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1
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Wang C, Yu T, Wang Y, Xu M, Wang J, Zhao Y, Wan Q, Wang L, Yang J, Zhou J, Li B, Yu Y, Shen Y. Targeting the EP2 receptor ameliorates inflammatory bowel disease in mice by enhancing the immunosuppressive activity of T reg cells. Mucosal Immunol 2025; 18:418-430. [PMID: 39746548 DOI: 10.1016/j.mucimm.2024.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (Treg) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E2 (PGE2), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE2 regulates Treg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE2 receptor subtype 2 (EP2) is highly expressed in Treg cells. Treg cell-specific deletion of EP2 resulted in increased Treg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of Treg cells in mice. Adoptive transfer of EP2-deficient Treg cells attenuated naïve CD4+ T cell transfer-induced colitis in Rag1-/- mice. Mice with EP2-deficient Treg cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a Treg-dependent manner. Mechanistically, activation of EP2 suppressed Treg cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE2/EP2 axis as a key negative modulator of Treg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.
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MESH Headings
- Animals
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
- Mice
- Inflammatory Bowel Diseases/immunology
- Inflammatory Bowel Diseases/metabolism
- Inflammatory Bowel Diseases/etiology
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP2 Subtype/genetics
- Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors
- Mice, Knockout
- Disease Models, Animal
- Dextran Sulfate
- Colitis/chemically induced
- Colitis/immunology
- Dinoprostone/metabolism
- Mice, Inbred C57BL
- Adoptive Transfer
- Immune Tolerance
- Humans
- Granzymes/metabolism
- Signal Transduction
- Trinitrobenzenesulfonic Acid
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Affiliation(s)
- Chenchen Wang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Tingting Yu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yuexin Wang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Mengtong Xu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jingjing Wang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yan Zhao
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Qiangyou Wan
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Lu Wang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jie Yang
- Department of Biochemistry and Molecular Biology, Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Jie Zhou
- Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Bin Li
- Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Yu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Yujun Shen
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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2
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Cheng S, Chen W, Guo Z, Ding C, Zuo R, Liao Q, Liu G. Paeonol alleviates ulcerative colitis by modulating PPAR-γ and nuclear factor-κB activation. Sci Rep 2024; 14:18390. [PMID: 39117680 PMCID: PMC11310503 DOI: 10.1038/s41598-024-68992-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the gastrointestinal tract. Although paeonol has been used for treating UC due to its anti-inflammatory and antioxidant effects, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of paeonol's action on UC by conducting in-vitro and in-vivo studies using NCM460 cells and RAW264.7 cells, and the DSS-induced mice colitis model. The in vitro studies demonstrate that paeonol exerts inhibitory effects on the activation of the NF-κB signaling pathway through upregulating PPARγ expression, thereby attenuating pro-inflammatory cytokine production, reducing reactive oxygen species levels, and promoting M2 macrophage polarization. These effects are significantly abrogated upon addition of the PPARγ inhibitor GW9662. Moreover, UC mice treated with paeonol showed increased PPARγ expression, which reduced inflammation and apoptosis to maintain intestinal epithelial barrier integrity. In conclusion, our findings suggest that paeonol inhibits the NF-κB signaling pathway by activating PPARγ, reducing inflammation and oxidative stress and improving Dss-induced colitis. This study provides a new insight into the mechanism of treating UC by paeonol.
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Affiliation(s)
- Shuyu Cheng
- School of Medicine Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China
| | - Wujin Chen
- The Third People's Hospital of Fujian Province, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, 350000, China
| | - Zhenzhen Guo
- School of Pharmaceutical Sciences Xiamen University, Xiamen University, Xiamen, 361102, China
| | - Chenchun Ding
- School of Medicine Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China
| | - Renjie Zuo
- School of Medicine Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China
| | - Quan Liao
- School of Medicine Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China
| | - Guoyan Liu
- School of Medicine Xiamen University, Xiamen University, Xiamen, 361102, Fujian, China.
- School of Pharmaceutical Sciences Xiamen University, Xiamen University, Xiamen, 361102, China.
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 350108, China.
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3
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Fuertes-Agudo M, Luque-Tévar M, Cucarella C, Martín-Sanz P, Casado M. Advances in Understanding the Role of NRF2 in Liver Pathophysiology and Its Relationship with Hepatic-Specific Cyclooxygenase-2 Expression. Antioxidants (Basel) 2023; 12:1491. [PMID: 37627486 PMCID: PMC10451723 DOI: 10.3390/antiox12081491] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
Oxidative stress and inflammation play an important role in the pathophysiological changes of liver diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes, thus playing a key role in protecting against oxidative damage. Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin biosynthesis. Its expression has always been associated with the induction of inflammation, but we have shown that, in addition to possessing other benefits, the constitutive expression of COX-2 in hepatocytes is beneficial in reducing inflammation and oxidative stress in multiple liver diseases. In this review, we summarized the role of NRF2 as a main agent in the resolution of oxidative stress, the crucial role of NRF2 signaling pathways during the development of chronic liver diseases, and, finally we related its action to that of COX-2, where it appears to operate as its partner in providing a hepatoprotective effect.
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Affiliation(s)
- Marina Fuertes-Agudo
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - María Luque-Tévar
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Carme Cucarella
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Paloma Martín-Sanz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
- Instituto de Investigaciones Biomédicas (IIB) “Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Marta Casado
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
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4
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Bénard A, Mittelstädt A, Klösch B, Glanz K, Müller J, Schoen J, Nüse B, Brunner M, Naschberger E, Stürzl M, Mattner J, Muñoz LE, Sohn K, Grützmann R, Weber GF. IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils. Cell Rep 2023; 42:112637. [PMID: 37300834 DOI: 10.1016/j.celrep.2023.112637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/03/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3-/- show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.
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Affiliation(s)
- Alan Bénard
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
| | - Anke Mittelstädt
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Bettina Klösch
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Karolina Glanz
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Jan Müller
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Janina Schoen
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Björn Nüse
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Maximilian Brunner
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Naschberger
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Stürzl
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Luis E Muñoz
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Georg F Weber
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
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5
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Wautier JL, Wautier MP. Pro- and Anti-Inflammatory Prostaglandins and Cytokines in Humans: A Mini Review. Int J Mol Sci 2023; 24:ijms24119647. [PMID: 37298597 DOI: 10.3390/ijms24119647] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/18/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFβ families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation.
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Affiliation(s)
- Jean-Luc Wautier
- Faculté de Médecine, Université Denis Diderot Paris Cité, 75013 Paris, France
| | - Marie-Paule Wautier
- Faculté de Médecine, Université Denis Diderot Paris Cité, 75013 Paris, France
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Transcriptional responses of human intestinal epithelial HT-29 cells to spore-displayed p40 derived from Lacticaseibacillus rhamnosus GG. BMC Microbiol 2022; 22:316. [PMID: 36550414 PMCID: PMC9772600 DOI: 10.1186/s12866-022-02735-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUNDS The aims of this study were to construct spore-displayed p40, a Lacticaseibacillus rhamnosus GG-derived soluble protein, using spore surface display technology and to evaluate transcriptional responses in human intestinal epithelial cells. RESULTS p40 was displayed on the surface of Bacillus subtilis spores using spore coat protein CotG as an anchor protein. Effects of spore-displayed p40 (CotG-p40) on gene expression of intestinal epithelial cell line HT-29 were evaluated by transcriptome analysis using RNA-sequencing. As a result of differentially expressed gene (DEG) analysis, 81 genes were up-regulated and 82 genes were down-regulated in CotG-p40 stimulated cells than in unstimulated cells. Gene ontology enrichment analysis showed that CotG-p40 affected biological processes such as developmental process, metabolic process, cell surface receptor linked signaling pathway, and retinoic acid metabolic process. Gene-gene network analysis suggested that 10 DEGs (EREG, FOXF1, GLI2, PTGS2, SPP1, MMP19, TNFRSF1B, PTGER4, CLDN18, and ALDH1A3) activated by CotG-p40 were associated with probiotic action. CONCLUSIONS This study demonstrates the regulatory effects of CotG-p40 on proliferation and homeostasis of HT-29 cells. This study provided comprehensive insights into the transcriptional response of human intestinal epithelial cells stimulated by CotG-p40.
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Matheny RW, Kolb AL, Geddis AV, Roberts BM. Celecoxib impairs primary human myoblast proliferation and differentiation independent of cyclooxygenase 2 inhibition. Physiol Rep 2022; 10:e15481. [PMID: 36325583 PMCID: PMC9630763 DOI: 10.14814/phy2.15481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 06/16/2023] Open
Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)-2-selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes. Primary muscle cells were treated with celecoxib or NS-398 (a pharmacological inhibitor of COX-2) as a control. Celecoxib administration significantly reduced myoblast proliferation, viability, fusion, and myotube area in a dose-dependent manner, whereas NS-398 had no effect on any of these outcomes. Celecoxib treatment was also associated with reduced phosphorylation of ribosomal protein S6 in myoblasts, and reduced phosphorylation of AKT, p70S6K, S6, and ERK in myotubes. In contrast, NS-398 did not alter phosphorylation of these molecules in myoblasts or myotubes. In myoblasts, celecoxib significantly reduced mitochondrial membrane potential and respiration, as evidenced by the decreased citric acid cycle (CAC) intermediates cis-aconitic acid, alpha-keto-glutarate acid, succinate acid, and malic acid. Similar results were observed in myotubes, although celecoxib also reduced pyruvic acid, citric acid, and fumaric acid. NS-398 did not affect CAC intermediates in myoblasts or myotubes. Together, these data reveal that celecoxib inhibits proliferation, differentiation, intracellular signaling, and mitochondrial function in primary human myoblasts and myotubes independent of its function as a COX-2 inhibitor.
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Affiliation(s)
- Ronald W. Matheny
- Military Performance DivisionUS Army Research Institute of Environmental MedicineNatickMassachusettsUSA
- Military Operational Medicine Research ProgramFt. DetrickMarylandUSA
| | - Alexander L. Kolb
- Military Performance DivisionUS Army Research Institute of Environmental MedicineNatickMassachusettsUSA
| | - Alyssa V. Geddis
- Military Performance DivisionUS Army Research Institute of Environmental MedicineNatickMassachusettsUSA
| | - Brandon M. Roberts
- Military Performance DivisionUS Army Research Institute of Environmental MedicineNatickMassachusettsUSA
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8
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Senousy SR, El-Daly M, Ibrahim ARN, Khalifa MMA, Ahmed ASF. Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study. Biomedicines 2022; 10:biomedicines10071613. [PMID: 35884918 PMCID: PMC9312943 DOI: 10.3390/biomedicines10071613] [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: 05/25/2022] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 12/30/2022] Open
Abstract
In cases of sepsis, the immune system responds with an uncontrolled release of proinflammatory cytokines and reactive oxygen species. The lungs, kidneys, and liver are among the early impacted organs during sepsis and are a direct cause of mortality. The aim of this study was to compare the effects of infliximab (IFX) and celecoxib (CLX) on septic rats that went through a cecal ligation and puncture (CLP) surgery to induce sepsis. This study included four groups: sham, CLP (untreated), and CLP-treated with CLX or IFX. The administration of “low dose” CLX or IFX was performed after 2 h following the induction of sepsis. Twenty-four hours following the induction of sepsis, the rats were sacrificed and blood samples were collected to evaluate kidney, liver, and lung injuries. MDA and NOx content, in addition to SOD activity and GSH levels, were evaluated in the tissue homogenates of each group. Tissue samples were also investigated histopathologically. In a separate experiment, the same groups were employed to evaluate the survival of septic rats in a 7-day observation period. The results of this study showed that treatment with either CLX or IFX ameliorated the three organs’ damage compared to septic-untreated rats, decreased oxidative stress, enhanced the antioxidant defense, and reduced serum cytokines. As a result, a higher survival rate resulted: 62.5% and 37.5% after the administration of CLX and IFX, respectively, compared to 0% in the CLP group after 7 days. No significant differences were observed between the two agents in all measured parameters. Histopathological examination confirmed the observed results. In conclusion, CLX and IFX ameliorated lung, kidney, and liver injuries associated with sepsis through anti-inflammatory and antioxidant actions, which correlated to the increase in survival observed with both of them.
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Affiliation(s)
- Shaymaa Ramzy Senousy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Ahmed R. N. Ibrahim
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61511, Egypt
- Correspondence: ; Tel.: +96-65-5408-8979
| | - Mohamed Montaser A. Khalifa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Al-Shaimaa F. Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
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9
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Ho WJ, Smith JNP, Park YS, Hadiono M, Christo K, Jogasuria A, Zhang Y, Broncano AV, Kasturi L, Dawson DM, Gerson SL, Markowitz SD, Desai AB. 15-PGDH regulates hematopoietic and gastrointestinal fitness during aging. PLoS One 2022; 17:e0268787. [PMID: 35587945 PMCID: PMC9119474 DOI: 10.1371/journal.pone.0268787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/08/2022] [Indexed: 11/30/2022] Open
Abstract
Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Julianne N. P. Smith
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Young Soo Park
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Matthew Hadiono
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Kelsey Christo
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Alvin Jogasuria
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Yongyou Zhang
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Alyssia V. Broncano
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Lakshmi Kasturi
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Dawn M. Dawson
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Stanton L. Gerson
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
- University Hospitals Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Sanford D. Markowitz
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
- University Hospitals Seidman Cancer Center, Cleveland, Ohio, United States of America
| | - Amar B. Desai
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
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10
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Kojima F, Sekiya H, Hioki Y, Kashiwagi H, Kubo M, Nakamura M, Maehana S, Imamichi Y, Yuhki KI, Ushikubi F, Kitasato H, Ichikawa T. Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate-induced colitis in mice lacking microsomal prostaglandin E synthase-1. Inflamm Regen 2022; 42:1. [PMID: 34983695 PMCID: PMC8725565 DOI: 10.1186/s41232-021-00188-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD. Supplementary Information The online version contains supplementary material available at 10.1186/s41232-021-00188-1.
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Affiliation(s)
- Fumiaki Kojima
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.
| | - Hiroki Sekiya
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yuka Hioki
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Hitoshi Kashiwagi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0373, Japan
| | - Masaki Nakamura
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Shotaro Maehana
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yoshitaka Imamichi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Koh-Ichi Yuhki
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Fumitaka Ushikubi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Hidero Kitasato
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Takafumi Ichikawa
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
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11
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Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
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Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
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12
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Li S, Wang T, Wu B, Fu W, Xu B, Pamuru RR, Kennett M, Vanamala JKP, Reddivari L. Anthocyanin-containing purple potatoes ameliorate DSS-induced colitis in mice. J Nutr Biochem 2021; 93:108616. [PMID: 33705951 DOI: 10.1016/j.jnutbio.2021.108616] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/19/2020] [Accepted: 02/04/2021] [Indexed: 12/13/2022]
Abstract
Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is on the rise worldwide. Approximately three million people suffer from IBD in the United States alone, but the current therapeutic options (e.g., corticosteroids) come with adverse side effects including reduced ability to fight infections. Thus, there is a critical need for developing effective, safe and evidence-based food products with anti-inflammatory activity. This study evaluated the antiinflammatory potential of purple-fleshed potato using a dextran sodium sulfate (DSS) murine model of colitis. Mice were randomly assigned to control (AIN-93G diet), P15 (15% purple-fleshed potato diet) and P25 (25% purple-fleshed potato diet) groups. Colitis was induced by 2% DSS administration in drinking water for six days. The results indicated that purple-fleshed potato supplementation suppressed the DSS-induced reduction in body weight and colon length as well as the increase in spleen and liver weights. P15 and P25 diets suppressed the elevation in the intestinal permeability, colonic MPO activity, mRNA expression and protein levels of pro-inflammatory interleukins IL-6 and IL-17, the relative abundance of specific pathogenic bacteria such as Enterobacteriaceae, Escherichia coli (E. coli) and pks+ E. coli, and the increased flagellin levels induced by DSS treatment. P25 alone suppressed the elevated systemic MPO levels in DSS-exposed mice, and elevated the relative abundance of Akkermansia muciniphila (A. muciniphila) as well as attenuated colonic mRNA expression level of IL-17 and the protein levels of IL-6 and IL-1β. Therefore, the purple-fleshed potato has the potential to aid in the amelioration of UC symptoms.
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Affiliation(s)
- Shiyu Li
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | - Tianmin Wang
- Department of Plant Science, Penn State University, University Park, Pennsylvania, USA
| | - Binning Wu
- Department of Plant Science, Penn State University, University Park, Pennsylvania, USA
| | - Wenyi Fu
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | - Baojun Xu
- Food Science and Technology Program, BNU-HKBU United International College, Zhuhai, Guangdong, China
| | - Ramachandra Reddy Pamuru
- Department of Food Science, Penn State University, UniversityPark, Pennsylvania, USA; Department of Biochemistry, Yogi Vemana University, Kadapa, Andhra Pradesh, India
| | - Mary Kennett
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, Pennsylvania, USA
| | - Jairam K P Vanamala
- Department of Food Science, Penn State University, UniversityPark, Pennsylvania, USA
| | - Lavanya Reddivari
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA.
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13
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Wang B, Sun S, Liu M, Chen H, Liu N, Wu Z, Wu G, Dai Z. Dietary L-Tryptophan Regulates Colonic Serotonin Homeostasis in Mice with Dextran Sodium Sulfate-Induced Colitis. J Nutr 2020; 150:1966-1976. [PMID: 32386234 DOI: 10.1093/jn/nxaa129] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/31/2019] [Accepted: 04/13/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown. OBJECTIVE We investigated the role of Trp supplementation on the serotonin receptor (HTR)-mediated immune response in the colon of mice with dextran sodium sulfate (DSS)-induced colitis. METHODS In Experiment 1, male C57BL/6 mice were randomly assigned to 1 of 4 groups: Control (Con) or L-Trp supplementation [0.1 mg/(g body weight·d) in drinking water] (Trp) with (+DSS) or without 2% DSS in drinking water from days 8 to 14 of the 17-d study. In Experiments 2 and 3, Trp + DSS (Expt. 2) or DSS (Expt. 3) mice were treated as described above and subcutaneously administered with HTR1A or HTR4 antagonists (or their combination) or an HTR2 agonist from days 8 to 14 of the 15-d study. Changes in immune cell phenotypes, inflammatory mediators, and related cell signaling molecules were assessed by flow cytometry, real-time PCR, or Western blot. The mRNA abundances of Trp hydroxylase (Tph1), serotonin reuptake transporter (Slc6a4), and Htr in the colon were also assessed. RESULTS Trp supplementation before DSS treatment upregulated the expression of colonic Slc6a4 (0.49 compared with 0.30), Htr1a (1.14 compared with 0.65), and Htr4 (1.08 compared with 0.70), downregulated the expression of Htr2a (1.54 compared with 1.89), and decreased the colonic serotonin concentration (11.5 compared with 14.8 nmol/g tissue) (P < 0.01). Trp regulated the DSS-induced immune response partly through attenuating the activation of toll-like receptor 4 (TLR4)-STAT3 signaling and nucleus p-65. Either an HTR2 agonist or HTR1A and HTR4 antagonists reversed the effects of Trp. CONCLUSIONS In mice treated with DSS, Trp supplementation before DSS administration improved colonic immune responses partly by reducing colonic serotonin and subsequent interactions with HTR1A and HTR4, which are known to be present on neutrophils and macrophages.
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Affiliation(s)
- Bin Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
| | - Shiqiang Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
| | - Moyan Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
| | - Hui Chen
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
| | - Ning Liu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, P.R. China
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, P.R. China
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14
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Song M, Lan Y, Wu X, Han Y, Wang M, Zheng J, Li Z, Li F, Zhou J, Xiao J, Cao Y, Xiao H. The chemopreventive effect of 5-demethylnobiletin, a unique citrus flavonoid, on colitis-driven colorectal carcinogenesis in mice is associated with its colonic metabolites. Food Funct 2020; 11:4940-4952. [PMID: 32459257 PMCID: PMC10726105 DOI: 10.1039/d0fo00616e] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
5-Demethylnobiletin (5DN) is a unique flavonoid mainly found in citrus fruits. In this study, we determined the chemopreventive effects of 5DN and its major colonic metabolites on both a colitis-driven colon carcinogenesis mouse model and a human colon cancer cell model. In azoxymethane/dextran sulfate sodium-treated mice, dietary 5DN (0.05% w/w in the diet) significantly decreased the tumor incidence, multiplicity and burden, and showed potent anti-proliferative, proapoptotic, and anti-inflammatory activities in mouse colon tissue. Three major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1), 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), were found in the colonic mucosa of 5DN-treated mice, and the combined level of these metabolites in mouse colonic mucosa was 1.56-fold higher than that of 5DN. Cell culture studies revealed that 5DN and its colonic metabolites profoundly inhibited the growth of human colon cancer cells by inducing cell cycle arrest, triggering apoptosis and modulating key signaling proteins related to cell proliferation and apoptosis. Importantly, the colonic metabolites, especially M1, showed much stronger effects than those produced by 5DN itself. Overall, our results demonstrated that dietary 5DN significantly inhibited colitis-driven colon carcinogenesis in mice, and this chemopreventive effect was associated with its metabolites in the colon.
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Affiliation(s)
- Mingyue Song
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China and Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Yaqi Lan
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Xian Wu
- Department of Food Science, University of Massachusetts, Amherst, MA, USA. and Department of Kinesiology and Health, Miami University, Oxford, OH, USA
| | - Yanhui Han
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Minqi Wang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jinkai Zheng
- Department of Food Science, University of Massachusetts, Amherst, MA, USA. and Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, P.R. China
| | - Zhengze Li
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Fang Li
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jiazhi Zhou
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou, Guangdong, P.R. China and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, Guangdong, P.R. China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
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15
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Chaparala A, Poudyal D, Tashkandi H, Witalison EE, Chumanevich AA, Hofseth JL, Nguyen I, Hardy O, Pittman DL, Wyatt MD, Windust A, Murphy EA, Nagarkatti M, Nagarkatti P, Hofseth LJ. Panaxynol, a bioactive component of American ginseng, targets macrophages and suppresses colitis in mice. Oncotarget 2020; 11:2026-2036. [PMID: 32547701 PMCID: PMC7275787 DOI: 10.18632/oncotarget.27592] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 04/03/2020] [Indexed: 12/11/2022] Open
Abstract
Ulcerative colitis has a significant impact on the quality of life for the patients, and can substantially increase the risk of colon cancer in patients suffering long-term. Conventional treatments provide only modest relief paired with a high risk of side effects, while complementary and alternative medicines can offer safe and effective options. Over the past decade, we have shown that both American ginseng and its hexane fraction (HAG) have anti-oxidant and anti-inflammatory properties that can suppress mouse colitis and prevent colitis-associated colon cancer. With the goal of isolating a single active compound, we further fractionated HAG, and found the most abundant molecule in this fraction was the polyacetylene, panaxynol (PA). After isolating and characterizing PA, we tested the efficacy of PA in the treatment and prevention of colitis in mice and studied the mechanism of action. We demonstrate here that PA effectively treats colitis in a Dextran Sulfate Sodium mouse model by targeting macrophages for DNA damage and apoptosis. This study provides additional mechanistic evidence that American ginseng can be used for conventional treatment of colitis and other diseases associated with macrophage dysfunction.
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Affiliation(s)
- Anusha Chaparala
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Deepak Poudyal
- Laboratory of Human Retrovirology and Immunoinformatics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Hossam Tashkandi
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Erin E Witalison
- Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC, USA
| | - Alexander A Chumanevich
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Jenna L Hofseth
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Ivy Nguyen
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Olivia Hardy
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Douglas L Pittman
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Michael D Wyatt
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - Anthony Windust
- Measurement Science and Standards, National Research Council, Ottawa, ON, Canada
| | - Elizabeth A Murphy
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Lorne J Hofseth
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA
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16
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Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene. Sci Rep 2020; 10:4883. [PMID: 32184453 PMCID: PMC7078201 DOI: 10.1038/s41598-020-61775-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 03/04/2020] [Indexed: 12/15/2022] Open
Abstract
Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1−/−) and conditional knockout in intestinal epithelial cells (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a−/− mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a−/− mice administered DSS and in macrophages isolated from Slco2a1−/− mice than in the WT counterparts. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a−/− mice. Concentrations of PGE2 in colon tissues and macrophages from Slco2a1−/− mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.
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17
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Yang M, Bose S, Lim SK, Kim H. Preventive Effects of Pyungwi-san against Dextran Sulfate Sodium- and Clostridium difficile-Induced Inflammatory Bowel Disease in Mice. Int J Mol Sci 2019; 20:ijms20246346. [PMID: 31888274 PMCID: PMC6940993 DOI: 10.3390/ijms20246346] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 12/20/2022] Open
Abstract
Several lines of evidence indicate that inflammatory bowel disease (IBD) is associated with Clostridium difficile (CD) infection as a consequence of gut dysbiosis. Currently available treatments of IBD are either not very effective or have adverse effects. Pyungwi-san (PWS), a traditional Chinese herbal formulation, has long been used to treat gastrointestinal disorders. The present study was conducted to investigate the efficacy of PWS against dextran sulfate sodium (DSS) + CD-induced IBD in mice. The animals received DSS in drinking water for seven days to produce DSS-induced acute colitis. In the DSS + CD group, the DSS-fed animals were orally administered with CD spores twice during the DSS treatment period. We observed that exposure of DSS + CD-treated animals to PWS significantly decreased the disease activity index; prevented the shortening of colonic length and increases in spleen size and weight; restored colonic histological parameters by significantly increasing mucus thickness, crypt depth, and goblet cell numbers; protected the tight junction proteins; improved the profiles of pro-inflammatory and anti-inflammatory cytokines; and normalized the abundance ratio of the Firmicutes/Bacteroidetes in the gut. Thus, PWS exerted a number of protective effects on DSS + CD-induced colitis, which might be mediated via restoration of a balance in gut microbial communities.
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Affiliation(s)
- Meng Yang
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, 814 Siksa-dong, Ilsandong-gu, Goyang-si 10326, Korea; (M.Y.); (S.-K.L.)
| | - Shambhunath Bose
- Scientific Consultant Board, BexPharm Korea Healthcare Ltd. 51, Seongsui-ro, Seongdong-gu, Seoul 04781, Korea;
| | - Soo-Kyoung Lim
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, 814 Siksa-dong, Ilsandong-gu, Goyang-si 10326, Korea; (M.Y.); (S.-K.L.)
| | - Hojun Kim
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, 814 Siksa-dong, Ilsandong-gu, Goyang-si 10326, Korea; (M.Y.); (S.-K.L.)
- Correspondence: ; Tel.: +82-31-961-9111; Fax: +82-31-961-9009
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18
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Wallace JL. Eicosanoids in the gastrointestinal tract. Br J Pharmacol 2019; 176:1000-1008. [PMID: 29485681 PMCID: PMC6451073 DOI: 10.1111/bph.14178] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/06/2018] [Accepted: 02/09/2018] [Indexed: 01/06/2023] Open
Abstract
Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low-grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the other hand, in some circumstances, these mediators can become major drivers of inflammatory processes when the lining of the GI tract is breached. Drugs such as nonsteroidal anti-inflammatories, by altering the production of various eicosanoids, can dramatically impact the ability of the GI tract to respond appropriately to injury. Disorders such as inflammatory bowel disease appear to be driven in part by altered production of eicosanoids. Several classes of drugs have been developed that target eicosanoids. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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Affiliation(s)
- John L Wallace
- Department of Physiology and PharmacologyUniversity of CalgaryCalgaryABT2N 4N1Canada
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19
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Nunes NS, Kim S, Sundby M, Chandran P, Burks SR, Paz AH, Frank JA. Temporal clinical, proteomic, histological and cellular immune responses of dextran sulfate sodium-induced acute colitis. World J Gastroenterol 2018; 24:4341-4355. [PMID: 30344419 PMCID: PMC6189848 DOI: 10.3748/wjg.v24.i38.4341] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 08/06/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the temporal clinical, proteomic, histological and cellular immune profiles of dextran sulfate sodium (DSS)-induced acute colitis.
METHODS Acute colitis was induced in C57Bl/6 female mice by administration of 1%, 2% or 3% DSS in drinking water for 7 d. Animals were monitored daily for weight loss, stool consistency and blood in the stool, while spleens and colons were harvested on day 8. A time course analysis was performed in mice ingesting 3% DSS, which included colon proteomics through multiplex assay, colon histological scoring by a blinded investigator, and immune response through flow cytometry or immunohistochemistry of the spleen, mesenteric lymph node and colon.
RESULTS Progressive worsening of clinical colitis was observed with increasing DSS from 1% to 3%. In mice ingesting 3% DSS, colon shortening and increase in pro-inflammatory factors starting at day 3 was observed, with increased spleen weights at day 6 and day 8. This coincided with cellular infiltration in the colon from day 2 to day 8, with progressive accumulation of macrophages F4/80+, T helper CD4+ (Th), T cytotoxic CD8+ (Tcyt) and T regulatory CD25+ (Treg) cells, and progressive changes in colonic pathology including destruction of crypts, loss of goblet cells and depletion of the epithelial barrier. Starting on day 4, mesenteric lymph node and/or spleen presented with lower levels of Treg, Th and Tcyt cells, suggesting an immune cell tropism to the gut.
CONCLUSION These results demonstrate that the severity of experimental colitis is dependent on DSS concentration, correlated with clinical, proteomic, histological and cellular immune response on 3% DSS.
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Affiliation(s)
- Natalia Schneider Nunes
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
- Gastroenterology and Hepatology Sciences Graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-093, Brazil
| | - Saejeong Kim
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
| | - Maggie Sundby
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
| | - Parwathy Chandran
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
| | - Scott Robert Burks
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
| | - Ana Helena Paz
- Gastroenterology and Hepatology Sciences Graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-093, Brazil
| | - Joseph Alan Frank
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
- National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, United States
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20
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Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the USA. It is of practical importance to identify novel therapeutic targets of CRC to develop new anti-cancer drugs and to discover novel biomarkers of CRC to develop new detection methods. Eicosanoids, which are metabolites of polyunsaturated fatty acids produced by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, are important lipid-signaling molecules involved in the regulation of inflammation and tumorigenesis. Substantial studies have shown that the profiles of eicosanoids are deregulated in CRC, and the enzymes, metabolites, and receptors in the eicosanoid signaling cascade play critical roles in regulating colonic inflammation and colon tumorigenesis. In this review, we discuss the roles of the COX, LOX, and CYP pathways in the carcinogenesis of CRC.
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Affiliation(s)
- Yuxin Wang
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Weicang Wang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Katherine Z Sanidad
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA
| | - Pei-An Shih
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Xinfeng Zhao
- College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Guodong Zhang
- Department of Food Science, University of Massachusetts, Amherst, MA, USA.
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, USA.
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21
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Nakajima A, Vogelzang A, Maruya M, Miyajima M, Murata M, Son A, Kuwahara T, Tsuruyama T, Yamada S, Matsuura M, Nakase H, Peterson DA, Fagarasan S, Suzuki K. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J Exp Med 2018; 215:2019-2034. [PMID: 30042191 PMCID: PMC6080902 DOI: 10.1084/jem.20180427] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/23/2018] [Accepted: 06/20/2018] [Indexed: 12/19/2022] Open
Abstract
Immunoglobulin A (IgA) promotes health by regulating the composition and function of gut microbiota, but the molecular requirements for such homeostatic IgA function remain unknown. We found that a heavily glycosylated monoclonal IgA recognizing ovalbumin coats Bacteroides thetaiotaomicron (B. theta), a prominent gut symbiont of the phylum Bacteroidetes. In vivo, IgA alters the expression of polysaccharide utilization loci (PUL), including a functionally uncharacterized molecular family provisionally named Mucus-Associated Functional Factor (MAFF). In both mice and humans, MAFF is detected predominantly in mucus-resident bacteria, and its expression requires the presence of complex microbiota. Expression of the MAFF system facilitates symbiosis with other members of the phylum Firmicutes and promotes protection from a chemically induced model of colitis. Our data reveal a novel mechanism by which IgA promotes symbiosis and colonic homeostasis.
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Affiliation(s)
- Akira Nakajima
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Alexis Vogelzang
- Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan
| | - Mikako Maruya
- Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan
| | - Michio Miyajima
- Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan
| | - Megumi Murata
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Aoi Son
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomomi Kuwahara
- Department of Microbiology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tatsuaki Tsuruyama
- Center for Anatomical, Pathological, Forensic Medical Research and Department of Drug and Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterology and Hepatology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Daniel A Peterson
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sidonia Fagarasan
- Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan
| | - Keiichiro Suzuki
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan .,Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan
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22
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Benelli R, Venè R, Ferrari N. Prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2), a complex target for colorectal cancer prevention and therapy. Transl Res 2018; 196:42-61. [PMID: 29421522 DOI: 10.1016/j.trsl.2018.01.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 12/15/2017] [Accepted: 01/09/2018] [Indexed: 12/16/2022]
Abstract
A plentiful literature has linked colorectal cancer (CRC) to inflammation and prostaglandin-endoperoxide synthase (PTGS)2 expression. Accordingly, several nonsteroidal antiinflammatory drugs (NSAIDs) have been tested often successfully in CRC chemoprevention despite their different ability to specifically target PTGS2 and the low or null expression of PTGS2 in early colon adenomas. Some observational studies showed an increased survival for patients with CRC assuming NSAIDs after diagnosis, but no clinical trial has yet demonstrated the efficacy of NSAIDs against established CRC, where PTGS2 is expressed at high levels. The major limits for the application of NSAIDs, or specific PTGS2 inhibitors, as adjuvant drugs in CRC are (1) a frequent confusion about the physiological role of PTGS1 and PTGS2, reflecting in CRC pathology and therapy; (2) the presence of unavoidable side effects linked to the intrinsic function of these enzymes; (3) the need of established criteria and markers for patient selection; and (4) the evaluation of the immunomodulatory potential of PTGS2 inhibitors as possible adjuvants for immunotherapy. This review has been written to rediscover the multifaceted potential of PTGS2 targeting, hoping it could act as a starting point for a new and more aware application of NSAIDs against CRC.
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Affiliation(s)
- Roberto Benelli
- OU Immunology, Ospedale Policlinico San Martino (Istituto di ricovero e cura a carattere scientifico per l'oncologia), Genoa, Italy.
| | - Roberta Venè
- OU Molecular Oncology & Angiogenesis, Ospedale Policlinico San Martino (Istituto di ricovero e cura a carattere scientifico per l'oncologia), Genoa, Italy
| | - Nicoletta Ferrari
- OU Molecular Oncology & Angiogenesis, Ospedale Policlinico San Martino (Istituto di ricovero e cura a carattere scientifico per l'oncologia), Genoa, Italy
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23
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Peng YJ, Shen TL, Chen YS, Mersmann HJ, Liu BH, Ding ST. Adiponectin and adiponectin receptor 1 overexpression enhance inflammatory bowel disease. J Biomed Sci 2018; 25:24. [PMID: 29540173 PMCID: PMC5851065 DOI: 10.1186/s12929-018-0419-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 02/06/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Adiponectin (ADN) is an adipokine derived from adipocytes. It binds to adiponectin receptor 1 and 2 (AdipoR1 and R2) to exert its function in regulating whole-body energy homeostasis and inflammatory responses. However, the role of ADN-AdipoR1 signaling in intestinal inflammation is controversial, and its role in the regulation of neutrophils is still unclear. Our goal was to clarify the role of AdipoR1 signaling in colitis and the effects on neutrophils. METHODS We generated porcine AdipoR1 transgenic mice (pAdipoR1 mice) and induced murine colitis using dextran sulfate sodium (DSS) to study the potential role of AdipoR1 in inflammatory bowel disease. We also treated a THP-1 macrophage and a HT-29 colon epithelial cell line with ADN recombinant protein to study the effects of ADN on inflammation. RESULTS After inducing murine colitis, pAdipoR1 mice developed more severe symptoms than wild-type (WT) mice. Treatment with ADN increased the expression of pro-inflammatory factors in THP-1 and HT-29 cells. Moreover, we also observed that the expression of cyclooxygenase2 (cox2), neutrophil chemokines (CXCL1, CXCL2 and CXCL5), and the infiltration of neutrophils were increased in the colon of pAdipoR1 mice. CONCLUSIONS Our study showed that ADN-AdipoR1 signaling exacerbated colonic inflammation through two possible mechanisms. First, ADN-AdipoR1 signaling increased pro-inflammatory factors. Second, AdipoR1 enhanced neutrophil chemokine expression and recruited neutrophils into the colonic tissue to increase inflammation.
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Affiliation(s)
- Yu-Ju Peng
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Tang-Long Shen
- Department of Plant Pathology and Microbiology, National Taiwan University, No.1, Sec.4, Roosevelt Road, Taipei, 10617 Taiwan
| | - Yu-Shan Chen
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Harry John Mersmann
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Bing-Hsien Liu
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Shih-Torng Ding
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
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24
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Osman J, Savari S, Chandrashekar NK, Bellamkonda K, Douglas D, Sjölander A. Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer. Oncotarget 2018; 8:34773-34786. [PMID: 28410235 PMCID: PMC5471010 DOI: 10.18632/oncotarget.16718] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/20/2017] [Indexed: 12/19/2022] Open
Abstract
Cysteinyl leukotriene receptor 1 (CysLT1R) has been shown to be up-regulated in the adenocarcinomas of colorectal cancer patients, which is associated with a poor prognosis. In a spontaneous model of colon cancer, CysLT1R disruption was associated with a reduced tumor burden in double-mutant female mice (ApcMin/+/Cysltr1-/-) compared to ApcMin/+ littermates. In the current study, we utilized a genetic approach to investigate the effect of CysLT1R in the induced azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated colon cancer. We found that AOM/DSS female mice with a global disruption of the Cysltr1 gene (Cysltr1-/-) had a higher relative body weight, a more normal weight/length colon ratio and smaller-sized colonic polyps compared to AOM/DSS wild-type counterparts. The Cysltr1-/- colonic polyps exhibited low-grade dysplasia, while wild-type polyps had an adenoma-like phenotype. The Cysltr1-/- colonic polyps exhibited significant decreases in nuclear β-catenin and COX-2 protein expression, while the normal crypts surrounding the polyps exhibited increased Mucin 2 expression. Furthermore, Cysltr1-/- mice exhibited an overall reduction in inflammation, with a significant decrease in proinflammatory cytokines, polyp 5-LOX expression and infiltration of CD45 leukocytes and F4/80 macrophages. In conclusion, the present genetic approach in an AOM/DSS model further supports an important role for CysLT1R in colon tumorigenesis.
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Affiliation(s)
- Janina Osman
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Sayeh Savari
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Naveen Kumar Chandrashekar
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Kishan Bellamkonda
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Desiree Douglas
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
| | - Anita Sjölander
- Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
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25
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Li J, Kong D, Wang Q, Wu W, Tang Y, Bai T, Guo L, Wei L, Zhang Q, Yu Y, Qian Y, Zuo S, Liu G, Liu Q, Wu S, Zang Y, Zhu Q, Jia D, Wang Y, Yao W, Ji Y, Yin H, Nakamura M, Lazarus M, Breyer RM, Wang L, Yu Y. Niacin ameliorates ulcerative colitis via prostaglandin D 2-mediated D prostanoid receptor 1 activation. EMBO Mol Med 2017; 9:571-588. [PMID: 28341703 PMCID: PMC5412792 DOI: 10.15252/emmm.201606987] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.
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Affiliation(s)
- Juanjuan Li
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Deping Kong
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qi Wang
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wu
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanping Tang
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingting Bai
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Guo
- Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lumin Wei
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qianqian Zhang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yu Yu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuting Qian
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengkai Zuo
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Guizhu Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qian Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Sheng Wu
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Zang
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Zhu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Daile Jia
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuanyang Wang
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Weiyan Yao
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong Ji
- The Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing Jiangsu, China
| | - Huiyong Yin
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Masataka Nakamura
- Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan
| | - Michael Lazarus
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City Ibaraki, Japan
| | - Richard M Breyer
- Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA.,Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lifu Wang
- Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Yu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China .,Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
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26
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Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun 2017; 89:41-52. [PMID: 29183643 PMCID: PMC5916452 DOI: 10.1016/j.jaut.2017.11.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 12/02/2022]
Abstract
In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
Th1 cells expressing miR-148a mediate colitis in a murine model of IBD. Antagomir-148a inhibits colitis by selectively depleting Th1 cells from the colon. Antagomir-148a does not affect the protective immunological memory.
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Affiliation(s)
| | - Georg Petkau
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | | | | | - Anja Andrea Kühl
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Katrin Lehmann
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - Melanie Weber
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - René Riedel
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | - Markus Bardua
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | | | - Cam Loan Tran
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany
| | - Bimba Franziska Hoyer
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany; Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Falk Hiepe
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany; Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin und Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Sebastian Herzog
- Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria
| | - Jürgen Wittmann
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany
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Kaur R, Manjal SK, Rawal RK, Kumar K. Recent synthetic and medicinal perspectives of tryptanthrin. Bioorg Med Chem 2017; 25:4533-4552. [DOI: 10.1016/j.bmc.2017.07.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/19/2017] [Accepted: 07/03/2017] [Indexed: 12/11/2022]
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Prostaglandin E 2-EP2 signaling as a node of chronic inflammation in the colon tumor microenvironment. Inflamm Regen 2017; 37:4. [PMID: 29259703 PMCID: PMC5725845 DOI: 10.1186/s41232-017-0036-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 01/06/2017] [Indexed: 01/22/2023] Open
Abstract
Background Colorectal cancer is the third most common cancer. Involvement of prostaglandin (PG) system in the pathogenesis of colorectal cancer has been suggested from clinical studies demonstrating therapeutic effect of NSAIDs including aspirin or selective COX-2 inhibitors. However, mechanisms on how PG regulates inflammatory responses leading to colorectal cancer development remain obscure. Further, careful attention is needed to use these drugs for a long time because of adverse effects due to non-specific inhibition of physiological PG production in addition to pathological one, making the development of alternatives to aspirin important. Recent studies using mouse model of colitis-associated colon cancer, azoxymethane (AOM)-dextran sodium sulfate (DSS) model, have revealed some of the mechanisms on how PG regulates inflammation in lesions and proposed PG receptor as a therapeutic target. Main body of abstract Among each PG receptor subtype examined, prostaglandin E receptor 2 (EP2) signaling specifically contributes to colorectal cancer formation and inflammation in lesions of AOM-DSS model. EP2 is expressed in neutrophils, infiltrated major inflammatory cells, and tumor-associated fibroblasts (TAFs) in the tumor stroma of this mouse model and also in clinical specimen from ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments between wild-type and EP2-deficient mice have confirmed the involvement of EP2 signaling in these two types of cells in the pathogenesis of the disease. EP2 signaling in both types of cells regulates the transition to and maintenance of inflammation in multiple steps to shape the tumor microenvironment which contributes to trigger and promote colorectal cancer. In this process, PGE2-EP2 signaling synergizes with TNF-α to amplify TNF-α-induced inflammatory responses, forms a positive feedback loop involving COX-2-PGE2-EP2 signaling to exacerbate PG-mediated inflammation once triggered, and alternates active cell populations participating in inflammation through forming self-amplification loop among neutrophils. Thus, EP2 signaling functions as a node of inflammatory responses in the tumor microenvironment. Based on such a notion, EP2 can become a strong candidate for therapeutic target of colorectal cancer treatment. Indeed, in AOM-DSS model, a selective EP2 antagonist, PF-04418948, potently suppresses colorectal tumor formation. Short conclusion PGE2-EP2 signaling functions as a node of chronic inflammation which shapes the tumor microenvironment and thus is a strong candidate of target for the chemoprevention of colorectal cancer.
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Ozer EK, Goktas MT, Kilinc I, Bariskaner H, Ugurluoglu C, Iskit AB. Celecoxib administration reduced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ injury in septic rats. Biomed Pharmacother 2016; 86:583-589. [PMID: 28024294 DOI: 10.1016/j.biopha.2016.11.102] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/23/2016] [Accepted: 11/24/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The cyclooxygenase (COX)-2 overexpression is associated with vascular injury and multiple organ failure in sepsis. However, constitutive COX-1 and basal COX-2 expressions have physiological effects. We aimed to investigate the effects of partial and selective COX-2 inhibition without affecting constitutive COX-1 and basal COX-2 activities by celecoxib on mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries, and survival in septic rats accomplished by cecal ligation and puncture (CLP). METHODS Wistar rats were allocated into Sham, CLP, Sham+celecoxib, CLP+celecoxib subgroups. 2h after Sham and CLP operations, celecoxib (0.5mg/kg) or vehicle (saline; 1mL/kg) was administered orally to rats. 18h after drug administrations, MABF and responses of isolated aortic rings to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological examinations. Furthermore, survival rate was monitored throughout 96h. RESULTS Celecoxib ameliorated mesenteric hypoperfusion and partially improved aortic dysfunction induced by CLP. Survival rate was%0 at 49th h in CLP group, but in CLP+celecoxib group it was 42.8% at the end of 96h. Serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were increased in CLP group that were prevented by celecoxib. The decreases in liver and spleen glutathione levels and the increases in liver, lung, spleen and kidney malondialdehyde levels in CLP group were blocked by celecoxib. The histopathological protective effects of celecoxib on organ injury due to CLP were also observed. CONCLUSIONS Celecoxib has protective effects on sepsis due to its preservative effects on mesenteric perfusion, aortic function and its anti-inflammatory and antioxidative effects.
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Affiliation(s)
- Erdem Kamil Ozer
- Department of Pharmacology, Faculty of Medicine, Selcuk University, Konya, Turkey.
| | - Mustafa Tugrul Goktas
- Department of Pharmacology, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey
| | - Ibrahim Kilinc
- Department of Biochemistry, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Hulagu Bariskaner
- Department of Pharmacology, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Ceyhan Ugurluoglu
- Department of Pathology, Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Alper Bektas Iskit
- Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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Brugman S. The zebrafish as a model to study intestinal inflammation. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 64:82-92. [PMID: 26902932 DOI: 10.1016/j.dci.2016.02.020] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 02/16/2016] [Accepted: 02/17/2016] [Indexed: 06/05/2023]
Abstract
Starting out as a model for developmental biology, during the last decade, zebrafish have also gained the attention of the immunologists and oncologists. Due to its small size, high fecundity and full annotation of its genome, the zebrafish is an attractive model system. The fact that fish are transparent early in life combined with the growing list of immune cell reporter fish, enables in vivo tracking of immune responses in a complete organism. Since zebrafish develop ex utero from a fertilized egg, immune development can be monitored from the start of life. Given that several gut functions and immune genes are conserved between zebrafish and mammals, the zebrafish is an interesting model organism to investigate fundamental processes underlying intestinal inflammation and injury. This review will first provide some background on zebrafish intestinal development, bacterial colonization and immunity, showing the similarities and differences compared to mammals. This will be followed by an overview of the existing models for intestinal disease, and concluded by future perspectives in light of the newest technologies and insights.
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Affiliation(s)
- Sylvia Brugman
- Animal Sciences Group, Cell Biology and Immunology, Wageningen University, De Elst 1, room Ee1253, 6708 WD Wageningen, Netherlands.
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31
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Wagnerova A, Babickova J, Liptak R, Celec P, Gardlik R. Beneficial effects of live and dead Salmonella
-based vector strain on the course of colitis in mice. Lett Appl Microbiol 2016; 63:340-346. [DOI: 10.1111/lam.12632] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/05/2016] [Indexed: 12/14/2022]
Affiliation(s)
- A. Wagnerova
- Institute of Molecular Biomedicine; Faculty of Medicine; Comenius University; Bratislava Slovakia
| | - J. Babickova
- Institute of Molecular Biomedicine; Faculty of Medicine; Comenius University; Bratislava Slovakia
- Institute for Clinical and Translational Research BMC; Biomedical Research Center; Slovak Academy of Sciences; Bratislava Slovakia
| | - R. Liptak
- Institute of Molecular Biomedicine; Faculty of Medicine; Comenius University; Bratislava Slovakia
| | - P. Celec
- Institute of Molecular Biomedicine; Faculty of Medicine; Comenius University; Bratislava Slovakia
- Institute for Clinical and Translational Research BMC; Biomedical Research Center; Slovak Academy of Sciences; Bratislava Slovakia
- Institute of Pathophysiology; Faculty of Medicine; Comenius University; Bratislava Slovakia
- Department of Molecular Biology; Faculty of Natural Sciences; Comenius University; Bratislava Slovakia
| | - R. Gardlik
- Institute of Molecular Biomedicine; Faculty of Medicine; Comenius University; Bratislava Slovakia
- Institute for Clinical and Translational Research BMC; Biomedical Research Center; Slovak Academy of Sciences; Bratislava Slovakia
- Institute of Pathophysiology; Faculty of Medicine; Comenius University; Bratislava Slovakia
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Molendijk I, Barnhoorn MC, de Jonge-Muller ESM, Mieremet-Ooms MAC, van der Reijden JJ, van der Helm D, Hommes DW, van der Meulen-de Jong AE, Verspaget HW. Intraluminal Injection of Mesenchymal Stromal Cells in Spheroids Attenuates Experimental Colitis. J Crohns Colitis 2016; 10:953-64. [PMID: 26896084 DOI: 10.1093/ecco-jcc/jjw047] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 02/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS In recent years, mesenchymal stromal cells [MSCs] emerged as a promising therapeutic option for various diseases, due to their immunomodulatory properties. We previously observed that intraperitoneally injected MSCs in experimental colitis form spherical shaped aggregates. Therefore, we aggregated MSCs in vitro into spheroids and injected them intraluminally in mice with established colitis, to investigate whether these MSC spheroids could alleviate the colitis. METHODS We injected 0.5 x 10(6) MSCs in spheroids, 2.0 x 10(6) MSCs in spheroids, or phosphate-buffered saline [PBS] as a treatment control, via an enema in mice with established dextran sulphate sodium [DSS]-induced colitis. Body weight was measured daily and disease activity score was determined at sacrifice. Endoscopy was performed to evaluate mucosal healing. After sacrifice, both systemic and local inflammatory responses were evaluated. RESULTS Intraluminally injected MSC spheroids alleviated DSS-induced colitis, resulting in significantly less body weight loss and lower disease activity score at sacrifice when a high dose of MSC spheroids was administered. However, the percentage of mucosal lesions in the distal colon and endoscopy scores were not significantly lower after treatment with 2.0 x 10(6) MSCs in spheroids compared with PBS-treated mice. Systemic inflammation marker serum amyloid A [SAA] was significantly reduced after treatment with 2.0 x 10(6) MSCs in spheroids. In addition, local cytokine levels of IFN-ɣ, TNF-α, IL-6, and IL-17a, as well as numbers of macrophages and neutrophils, showed a clear decrease-though not always significant-after intraluminal injection of the MSC spheroids. CONCLUSION Intraluminally injected MSC spheroids at least partially attenuate experimental colitis, with fewer phagocytes and proinflammmatory cytokines, when a high dose of MSCs in spheroids was administered.
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Affiliation(s)
- Ilse Molendijk
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marieke C Barnhoorn
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Marij A C Mieremet-Ooms
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Johan J van der Reijden
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Daniel W Hommes
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Morales Fénero CI, Colombo Flores AA, Câmara NOS. Inflammatory diseases modelling in zebrafish. World J Exp Med 2016; 6:9-20. [PMID: 26929916 PMCID: PMC4759353 DOI: 10.5493/wjem.v6.i1.9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/20/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The ingest of diets with high content of fats and carbohydrates, low or no physical exercise and a stressful routine are part of the everyday lifestyle of most people in the western world. These conditions are triggers for different diseases with complex interactions between the host genetics, the metabolism, the immune system and the microbiota, including inflammatory bowel diseases (IBD), obesity and diabetes. The incidence of these disorders is growing worldwide; therefore, new strategies for its study are needed. Nowadays, the majority of researches are in use of murine models for understand the genetics, physiopathology and interaction between cells and signaling pathways to find therapeutic solutions to these diseases. The zebrafish, a little tropical water fish, shares 70% of our genes and conserves anatomic and physiological characteristics, as well as metabolical pathways, with mammals, and is rising as a new complementary model for the study of metabolic and inflammatory diseases. Its high fecundity, fast development, transparency, versatility and low cost of maintenance makes the zebrafish an interesting option for new researches. In this review, we offer a discussion of the existing genetic and induced zebrafish models of two important Western diseases that have a strong inflammatory component, the IBD and the obesity.
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Murase R, Sato H, Yamamoto K, Ushida A, Nishito Y, Ikeda K, Kobayashi T, Yamamoto T, Taketomi Y, Murakami M. Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility. J Biol Chem 2016; 291:6895-911. [PMID: 26828067 DOI: 10.1074/jbc.m116.715672] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Indexed: 12/31/2022] Open
Abstract
Within the secreted phospholipase A2(sPLA2) family, group X sPLA2(sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies usingPla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2(cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2 Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizerin vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.
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Affiliation(s)
- Remi Murase
- From the Lipid Metabolism Project and School of Pharmacy, Showa University, Tokyo 142-8555, Japan
| | | | | | - Ayako Ushida
- From the Lipid Metabolism Project and Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan
| | - Yasumasa Nishito
- Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Kazutaka Ikeda
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan, and
| | - Tetsuyuki Kobayashi
- Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan
| | | | | | - Makoto Murakami
- From the Lipid Metabolism Project and AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
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Goldsmith JR, Tomkovich S, Jobin C. A Rapid Screenable Assay for Compounds That Protect Against Intestinal Injury in Zebrafish Larva. Methods Mol Biol 2016; 1422:281-93. [PMID: 27246041 DOI: 10.1007/978-1-4939-3603-8_25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This chapter describes a method to assay compounds modulating NSAID-induced intestinal injury in zebrafish larvae. The assay employs the NSAID glafenine, which causes intestinal epithelial cell damage and death by inducing organelle stress responses (endoplasmic reticulum and mitochondrial) and blocking the unfolded protein response pathway. This epithelial damage includes sloughing of intestinal cells into the lumen and out the cloaca of the zebrafish larvae. Exposing larvae to acridine orange highlights this injury when visualized under fluorescence microscope; injured fish develop intensely red-staining intestines, as well as a "tube" or cord of red color extending through the intestine and out the cloaca. Using this rapid visually screenable method, various candidate compounds were successfully tested for their ability to prevent glafenine-induced intestinal injury. Because this assay involves examination of larval zebrafish intestinal pathology, we have also included our protocol for preparation and analysis of zebrafish histology. The protocol includes numerous steps to generate high-quality zebrafish histology slides, as well as protocols to establish accurate anatomic localization of any given tissue cross-section-processes that are made technically difficult by the small size of zebrafish larvae.
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Affiliation(s)
- Jason R Goldsmith
- Department of Internal Medicine, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, 48109, MI, USA
| | - Sarah Tomkovich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27713, USA.,Division of Gastroenterology, Department of Medicine, College of Medicine, University of Florida, CGRC, 2033 Mowry Rd, Office 461, P.O. Box 103633, 32610, Gainesville, FL, 32611-0882, USA
| | - Christian Jobin
- Division of Gastroenterology, Department of Medicine, College of Medicine, University of Florida, CGRC, 2033 Mowry Rd, Office 461, P.O. Box 103633, 32610, Gainesville, FL, 32611-0882, USA.
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36
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Wound repair: role of immune-epithelial interactions. Mucosal Immunol 2015; 8:959-68. [PMID: 26174765 PMCID: PMC4916915 DOI: 10.1038/mi.2015.63] [Citation(s) in RCA: 208] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 05/28/2015] [Indexed: 02/07/2023]
Abstract
The epithelium serves as a highly selective barrier at mucosal surfaces. Upon injury, epithelial wound closure is orchestrated by a series of events that emanate from the epithelium itself as well as by the temporal recruitment of immune cells into the wound bed. Epithelial cells adjoining the wound flatten out, migrate, and proliferate to rapidly cover denuded surfaces and re-establish mucosal homeostasis. This process is highly regulated by proteins and lipids, proresolving mediators such as Annexin A1 protein and resolvins released into the epithelial milieu by the epithelium itself and infiltrating innate immune cells including neutrophils and macrophages. Failure to achieve these finely tuned processes is observed in chronic inflammatory diseases that are associated with non-healing wounds. An improved understanding of mechanisms that mediate repair is important in the development of therapeutics aimed to promote mucosal wound repair.
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Reddy KVK, Naidu KA. Maternal and neonatal dietary intake of balanced n-6/n-3 fatty acids modulates experimental colitis in young adult rats. Eur J Nutr 2015; 55:1875-90. [PMID: 26246200 DOI: 10.1007/s00394-015-1004-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 07/21/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND The imbalance of n-6 and n-3 polyunsaturated fatty acids in the maternal diet impairs intestinal barrier development and sensitizes the colon response to inflammatory insults in the young rats. With a view to overcoming this issue, we designed this study to investigate the effect of maternal and neonatal intake of different proportions of n-6/n-3 fatty acids on colon inflammation in the young adult rats. METHODS Female Wistar rats were assigned into four groups, and each group fed one of four semisynthetic diets, namely n-6, low n-3, n-6/n-3 and n-3 fatty acids for 8 weeks prior to mating, during gestation and lactation periods. At weaning, the pups were separated from the dams and fed diet similar to the mothers. Colitis was induced on postnatal day 35, by administering 2 % dextran sulfate sodium in drinking water for 10 days. Colitis was assessed based on the clinical and inflammatory markers in the colon. Fatty acid analysis was done in liver, RBC, colon and spleen. RESULTS A balanced n-6/n-3 PUFA diet significantly improved the body weight loss, rectal bleeding and mortality in rats. This was associated with lower myeloperoxidase activity, nitric oxide, prostaglandin E2, TNF-α and IL-6, IL-8, COX-2 and iNOS levels in the colon tissues. Fatty acid analysis has shown that the arachidonic acid/docosahexaenoic acid ratio was significantly lower in liver, RBC, colon and spleen in n-6/n-3 and n-3 diet groups. CONCLUSION We demonstrate that balanced n-6/n-3 PUFA supplementation in maternal and neonatal diet alters systemic AA/DHA ratio and attenuates colon inflammation in the young adult rats.
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Affiliation(s)
- K Vijay Kumar Reddy
- Department of Biochemistry and Nutrition, CSIR-Central Food Technological Research Institute, Mysore, 570020, India
| | - K Akhilender Naidu
- Department of Biochemistry and Nutrition, CSIR-Central Food Technological Research Institute, Mysore, 570020, India.
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L13a-dependent translational control in macrophages limits the pathogenesis of colitis. Cell Mol Immunol 2015; 13:816-827. [PMID: 26166763 DOI: 10.1038/cmi.2015.53] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Revised: 05/14/2015] [Accepted: 05/15/2015] [Indexed: 12/19/2022] Open
Abstract
Sustained inflammation from infiltrated immune cells plays a pivotal role in the pathogenesis of ulcerative colitis (UC). Previously, we established the role of ribosomal protein L13a in the regulation of an inflammation-responsive post-transcriptional operon in myeloid cells. However, the role of this protein as a molecular cue to control the severity of colitis is not known. Here, we examined whether L13a-dependent translational control in macrophages could serve as an endogenous defense against colitis. The administration of dextran sodium sulfate induced experimental colitis in myeloid-specific L13a-knockout (KO) and control mice. Pathological scoring and injury to the colon mucosa evaluated the severity of colitis. The steady-state levels of several pro-inflammatory cytokines and chemokines were determined through ELISA and polyribosome profile analysis. Rapid weight loss, severe rectal bleeding, shortening of the colon, and significantly reduced survival rate were observed in the KO mice. Histopathological analysis of the colons of KO mice showed a severe disruption of epithelial crypts with immune cell infiltrates. Elevated levels of several inflammatory cytokines and chemokines and abrogation of their naturally imposed translational silencing were observed in the colons of the KO mice. Higher serum levels of several pro-inflammatory cytokines and the release of gut bacteria and endotoxins into the blood streams of KO mice were detected, suggesting the amplification of the inflammatory response to septicemia. Taken together, these results reveal an essential role for L13a in the endogenous protection against UC and demonstrate the potential for new therapeutic opportunities through the deliberate promotion of this mechanism.
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Starke RM, Chalouhi N, Ding D, Hasan DM. Potential role of aspirin in the prevention of aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 2015; 39:332-42. [PMID: 25967073 DOI: 10.1159/000381137] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 02/18/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Inflammation is a key element behind the pathophysiology of cerebral aneurysm formation and rupture. Aspirin is a potent inhibitor of cyclooxygenase-2 (COX), which plays a critical role in the expression of immune modulators known to contribute to cerebral aneurysm formation and rupture. Currently, there are no pharmacological therapies for patients with cerebral aneurysms. Both endovascular and microsurgical interventions may be associated with significant morbidity and mortality. Potentially, a medical alternative that prevents aneurysm progression and rupture may be a beneficial therapy for a significant number of patients. SUMMARY In animal models, treatment with aspirin and genetic inactivation of COX-2 decreases aneurysm formation and rupture. Selective inhibition of COX-1 did not decrease aneurysm rupture, suggesting that selection inhibition of COX-2 may be critical in thwarting aneurysm progression. Walls of ruptured human intracranial aneurysms have higher levels of COX-2 and microsomal prostaglandin E2 synthase 1 (mPGES-1), both of which are known to be inhibited by aspirin. In a pilot study, patients undergoing microsurgical clipping had attenuated expression of COX-2, mPGES-1, and macrophages in aneurysm walls after 3 months of aspirin therapy versus those that did not receive aspirin. Additionally, in patients undergoing endovascular therapy, local circulating expression of chemokines and COX-2 were increased in blood samples taken from within aneurysm domes as compared to peripheral blood sample controls. Treatment with aspirin also resulted in decreased expression of COX-2 within leukocytes within aneurysms as compared to peripheral blood samples. Novel molecular imaging with ferumoxytol-enhanced MRI may help in the identification of patients at increased risk for aneurysm rupture and assessment of a response to aspirin therapy. Key Messages: Aspirin has been found to be a safe in patients harboring cerebral aneurysms and clinical studies provide evidence that it may decrease the overall rate of rupture. Furthermore, aspirin is an accessible and inexpensive medicine for patients who may not have access to endovascular or microsurgical treatment or for patients who are deemed low risk of aneurysm rupture, high risk for intervention, or both. Future clinical trials are indicated to determine the overall effect of aspirin on aneurysm progression and rupture. This review provides an update on the potential mechanisms and benefits of aspirin in the treatment of cerebral aneurysms.
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Affiliation(s)
- Robert M Starke
- Department of Neurological Surgery, University of Virginia, Charlottesville, Va., USA
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40
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In vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma. Chem Biol Interact 2015; 233:81-94. [PMID: 25824412 DOI: 10.1016/j.cbi.2015.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 02/03/2015] [Accepted: 03/18/2015] [Indexed: 11/30/2022]
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Zhang N, Subbaramaiah K, Yantiss RK, Zhou XK, Chin Y, Benezra R, Dannenberg AJ. Id1 Deficiency Protects against Tumor Formation in Apc(Min/+) Mice but Not in a Mouse Model of Colitis-Associated Colon Cancer. Cancer Prev Res (Phila) 2015; 8:303-11. [PMID: 25623217 PMCID: PMC4832599 DOI: 10.1158/1940-6207.capr-14-0411] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 01/19/2015] [Indexed: 01/12/2023]
Abstract
Different mechanisms contribute to the development of sporadic, hereditary and colitis-associated colorectal cancer. Inhibitor of DNA binding/differentiation (Id) proteins act as dominant-negative antagonists of basic helix-loop-helix transcription factors. Id1 is a promising target for cancer therapy, but little is known about its role in the development of colon cancer. We used immunohistochemistry to demonstrate that Id1 is overexpressed in human colorectal adenomas and carcinomas, whether sporadic or syndromic. Furthermore, elevated Id1 levels were found in dysplasia and colon cancer arising in patients with inflammatory bowel disease. Because levels of PGE2 are also elevated in both colitis and colorectal neoplasia, we determined whether PGE2 could induce Id1. PGE2 via EP4 stimulated protein kinase A activity resulting in enhanced pCREB-mediated Id1 transcription in human colonocytes. To determine the role of Id1 in carcinogenesis, two mouse models were used. Consistent with the findings in humans, Id1 was overexpressed in tumors arising in both Apc(Min) (/+) mice, a model of familial adenomatous polyposis, and in experimental colitis-associated colorectal neoplasia. Id1 deficiency led to significant decrease in the number of intestinal tumors in Apc(Min) (/+) mice and prolonged survival. In contrast, Id1 deficiency did not affect the number or size of tumors in the model of colitis-associated colorectal neoplasia, likely due to exacerbation of colitis associated with Id1 loss. Collectively, these results suggest that Id1 plays a role in gastrointestinal carcinogenesis. Our findings also highlight the need for different strategies to reduce the risk of colitis-associated colorectal cancer compared with sporadic or hereditary colorectal cancer.
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Affiliation(s)
- Ning Zhang
- Department of Medicine, Weill Cornell Medical College, New York, New York. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kotha Subbaramaiah
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York
| | - Xi Kathy Zhou
- Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York
| | - Yvette Chin
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Robert Benezra
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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42
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Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: pathophysiology and clinical associations. Inflamm Bowel Dis 2014; 20:2493-502. [PMID: 25230166 DOI: 10.1097/mib.0000000000000165] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) produce significant gastrointestinal (GI) adverse events. Laboratory and clinical studies suggest that NSAIDs have the potential to trigger the onset or relapse of inflammatory bowel disease. In this review, the currently available information on the mechanism of action of NSAID injury of the GI tract and the pathophysiology of GI effects of NSAIDs, including immune dysregulation will be assessed. A detailed description of NSAID effects on individual GI organs will be discussed. This is followed by a MEDLINE review of clinical literature on the relationship between NSAID ingestion and the development and worsening of inflammatory bowel disease.
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43
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Montrose DC, Nakanishi M, Murphy RC, Zarini S, McAleer JP, Vella AT, Rosenberg DW. The role of PGE2 in intestinal inflammation and tumorigenesis. Prostaglandins Other Lipid Mediat 2014; 116-117:26-36. [PMID: 25460828 DOI: 10.1016/j.prostaglandins.2014.10.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 09/30/2014] [Accepted: 10/10/2014] [Indexed: 12/24/2022]
Abstract
Release of the free fatty acid arachidonic acid (AA) by cytoplasmic phospholipase A2 (cPLA2) and its subsequent metabolism by the cyclooxygenase and lipoxygenase enzymes produces a broad panel of eicosanoids including prostaglandins (PGs). This study sought to investigate the roles of these mediators in experimental models of inflammation and inflammation-associated intestinal tumorigenesis. Using the dextran sodium sulfate (DSS) model of experimental colitis, we first investigated how a global reduction in eicosanoid production would impact intestinal injury by utilizing cPLA2 knockout mice. cPLA2 deletion enhanced colonic injury, reflected by increased mucosal ulceration and pro-inflammatory cytokine expression. Increased disease severity was associated with a significant reduction in the levels of several eicosanoid metabolites, including PGE2. We further assessed the precise role of PGE2 synthesis on mucosal injury and repair by utilizing mice with a genetic deletion of microsomal PGE synthase-1 (mPGES-1), the terminal synthase in the formation of inducible PGE2. DSS exposure caused more extensive acute injury as well as impaired recovery in knockout mice compared to wild-type littermates. Increased intestinal damage was associated with both reduced PGE2 levels as well as altered levels of other eicosanoids including PGD2. To determine whether this metabolic redirection impacted inflammation-associated intestinal tumorigenesis, Apc(Min/+) and Apc(Min/+):mPGES-1(-/-) mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in Apc(Min/+):mPGES-1(-/-) mice. These results demonstrate the importance of the balance of prostaglandins produced in the intestinal tract for maintaining intestinal homeostasis and impacting tumor development.
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Affiliation(s)
- David C Montrose
- Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Masako Nakanishi
- Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Robert C Murphy
- Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, United States
| | - Simona Zarini
- Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, United States
| | - Jeremy P McAleer
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Anthony T Vella
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Daniel W Rosenberg
- Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States.
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44
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Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis. Proc Natl Acad Sci U S A 2014; 111:E4658-67. [PMID: 25316791 DOI: 10.1073/pnas.1415762111] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.
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Kaushal N, Kudva AK, Patterson AD, Chiaro C, Kennett MJ, Desai D, Amin S, Carlson BA, Cantorna MT, Prabhu KS. Crucial role of macrophage selenoproteins in experimental colitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 193:3683-92. [PMID: 25187657 PMCID: PMC4170023 DOI: 10.4049/jimmunol.1400347] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between selenium (Se) status and IBD-induced inflammation, our objective was to demonstrate that selenoproteins in macrophages were essential to suppress proinflammatory mediators, in part, by the modulation of arachidonic acid metabolism. Acute colitis was induced using 4% dextran sodium sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.08 ppm; sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite) diets. Selenocysteinyl transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were used to examine the role of selenoproteins in macrophages on disease progression and severity using histopathological evaluation, expression of proinflammatory and anti-inflammatory genes, and modulation of PG metabolites in urine and plasma. Whereas Se-deficient and Se-adequate mice showed increased colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased colitis-associated inflammation with an upregulation of expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of 15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH, lack of selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific selenoproteins and upregulation of 15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving effects. Selenoproteins in macrophages protect mice from dextran sodium sulfate-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate inflammation, suggesting a therapeutic role for Se in IBD.
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Affiliation(s)
- Naveen Kaushal
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - Avinash K Kudva
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - Andrew D Patterson
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - Christopher Chiaro
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - Mary J Kennett
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - Dhimant Desai
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033; and
| | - Shantu Amin
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033; and
| | - Bradley A Carlson
- Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Margherita T Cantorna
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802
| | - K Sandeep Prabhu
- Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
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Viennois E, Baker MT, Xiao B, Wang L, Laroui H, Merlin D. Longitudinal study of circulating protein biomarkers in inflammatory bowel disease. J Proteomics 2014; 112:166-79. [PMID: 25230104 DOI: 10.1016/j.jprot.2014.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Revised: 08/15/2014] [Accepted: 09/05/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED Inflammatory bowel diseases (IBDs) are chronic and progressive inflammatory disorders of the gastrointestinal tract. In IBD, protein serological biomarkers could be relevant tools for assessing disease activity, performing early-stage diagnosis and managing the treatment. Using the interleukin-10 knockout (IL-10(-/-)) mouse, a model that develops a time-dependent IBD-like disorder that predominates in the colon; we performed longitudinal studies of circulating protein biomarkers in IBD. Circulating protein profiles in serum samples collected from 30-, 93-, to 135-day-old IL-10(-/-) mice were investigated using two-dimensional differential gel electrophoresis and MALDI-TOF/TOF tandem mass spectrometry. A total of 15 different proteins were identified and confirmed by ELISA and Western blot to be differentially accumulated in serum samples from mid- to late-stage IL-10(-/-) mice compared to early non-inflamed IL-10(-/-) mice. The use of another model of colitis and an extra-intestinal inflammation model validated this biomarker panel and demonstrated that comprised some global inflammatory markers, some intestinal inflammation-specific markers and some chronic intestinal inflammation markers. Statistical analyses using misclassification error rate charts validated the use of these identified proteins as powerful biomarkers of colitis. Unlike standard biomarker screening studies, our analyses identified a panel of proteins that allowed the definition of protein signatures that reflect colitis status. BIOLOGICAL SIGNIFICANCE Crohn's disease (CD) and ulcerative colitis (UC) are the most common inflammatory bowel diseases (IBDs) occurring in humans. The major current diagnosis tool is colonoscopy, which is invasive and could lead to false diagnosis. The emergence of serological biomarkers enables the use of new diagnosis tools such as protein signatures for IBD diagnosis/management. Using 2D-DIGE coupled to mass spectrometry, our longitudinal study in a mouse model of colitis identified a signature of protein biomarkers for specific stages of disease.
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Affiliation(s)
- Emilie Viennois
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; Veterans Affairs Medical Center, Decatur, GA, USA.
| | - Mark T Baker
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Bo Xiao
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Lixin Wang
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; Veterans Affairs Medical Center, Decatur, GA, USA
| | - Hamed Laroui
- Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Chemistry Department, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA; Veterans Affairs Medical Center, Decatur, GA, USA
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Parlato M, Yeretssian G. NOD-like receptors in intestinal homeostasis and epithelial tissue repair. Int J Mol Sci 2014; 15:9594-627. [PMID: 24886810 PMCID: PMC4100112 DOI: 10.3390/ijms15069594] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 05/16/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
The intestinal epithelium constitutes a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. Following injury, the epithelial integrity is restored by rapid migration of intestinal epithelial cells (IECs) across the denuded area in a process known as wound healing. Hence, through a sequence of events involving restitution, proliferation and differentiation of IECs the gap is resealed and homeostasis reestablished. Relapsing damage followed by healing of the inflamed mucosa is a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). While several regulatory peptides, growth factors and cytokines stimulate restitution of the epithelial layer after injury, recent evidence in the field underscores the contribution of innate immunity in controlling this process. In particular, nucleotide-binding and oligomerization domain-like receptors (NLRs) play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Here, we review the process of intestinal epithelial tissue repair and we specifically focus on the impact of NLR-mediated signaling mechanisms involved in governing epithelial wound healing during disease.
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Affiliation(s)
- Marianna Parlato
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Garabet Yeretssian
- Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Abstract
Understanding a complex pathology such as inflammatory bowel disease, where host genetics (innate and adaptive immunity, barrier function) and environmental factors (microbes, diet, and stress) interact together to influence disease onset and severity, requires multipronged approaches to model these numerous variables. Researchers have typically relied on preclinical models of mouse and rat origin to push the boundary of knowledge further. However, incorporation of novel vertebrate models may contribute to new knowledge on specific aspects of intestinal homeostasis. An emerging literature has seen the use of zebrafish as a novel animal system to study key aspects of host-microbe interactions in the intestine. In this review, we briefly introduce components of host-microbiota interplay in the developing zebrafish intestine and summarize key lessons learned from this animal system; review important chemically induced and genetically engineered zebrafish models of intestinal immune disorders; and discuss perspectives and limitations of the zebrafish model system.
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Affiliation(s)
- Ye Yang
- Department of Medicine, University of Florida, Gainesville, Florida
| | - Sarah Tomkovich
- Department of Medicine, University of Florida, Gainesville, Florida,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Christian Jobin
- Department of Medicine, University of Florida, Gainesville, Florida,Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida
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49
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Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth. Proc Natl Acad Sci U S A 2014; 111:7084-9. [PMID: 24763687 DOI: 10.1073/pnas.1324233111] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.
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50
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Zagato E, Mileti E, Massimiliano L, Fasano F, Budelli A, Penna G, Rescigno M. Lactobacillus paracasei CBA L74 metabolic products and fermented milk for infant formula have anti-inflammatory activity on dendritic cells in vitro and protective effects against colitis and an enteric pathogen in vivo. PLoS One 2014; 9:e87615. [PMID: 24520333 PMCID: PMC3919712 DOI: 10.1371/journal.pone.0087615] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 12/21/2013] [Indexed: 12/31/2022] Open
Abstract
The rapid expansion of commercially available fermented food products raises important safety issues particularly when infant food is concerned. In many cases, the activity of the microorganisms used for fermentation as well as what will be the immunological outcome of fermented food intake is not known. In this manuscript we used complex in vitro, ex-vivo and in vivo systems to study the immunomodulatory properties of probiotic-fermented products (culture supernatant and fermented milk without live bacteria to be used in infant formula). We found in vitro and ex-vivo that fermented products of Lactobacillus paracasei CBA L74 act via the inhibition of proinflammatory cytokine release leaving anti-inflammatory cytokines either unaffected or even increased in response to Salmonella typhimurium. These activities are not dependent on the inactivated bacteria but to metabolic products released during the fermentation process. We also show that our in vitro systems are predictive of an in vivo efficacy by the fermented products. Indeed CBA L74 fermented products (both culture medium and fermented milk) could protect against colitis and against an enteric pathogen infection (Salmonella typhimurium). Hence we found that fermented products can act via the inhibition of immune cell inflammation and can protect the host from pathobionts and enteric pathogens. These results open new perspectives in infant nutrition and suggest that L. paracasei CBA L74 fermented formula can provide immune benefits to formula-fed infants, without carrying live bacteria that may be potentially dangerous to an immature infant immune system.
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Affiliation(s)
- Elena Zagato
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Erika Mileti
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | - Lucia Massimiliano
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
| | | | | | - Giuseppe Penna
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
- * E-mail: (GP); (MR)
| | - Maria Rescigno
- Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
- * E-mail: (GP); (MR)
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