the “automated” control of cerebral perfusion, termed “cerebral autoregulation.” Recent evidence suggests that disrupted cerebral autoregulation is an important aspect of SAH-induced brain injury. This review presents the key clinical aspects of cerebral autoregulation and its disruption in SAH: it provides a mechanistic overview of cerebral autoregulation, describes current clinical methods for measuring autoregulation in SAH patients and reviews current and emerging therapeutic options for SAH patients. Recent advancements should fuel optimism that microvascular dysfunction and cerebral autoregulation can be rectified in SAH patients.
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Affiliation(s)
- Darcy Lidington
- Department of Physiology, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Microvascular Medicine at the Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Toronto, ON, Canada
| | - Hoyee Wan
- Department of Physiology, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Microvascular Medicine at the Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Toronto, ON, Canada
| | - Steffen-Sebastian Bolz
- Department of Physiology, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Microvascular Medicine at the Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Toronto, ON, Canada.,Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, ON, Canada
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38
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Emre C, Do KV, Jun B, Hjorth E, Alcalde SG, Kautzmann MAI, Gordon WC, Nilsson P, Bazan NG, Schultzberg M. Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease. Acta Neuropathol Commun 2021; 9:116. [PMID: 34187579 PMCID: PMC8244172 DOI: 10.1186/s40478-021-01216-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 06/08/2021] [Indexed: 12/19/2022] Open
Abstract
Sustained brain chronic inflammation in Alzheimer’s disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates β-amyloid (Aβ) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aβ pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.
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Md Dom ZI, Pipino C, Krolewski B, O'Neil K, Satake E, Krolewski AS. Effect of TNFα stimulation on expression of kidney risk inflammatory proteins in human umbilical vein endothelial cells cultured in hyperglycemia. Sci Rep 2021; 11:11133. [PMID: 34045516 PMCID: PMC8160214 DOI: 10.1038/s41598-021-90496-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFα. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFα in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFα-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFα. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes.
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Affiliation(s)
- Zaipul I Md Dom
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Caterina Pipino
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA.,Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Bozena Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Eiichiro Satake
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Andrzej S Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA. .,Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA.
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Seria E, Galea G, Borg J, Schembri K, Grech G, Tagliaferro SS, Felice A. Novel leukocyte-depleted platelet-rich plasma-based skin equivalent as an in vitro model of chronic wounds: a preliminary study. BMC Mol Cell Biol 2021; 22:28. [PMID: 33971814 PMCID: PMC8111747 DOI: 10.1186/s12860-021-00366-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 04/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic leg ulcerations are associated with Haemoglobin disorders, Type2 Diabetes Mellitus, and long-term venous insufficiency, where poor perfusion and altered metabolism develop into a chronic inflammation that impairs wound closure. Skin equivalent organotypic cultures can be engineered in vitro to study skin biology and wound closure by modelling the specific cellular components of the skin. This study aimed to develop a novel bioactive platelet-rich plasma (PRP) leukocyte depleted scaffold to facilitate the study of common clinical skin wounds in patients with poor chronic skin perfusion and low leukocyte infiltration. A scratch assay was performed on the skin model to mimic two skin wound conditions, an untreated condition and a condition treated with recombinant tumour necrotic factor (rTNF) to imitate the stimulation of an inflammatory state. Gene expression of IL8 and TGFA was analysed in both conditions. Statistical analysis was done through ANOVA and paired student t-test. P < 0.05 was considered significant. RESULTS A skin model that consisted of a leukocyte-depleted, platelet-rich plasma scaffold was setup with embedded fibroblasts as dermal equivalents and seeded keratinocytes as multi-layered epidermis. Gene expression levels of IL8 and TGFA were significantly different between the control and scratched conditions (p < 0.001 and p < 0.01 respectively), as well as between the control and treated conditions (p < 0.01 and p < 0.001 respectively). The scratch assay induced IL8 upregulation after 3 h (p < 0.05) which continued to increase up to day 1 (p < 0.05). On the other hand, the administration of TNF led to the downregulation of IL8 (p < 0.01), followed by an upregulation on day 2. IL8 gene expression decreased in the scratched condition after day 1 as the natural healing process took place and was lower than in the treated condition on day 8 (p < 0.05). Both untreated and treated conditions showed a downregulation of TGFA 3 h after scratch when compared with the control condition (p < 0.01). Administration of rTNF showed significant downregulation of TGFA after 24 h when compared with the control (p < 0.01) and treated conditions (p < 0.05). CONCLUSION This study suggests that a leukocyte-depleted PRP-based skin equivalent can be a useful model for the in vitro study of chronic skin wounds related to poor skin perfusion.
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Affiliation(s)
- Elisa Seria
- Department of Physiology and Biochemistry and Centre of Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta.
| | - George Galea
- National Blood Transfusion Centre and Department of Pathology, University of Malta, Msida, MSD2080, Malta
| | - Joseph Borg
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, MSD2080, Malta
| | - Kevin Schembri
- Department of Surgery, Faculty of Medicine and Surgery, University of Malta Medical School and Mater Dei Hospital, Msida, MSD2080, Malta
| | - Gabriella Grech
- Department of Surgery, Faculty of Medicine and Surgery, University of Malta Medical School and Mater Dei Hospital, Msida, MSD2080, Malta
| | - Sarah Samut Tagliaferro
- Department of Physiology and Biochemistry and Centre of Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta
| | - Alexander Felice
- Department of Physiology and Biochemistry and Centre of Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta
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Jagdmann S, Berchtold D, Gutbier B, Witzenrath M, Meisel A, Meisel C, Dames C. Efficacy and safety of intratracheal IFN-γ treatment to reverse stroke-induced susceptibility to pulmonary bacterial infections. J Neuroimmunol 2021; 355:577568. [PMID: 33862420 DOI: 10.1016/j.jneuroim.2021.577568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 04/01/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022]
Abstract
Stroke-induced immunosuppression contributes to the development of stroke-associated pneumonia (SAP). Experiments in mice demonstrated that apoptosis of IFN-γ producing cells and reduced IFN-γ secretion resulted in impaired immune responses and the development of pneumonia after middle cerebral artery occlusion (MCAo). In the present study, we investigated the efficacy of intratracheal IFN-γ treatment to prevent SAP and demonstrated that modest benefits on pulmonary cytokine response in IFN-γ treated stroke mice did not prevent spontaneously developing infections and even slightly reduced bacterial clearance of aspirated pneumococci. Our results suggest that pulmonary IFN-γ treatment is not an effective preventive measure for SAP.
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Affiliation(s)
- Sandra Jagdmann
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute for Medical Immunology, Augustenburger Platz 1, Berlin 13353, Germany.
| | - Daniel Berchtold
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Experimental Neurology, Charitéplatz 1, Berlin 10117, Germany.
| | - Birgitt Gutbier
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Division of Pulmonary Inflammation, Charitéplatz 1, Berlin 10117, Germany.
| | - Martin Witzenrath
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Division of Pulmonary Inflammation, Charitéplatz 1, Berlin 10117, Germany; Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Infectious Diseases and Respiratory Medicine, Charitéplatz 1, Berlin 10117, Germany.
| | - Andreas Meisel
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Experimental Neurology, Charitéplatz 1, Berlin 10117, Germany; Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Center for Stroke Research Berlin, Charitéplatz 1, Berlin 10117, Germany; Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Neurocure Cluster of Excellence, Charitéplatz 1, Berlin 10117, Germany; Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Neurology, Charitéplatz 1, Berlin 10117, Germany.
| | - Christian Meisel
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute for Medical Immunology, Augustenburger Platz 1, Berlin 13353, Germany; Labor Berlin-Charité Vivantes, Sylter Str. 2, Berlin 13353, Germany.
| | - Claudia Dames
- Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute for Medical Immunology, Augustenburger Platz 1, Berlin 13353, Germany; Charité - Universitätsmedizin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Experimental Neurology, Charitéplatz 1, Berlin 10117, Germany.
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Location, location, location: how the tissue microenvironment affects inflammation in RA. Nat Rev Rheumatol 2021; 17:195-212. [PMID: 33526927 DOI: 10.1038/s41584-020-00570-2] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 01/30/2023]
Abstract
Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, or at all in some individuals, and cannot cure or prevent this disease. One major obstacle to developing better drugs is a lack of complete understanding of how inflammatory joint disease arises and progresses. Emerging evidence indicates an important role for the tissue microenvironment in the pathogenesis of RA. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix (ECM). These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a main site of disease activity in RA, positional and disease stage-specific cellular diversity exist. Improved understanding of the architecture of the synovium from gross anatomy to the single-cell level, in parallel with evidence demonstrating how the synovial ECM is vital for synovial homeostasis and how dysregulated signals from the ECM promote chronic inflammation and tissue destruction in the RA joint, has opened up new ways of thinking about the pathogenesis of RA. These new ideas provide novel therapeutic approaches for patients with difficult-to-treat disease and could also be used in disease prevention.
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Genetic polymorphism of tumor necrosis factor alpha (TNF-α) and tumor necrosis factor beta (TNF-β) genes and risk of oral pre-cancer and cancer in North Indian population. Oral Maxillofac Surg 2021; 26:33-43. [PMID: 33779868 DOI: 10.1007/s10006-020-00929-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/02/2020] [Indexed: 10/21/2022]
Abstract
OBJECTIVE There are inconclusive data connecting single-nucleotide polymorphisms (SNPs) of TNF-α (rs361525) and TNF-β (rs909253) to potential malignant oral disorder (PMOD) such as lichen planus and oral fibrosis. Here, we have investigated the risk of oral squamous cell carcinoma as well as oral pre-cancerous lesions in North Indian population with the polymorphism of the TNFα/ β genes. MATERIAL AND METHODS A total 500 patients with oral pre-cancer and OSCC and 500 healthy volunteers were genotypes for the TNF-α (-238) G/A (rs361525) and TNF-β (252) A/G (rs909253) gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test. RESULTS Compared to the GG genotype, the GA genotype of TNF-α (G238A) polymorphism (rs361525) has been found to significantly increase the risk of oral disease (OR = 1.99) and especially the risk of lichen planus and OSCC (OR = 2.805 and 5.790, respectively). Similarly, the risk of oral disease was also more in the heterozygote (AG) than the common allele homozygote (AA) of TNF-β (A252G) polymorphism (rs909253) (OR = 1.483). CONCLUSION We conclude that the SNPs rs361525 and rs909253 were significantly associated with oral pre-cancer and OSCC.
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The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol Sci 2021; 22:ijms22052719. [PMID: 33800290 PMCID: PMC7962638 DOI: 10.3390/ijms22052719] [Citation(s) in RCA: 779] [Impact Index Per Article: 194.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases.
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Khajouei A, Hosseini E, Abdizadeh T, Kian M, Ghasemi S. Beneficial effects of minocycline on the ovary of polycystic ovary syndrome mouse model: Molecular docking analysis and evaluation of TNF-α, TNFR2, TLR-4 gene expression. J Reprod Immunol 2021; 144:103289. [PMID: 33610928 DOI: 10.1016/j.jri.2021.103289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 02/01/2021] [Accepted: 02/08/2021] [Indexed: 11/29/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common cause of ovulatory infertility. Inflammation may be involved in the pathogenesis and development of PCOS. We investigated the anti-inflammatory effect of minocycline on TNF-α, TNFR2, and TLR4 expression levels and the key features of PCOS in a mouse model. Molecular docking was performed by Molecular Operating Environment software. PCOS was induced by estradiol valerate injection (EV) (2 mg/kg/day) in 40 mice. After 28 days, the mice were divided into five groups, including control, PCOS, minocycline control, minocycline PCOS model (50 mg/kg), and letrozole PCOS (0.5 mg/kg). The Levels of FSH, LH, E2, and testosterone were determined by ELISA. H&E staining was used for histological analysis in the ovarian tissues. Docking scores were -10.35, -10.57, and -12.45 kcal/mol for TNFα, TLR-4, and TNFR2, respectively. The expression levels of TNF-α, TNFR2, and TLR4 were detected by Real-Time PCR. PCOS models exhibited acyclicity, a significant increase in E2 levels (P < 0.01), and no difference in FSH, LH, and testosterone. The expression levels of TNF-α, TNFR2, and TLR-4 significantly increased in PCOS (2.70, 7.90, and 14.83-fold, respectively). EV treatment significantly increased graafian follicles (P < 0.001) and decreased corpus luteum (CL) (P < 0.01). Minocycline treatment in PCOS led to a significant decrease in E2 (P < 0.01) and graafian follicles (P < 0.001) and a significant increase in the CL numbers (P < 0.05). Our findings showed the positive effects of minocycline on estradiol level, CL and graafian follicles counts, suggesting that minocycline might inhibit these proteins and improve ovulation in our mouse model of PCOS.
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Affiliation(s)
- Azadeh Khajouei
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Elham Hosseini
- Department of Obstetrics and Gynecology, IVF Clinic, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Tooba Abdizadeh
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Mahdie Kian
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Sorayya Ghasemi
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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Wu L, Li X, Lin Q, Chowdhury F, Mazumder MH, Du W. FANCD2 and HES1 suppress inflammation-induced PPARɣ to prevent haematopoietic stem cell exhaustion. Br J Haematol 2021; 192:652-663. [PMID: 33222180 PMCID: PMC7856217 DOI: 10.1111/bjh.17230] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
The Fanconi anaemia protein FANCD2 suppresses PPARƔ to maintain haematopoietic stem cell's (HSC) function; however, the underlying mechanism is not known. Here we show that FANCD2 acts in concert with the Notch target HES1 to suppress inflammation-induced PPARƔ in HSC maintenance. Loss of HES1 exacerbates FANCD2-KO HSC defects. However, deletion of HES1 does not cause more severe inflammation-mediated HSC defects in FANCD2-KO mice, indicating that both FANCD2 and HES1 are required for limiting detrimental effects of inflammation on HSCs. Further analysis shows that both FANCD2 and HES1 are required for transcriptional repression of inflammation-activated PPARg promoter. Inflammation orchestrates an overlapping transcriptional programme in HSPCs deficient for FANCD2 and HES1, featuring upregulation of genes in fatty acid oxidation (FAO) and oxidative phosphorylation. Loss of FANCD2 or HES1 augments both basal and inflammation-primed FAO. Targeted inhibition of PPARƔ or the mitochondrial carnitine palmitoyltransferase-1 (CPT1) reduces FAO and ameliorates HSC defects in inflammation-primed HSPCs deleted for FANCD2 or HES1 or both. Finally, depletion of PPARg or CPT1 restores quiescence in these mutant HSCs under inflammatory stress. Our results suggest that this novel FANCD2/HES1/PPARƔ axis may constitute a key component of immunometabolic regulation, connecting inflammation, cellular metabolism and HSC function.
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Affiliation(s)
- Limei Wu
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
| | - Xue Li
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
| | - Qiqi Lin
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
| | - Fabliha Chowdhury
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
| | - Md H. Mazumder
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
| | - Wei Du
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University
- Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University Cancer Institute, Morgantown, WV
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine
- Genome Stability Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
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Tsujimoto H, Kobayashi M, Sugasawa H, Ono S, Kishi Y, Ueno H. Potential mechanisms of tumor progression associated with postoperative infectious complications. Cancer Metastasis Rev 2021; 40:285-296. [PMID: 33389285 DOI: 10.1007/s10555-020-09945-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
There is increasing evidence that postoperative infectious complications (PICs) are associated with poor prognosis after potentially curative surgery. However, the role that PICs play in tumor development remains unclear. In this article, we reviewed the literature for novel insights on the mechanisms of cancer progression associated with PICs. The Medline and EMBASE databases were searched for publications regarding the role of suppression of antitumor immunity by PIC in tumor progression and selected 916 manuscripts were selected for this review. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding cancer progression under septic conditions. Initially, sepsis/microbial infection dramatically activates the systemic immune system with increases in pro-inflammatory mediators, which results in the development of systemic inflammatory response syndrome; however, when sepsis persists in septic patients, a shift toward an anti-inflammatory immunosuppressive state, characterized by macrophage deactivation, reduced antigen presentation, T cell anergy, and a shift in the T helper cell pattern to a predominantly TH2-type response, occurs. Thus, various cytokine reactions and the immune status dynamically change during microbial infection, including PIC. We proposed three possible mechanisms for the tumor progression associated with PIC: first, a mechanism in which microbes and/or microbial PAMPs may be directly involved in cancer growth; second, a mechanism in which factors released from immunocompetent cells during infections may affect tumor progression; and third, a mechanism in which factors suppress host tumor immunity during infections, which may result in tumor progression. A more detailed understanding by surgeons of the immunological features in cancer patients with PIC can subsequently open new avenues for improving unfavorable long-term oncological outcomes associated with PICs.
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Affiliation(s)
- Hironori Tsujimoto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan.
| | - Minako Kobayashi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Hidekazu Sugasawa
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Satoshi Ono
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
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Li JJ, Yi S, Wei L. Ocular Microbiota and Intraocular Inflammation. Front Immunol 2020; 11:609765. [PMID: 33424865 PMCID: PMC7786018 DOI: 10.3389/fimmu.2020.609765] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 11/23/2020] [Indexed: 12/20/2022] Open
Abstract
The term ocular microbiota refers to all types of commensal and pathogenic microorganisms present on or in the eye. The ocular surface is continuously exposed to the environment and harbors various commensals. Commensal microbes have been demonstrated to regulate host metabolism, development of immune system, and host defense against pathogen invasion. An unbalanced microbiota could lead to pathogenic microbial overgrowth and cause local or systemic inflammation. The specific antigens that irritate the deleterious immune responses in various inflammatory eye diseases remain obscure, while recent evidence implies a microbial etiology of these illnesses. The purpose of this review is to provide an overview of the literature on ocular microbiota and the role of commensal microbes in several eye diseases. In addition, this review will also discuss the interaction between microbial pathogens and host factors involved in intraocular inflammation, and evaluate therapeutic potential of targeting ocular microbiota to treat intraocular inflammation.
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Affiliation(s)
- Jing Jing Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Sanjun Yi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lai Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Quan W, Ma S, Zhu Y, Shao Q, Hou J, Li X. Apigenin-7- O-β-d-(6″- p-coumaroyl)-glucopyranoside reduces myocardial ischaemia/reperfusion injury in an experimental model via regulating the inflammation response. PHARMACEUTICAL BIOLOGY 2020; 58:80-88. [PMID: 31887257 PMCID: PMC6968710 DOI: 10.1080/13880209.2019.1701043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/18/2019] [Accepted: 11/30/2019] [Indexed: 05/25/2023]
Abstract
Context: Traditionally, Clematis tangutica Korsh. (Ranunculaceae) is used as a Tibetan herb for treating indigestion and blood stasis in China. Recently, a flavonoid glycoside, apigenin-7-O-β-d-(6″-p-coumaroyl)-glucopyranoside (APG), was isolated from the whole plant of C. tangutica.Objective: To investigate the cardioprotective effects of APG against myocardial ischaemia/reperfusion injury (MI/RI) and the possible mechanism.Materials and methods: Animals were subjected to 30 min/3 h MI/RI model. At the end of reperfusion, infarct size (IS), histopathology, serum levels CK-MB, LDH, TNF-α, IL-6 and MPO activities were detected. Phospho-IκB-α, ICAM-1 and NF-κB were assessed in vivo. Neonatal rat cardiomyocytes were pre-treated with or without APG, followed by stimulation with 8 h/2 h oxygen and glucose deprived/reoxygenation (OGD/R) model. Cell viability, LDH and cardiomyocyte apoptosis were assessed. The expression levels of phospho-IκB-α and NF-κB were measured in vitro.Results: Treatment with APG significantly reduced the following indicators in vivo (p < 0.05): (1) the IS (16.2%); (2) morphology score (1.67); (3) myocardial injury enzymes: CK-MB (26.2 ng/mL) and LDH (688 U/L); (4) pro-inflammatory cytokines: TNF-α (31.5 pg/mL) and IL-6 (163.8 pg/mL); (5) MPO activity (2.75 U/mg); (6) expression levels of phospho-IκB-α (0.47), NF-κB (2.87) and ICAM-1 (10.2). Moreover, treatment with APG also remarkably (p < 0.05) attenuated the following indicators in vitro: (1) LDH level (206 U/L); (2) cardiomyocyte apoptosis; (3) phospho-IκB-α (1.37) and NF-κB (2.50).Conclusions: APG possesses protective effects against MI/RI injury in rats and OGD/R-induced injury in cardiomyocytes by suppressing translocation of NF-κB and reducing inflammatory response; consequently, APG is helpful for treatment of ischaemic heart disease.
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Affiliation(s)
- Wei Quan
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, China
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Shanbo Ma
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Yanrong Zhu
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Qing Shao
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, China
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Jixing Hou
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Xiaoqiang Li
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, China
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Hayashi S, Matsubara T, Fukuda K, Funahashi K, Hashimoto M, Maeda T, Kamenaga T, Takashima Y, Matsumoto T, Niikura T, Kuroda R. Predictive factors for effective selection of Interleukin-6 inhibitor and tumor necrosis factor inhibitor in the treatment of rheumatoid arthritis. Sci Rep 2020; 10:16645. [PMID: 33024253 PMCID: PMC7538428 DOI: 10.1038/s41598-020-73968-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 09/15/2020] [Indexed: 12/27/2022] Open
Abstract
Treatment of rheumatoid arthritis (RA) is aimed at long-term remission and inhibition of joint destruction by different biologic drugs. However, the choice of a particular biologic agent based on individual cases of RA remains unestablished. Interleukin-6 (IL-6) inhibitor and tumor necrosis factor (TNF) inhibitor are common biologics used for the treatment of RA. This study aimed to investigate predictive factors for effective selection of tocilizumab (IL-6 inhibitor) and etanercept (TNF inhibitor) in patients with RA. This is a retrospective cohort study. The 196 patients analyzed in this study were divided into four groups: tocilizumab treatment as the first biologic group (TCZ first, 42 patients), tocilizumab as second/ third biologic group (TCZ second, 34 patients), etanercept as the first biologic group (ETN first, 103 patients) and etanercept as second/third group (ETN second, 17 patients). Visual analog scale (VAS), clinical disease activity index (CDAI), and modified health assessment questionnaire (mHAQ) scores at the initiation of biologic treatment and after 6 months of tocilizumab and etanercept therapy were measured and compared to clinical parameters and radiographical parameters among the four groups. CRP, MMP-3, VAS, CDAI, and HAQ were improved after 6 months of treatment in all groups. Improvement of clinical outcomes was correlated with CRP value, duration of RA, and Sharp scores at the initiation of treatment. Multivariate analysis demonstrated improvement in CDAI was significantly associated with the yearly progression of erosion according to the Sharp score in TCZ first group (OR, 1.5; 95% CI, 1.03–2.07) and was negatively associated with the duration of RA (OR, 0.49; 95% CI, 0.29–0.86) at the initiation of treatment with ETN first group. We identified the predictive factors for effective selection of tocilizumab and etanercept treatment and established the effectiveness of tocilizumab for the patients with rapid progressive joint erosion and etanercept for the early administration from diagnosis of RA.
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Affiliation(s)
- Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Tsukasa Matsubara
- Department of Orthopaedic Surgery, Matsubara Mayflower Hospital, Kato, Japan
| | - Koji Fukuda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | | | | | - Toshihisa Maeda
- Department of Orthopaedic Surgery, Matsubara Mayflower Hospital, Kato, Japan
| | - Tomoyuki Kamenaga
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoshinori Takashima
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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