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Dimitrov G, Ryffel B, Togbe D, Quesniaux V. cGAS-STING DNA-sensing in inflammatory bowel diseases. Trends Mol Med 2025; 31:165-180. [PMID: 39448330 DOI: 10.1016/j.molmed.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/19/2024] [Accepted: 10/01/2024] [Indexed: 10/26/2024]
Abstract
Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.
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Affiliation(s)
- Georges Dimitrov
- Pediatrics and pediatric surgery, University Hospital Center of Orleans, Orleans 45100, France; Laboratory of Immuno-Neuro Modulation (INEM), UMR7355, CNRS and University of Orleans, 45071, Orleans, France
| | - Bernhard Ryffel
- Laboratory of Immuno-Neuro Modulation (INEM), UMR7355, CNRS and University of Orleans, 45071, Orleans, France
| | - Dieudonnée Togbe
- Laboratory of Immuno-Neuro Modulation (INEM), UMR7355, CNRS and University of Orleans, 45071, Orleans, France; University of Orleans, Orleans, France.
| | - Valérie Quesniaux
- Laboratory of Immuno-Neuro Modulation (INEM), UMR7355, CNRS and University of Orleans, 45071, Orleans, France.
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2
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Papierska K, Judasz E, Tonińska W, Kubicki M, Krajka-Kuźniak V. Modulatory Effects of Chalcone Thio-Derivatives on NF-κB and STAT3 Signaling Pathways in Hepatocellular Carcinoma Cells: A Study on Selected Active Compounds. Int J Mol Sci 2024; 25:10739. [PMID: 39409068 PMCID: PMC11476945 DOI: 10.3390/ijms251910739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/29/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and STAT3 signaling pathways involved in inflammatory processes and cell proliferation in human liver cancer cells. Cell survival was assessed for cancer (HepG2) and normal (THLE-2) cell lines. Activation of NF-κB and STAT3 signaling pathways and the expression of proteins controlled by these pathways were estimated by Western blot, and qRT-PCR assessed the expression of NF-κB and STAT3 target genes. We also evaluated the impact on the selected kinases responsible for the phosphorylation of the studied transcription factors by MagneticBead-Based Multiplex Immunoassay. Among the thio-derivatives tested, especially derivatives 1 and 5, there was an impact on cell viability, cell cycle, apoptosis, and activation of NF-κB and STAT3 pathways in hepatocellular carcinoma (HCC), which confirms the possibilities of using them in combinatorial molecular targeted therapy of HCC. The tested synthetic thio-chalcones exhibit anticancer activity by initiating proapoptotic processes in HCC while showing low toxicity to non-cancerous cells. These findings confirm the possibility of using chalcone thio-derivatives in molecularly targeted combination therapy for HCC.
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Affiliation(s)
- Katarzyna Papierska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland; (E.J.); (W.T.); (V.K.-K.)
| | - Eliza Judasz
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland; (E.J.); (W.T.); (V.K.-K.)
| | - Wiktoria Tonińska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland; (E.J.); (W.T.); (V.K.-K.)
| | - Maciej Kubicki
- Faculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, 61-712 Poznań, Poland;
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland; (E.J.); (W.T.); (V.K.-K.)
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Herppich S, Hoenicke L, Kern F, Kruse F, Smout J, Greweling-Pils MC, Geffers R, Burton OT, Liston A, Keller A, Floess S, Huehn J. Zfp362 potentiates murine colonic inflammation by constraining Treg cell function rather than promoting Th17 cell differentiation. Eur J Immunol 2023; 53:e2250270. [PMID: 37366299 DOI: 10.1002/eji.202250270] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 05/02/2023] [Accepted: 06/09/2023] [Indexed: 06/28/2023]
Abstract
Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362-/- mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362-/- mice appeared clinically normal, showed no phenotypic alterations in the T-cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3+ Treg cells and IL-10+ and RORγt+ Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4+ T cells from Zfp362-/- mice into Rag2-/- mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362+/+ littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation.
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Affiliation(s)
- Susanne Herppich
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Lisa Hoenicke
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Fabian Kern
- Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, Saarland University, Saarbrücken, Germany
- Department of Clinical Bioinformatics, Saarland University, Homburg, Germany
| | - Friederike Kruse
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Justine Smout
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Oliver T Burton
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK
| | - Adrian Liston
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK
| | - Andreas Keller
- Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, Saarland University, Saarbrücken, Germany
- Department of Clinical Bioinformatics, Saarland University, Homburg, Germany
| | - Stefan Floess
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jochen Huehn
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Atanga R, Romero AS, Hernandez AJ, Peralta-Herrera E, Merkley SD, In JG, Castillo EF. Inflammatory macrophages prevent colonic goblet and enteroendocrine cell differentiation through Notch signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.29.547119. [PMID: 37425818 PMCID: PMC10327198 DOI: 10.1101/2023.06.29.547119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. Utilizing IL-10-deficient (Il10-/-) mice, a model of spontaneous colitis, we found an increase in Notch activity in the colonic epithelium as well as an increase in intestinal macrophages expressing Notch ligands, which are increased in macrophages upon inflammatory stimuli. Furthermore, a co-culture system of inflammatory macrophages and intestinal stem and proliferative cells during differentiation reduced goblet and enteroendocrine cells. This was recapitulated when utilizing a Notch agonist on human colonic organoids (colonoids). In summary, our findings indicate that inflammatory macrophages upregulate notch ligands that activate notch signaling in ISC via cell-cell interactions, which in turn inhibits secretory lineage differentiation in the gastrointestinal (GI) tract.
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Affiliation(s)
- Roger Atanga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Aaron S. Romero
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Anthony Jimenez Hernandez
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | | | - Seth D. Merkley
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
| | - Julie G. In
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
- Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM
| | - Eliseo F. Castillo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM
- Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM
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Yu K, Liao S, Li C, Song Y, Mei Z, Lv L. Establishment of a lipopolysaccharide-induced inflammation model of human fetal colon cells. Mol Biol Rep 2023:10.1007/s11033-023-08465-7. [PMID: 37155012 DOI: 10.1007/s11033-023-08465-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/14/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a global health problem and there are few cell models for IBD at present. To culture a human fetal colon (FHC) cell line in vitro and establish an FHC cell inflammation model that meets the requirements for high expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). METHODS AND RESULTS FHC cells were cultured with various concentrations of Escherichia coli lipopolysaccharide (LPS) in appropriate media for 0.5, 1, 2, 4, 8, 16 and 24 h to stimulate an inflammatory reaction. The viability of FHC cells was detected by a Cell Counting Kit-8 (CCK-8) assay. The transcriptional levels and protein expression changes of IL-6 and TNF-α in FHC cells were detected by Quantitative Real‑Time Polymerase Chain Reaction (qRT-PCR) and Enzyme‑Linked Immunosorbent Assay (ELISA), respectively. Appropriate stimulation conditions were selected (i.e., LPS concentration and treatment time), based on changes in cell survival rate, and IL-6 and TNF-α expression levels. An LPS concentration higher than 100 µg/mL or a treatment time longer than 24 h resulted in morphological changes and decreased cell survival. By contrast, expression levels of IL-6 and TNF-α significantly increased within 24 h when LPS concentration lower than 100 µg/mL and peaked at 2 h, whilst maintaining cell morphology and viability in FHC cells. CONCLUSION The treatment of FHC cells with 100 µg/mL LPS within 24 h was optimal in terms of stimulating IL-6 and TNF-α expression.
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Affiliation(s)
- Keqi Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China
| | - Ya Song
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China.
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, P.R. China.
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6
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Wang X, Chen S, Wang J, Chen Y, Guo Y, Wang Q, Liu Z, Zeng H, Xu C. Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism. Int J Biol Sci 2023; 19:2150-2166. [PMID: 37151883 PMCID: PMC10158032 DOI: 10.7150/ijbs.80441] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis. Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored. Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression. Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Flood P, Fanning A, Woznicki JA, Crowley T, Christopher A, Vaccaro A, Houston A, McSweeney S, Ross S, Hogan A, Brint E, Skowyra A, Bustamante M, Ambrose M, Moloney G, MacSharry J, Hammarström ML, Hurley M, Fitzgibbons C, Quigley EMM, Shanahan F, Zulquernain SA, McCarthy J, Dodson GS, Dabbagh K, McRae BL, Melgar S, Nally K. DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids. Am J Physiol Gastrointest Liver Physiol 2022; 323:G439-G460. [PMID: 36165492 DOI: 10.1152/ajpgi.00104.2022] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-β or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-β, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.
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Affiliation(s)
- Peter Flood
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Aine Fanning
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Tadhg Crowley
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | | | - Aileen Houston
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
| | | | - Sarah Ross
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Aileen Hogan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Elizabeth Brint
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Pathology, Cork University Hospital, University College Cork, Clinical Sciences Building, Cork, Ireland
| | | | | | - Monica Ambrose
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John MacSharry
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
- School of Medicine, University College Cork, Cork, Ireland
| | - Marie-Louise Hammarström
- Section of Infection and Immunology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | - Margot Hurley
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
| | | | | | - Fergus Shanahan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
| | - Syed A Zulquernain
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
| | - Jane McCarthy
- Department of Gastroenterology, Mercy University Hospital, Cork, Ireland
| | | | | | - Bradford L McRae
- Immunology Discovery, Abbvie Bioresearch Center, Worcester, Massachusetts
| | - Silvia Melgar
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Ken Nally
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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Polyamines and Their Metabolism: From the Maintenance of Physiological Homeostasis to the Mediation of Disease. MEDICAL SCIENCES (BASEL, SWITZERLAND) 2022; 10:medsci10030038. [PMID: 35893120 PMCID: PMC9326668 DOI: 10.3390/medsci10030038] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 12/13/2022]
Abstract
The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, export, de novo synthesis, and catabolism. Enzymes and enzymatic cascades involved in polyamine metabolism have been well characterized. This knowledge has been used for the development of novel compounds for research and medical applications. Furthermore, studies have shown that disturbances in polyamine levels and their metabolic pathways, as a result of spontaneous mutations in patients, genetic engineering in mice or experimentally induced injuries in rodents, are associated with multiple maladaptive changes. The adverse effects of altered polyamine metabolism have also been demonstrated in in vitro models. These observations highlight the important role these molecules and their metabolism play in the maintenance of physiological normalcy and the mediation of injury. This review will attempt to cover the extensive and diverse knowledge of the biological role of polyamines and their metabolism in the maintenance of physiological homeostasis and the mediation of tissue injury.
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Gardnerella vaginalis induces matrix metalloproteinases in the cervicovaginal epithelium through TLR-2 activation. J Reprod Immunol 2022; 152:103648. [PMID: 35679790 PMCID: PMC9313515 DOI: 10.1016/j.jri.2022.103648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/07/2022] [Accepted: 05/20/2022] [Indexed: 11/21/2022]
Abstract
Lactobacillus-deficient cervicovaginal microbiota, including Gardnerella vaginalis, are implicated in cervical remodeling and preterm birth. Mechanisms by which microbes drives outcomes are not fully elucidated. We hypothesize that Gardnerella vaginalis induces matrix metalloproteinases through TLR-2, leading to epithelial barrier dysfunction and premature cervical remodeling. Cervicovaginal cells were treated with live Gardnerella vaginalis or Lactobacillus crispatus or their bacteria-free supernatants for 24 h. For TLR-2 experiments, cells were pretreated with TLR-2 blocking antibody. A Luminex panel was run on cell media. For human data, we conducted a case-control study from a prospective pregnancy cohort of Black individuals with spontaneous preterm (sPTB) (n = 40) or term (n = 40) births whose vaginal microbiota had already been characterized. Cervicovaginal fluid was obtained between 20 and 24 weeks' gestation. Short cervix was defined as < 25 mm by second trimester transvaginal ultrasound. MMP-9 was quantified by ELISA. Standard analytical approaches were used to determine differences across in vitro conditions, as well as MMP-9 and associations with clinical outcomes. Gardnerella vaginalis induced MMP-1 in cervical cells (p = 0.01) and MMP-9 in cervical and vaginal (VK2) cells (p ≤ 0.001 for all). TLR-2 blockade mitigated MMP-9 induction by Gardnerella vaginalis. MMP-9 in cervicovaginal fluid is higher among pregnant individuals with preterm birth, short cervix, and Lactobacillus-deficient microbiota (p < 0.05 for all). MMP-9 is increased in the cervicovaginal fluid of pregnant individuals with subsequent sPTB. Our in vitro work ascribes a potential mechanism by which a cervicovaginal microbe, commonly associated with adverse pregnancy outcomes, may disrupt the cervicovaginal epithelial barrier and promote premature cervical remodeling in spontaneous preterm birth.
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10
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Ngo PA, Neurath MF, López-Posadas R. Impact of Epithelial Cell Shedding on Intestinal Homeostasis. Int J Mol Sci 2022; 23:ijms23084160. [PMID: 35456978 PMCID: PMC9027054 DOI: 10.3390/ijms23084160] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances.
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Affiliation(s)
- Phuong A. Ngo
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Correspondence:
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11
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Porter RJ, Arends MJ, Churchhouse AMD, Din S. Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational Risks from Mechanisms to Medicines. J Crohns Colitis 2021; 15:2131-2141. [PMID: 34111282 PMCID: PMC8684457 DOI: 10.1093/ecco-jcc/jjab102] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The cumulative impact of chronic inflammation in patients with inflammatory bowel diseases predisposes to the development of inflammatory bowel disease-associated colorectal cancer [IBD-CRC]. Inflammation can induce mutagenesis, and the relapsing-remitting nature of this inflammation, together with epithelial regeneration, may exert selective pressure accelerating carcinogenesis. The molecular pathogenesis of IBD-CRC, termed the 'inflammation-dysplasia-carcinoma' sequence, is well described. However, the immunopathogenesis of IBD-CRC is less well understood. The impact of novel immunosuppressive therapies, which aim to achieve deep remission, is mostly unknown. Therefore, this timely review summarizes the clinical context of IBD-CRC, outlines the molecular and immunological basis of disease pathogenesis, and considers the impact of novel biological therapies.
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Affiliation(s)
- Ross J Porter
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, UK
- NHS Lothian Edinburgh IBD Unit, Western General Hospital, UK
| | - Mark J Arends
- Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Cancer & Genetics, Western General Hospital, University of Edinburgh, UK
| | | | - Shahida Din
- NHS Lothian Edinburgh IBD Unit, Western General Hospital, UK
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12
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Gao W, Zhang T, Wu H. Emerging Pathological Engagement of Ferroptosis in Gut Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4246255. [PMID: 34733403 PMCID: PMC8560274 DOI: 10.1155/2021/4246255] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/06/2021] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is mainly characterized by chronic and progressive inflammation that damages the gastrointestinal mucosa. Increasing studies have enlightened that dysregulated cell death occurs in the inflamed sites, leading to the disruption of the intestinal barrier and aggravating inflammatory response. Ferroptosis, a newly characterized form of regulated cell death, is driven by the lethal accumulation of lipid peroxides catalyzed by cellular free iron. It has been widely documented that the fundamental features of ferroptosis, including iron deposition, GSH exhaustion, GPX4 inactivation, and lipid peroxidation, are manifested in the injured gastrointestinal tract in IBD patients. Furthermore, manipulation of the critical ferroptotic genes could alter the progression, severity, or even morbidity of the experimental colitis. Herein, we critically summarize the recent advances in the field of ferroptosis, focusing on interpreting the potential engagement of ferroptosis in the pathogenesis of IBD. Moreover, we are attempting to shed light on a perspective insight into the possibility of targeting ferroptosis as novel therapeutic designs for the clinical intervention of these gastrointestinal diseases.
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Affiliation(s)
- Weihua Gao
- Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
- State Key Laboratory of Agricultural Microbiology, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
- Interdisciplinary Sciences Institute, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Ting Zhang
- Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
- Interdisciplinary Sciences Institute, Huazhong Agricultural University, Wuhan, Hubei 430070, China
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Hao Wu
- Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
- Interdisciplinary Sciences Institute, Huazhong Agricultural University, Wuhan, Hubei 430070, China
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
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13
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Kong L, Qian K, Wu S, Li B, Guo Z, Yin X, Huang Y, Ye J, Tu X, Fu S. Functional characterization of TNF-α in pufferfish (Takifugu obscurus) in immune response and apoptosis against Aeromonas hydrophila. JOURNAL OF FISH DISEASES 2021; 44:1343-1353. [PMID: 33956340 DOI: 10.1111/jfd.13393] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 06/12/2023]
Abstract
Tumour necrosis factor-α (TNF-α) is a multifunctional cytokine involved in immune system homeostasis, antimicrobial defence, regulation of apoptosis, cell proliferation and differentiation. Although the pro-inflammatory property of TNF-α has been made new progress, detailed research on host defence against bacterial infection and inducing apoptosis remains to be revealed in early vertebrates. Here, we reported the TNF-α homologue (ToTNF-α) from pufferfish (Takifugu obscurus). The open reading frame (ORF) of ToTNF-α was 753 bp, encoding a protein of 250 aa contained the TNF family signature and conserved cysteine residues. The mRNA expression of ToTNF-α had a wide range of tested tissues, with the highest expression in the skin. After Aeromonas hydrophila infection, the mRNA expression of ToTNF-α was significantly up-regulated both in vivo and in vitro experiments. After stimulation by recombinant protein of ToTNF-α ((r)ToTNF-α), the relative expressions of endogenous TNF-α, caspase 8, caspase 3, p53, and Bax inhibitor-1 in head kidney leucocytes were all notably up-regulated. These results showed that ToTNF-α might induce apoptosis depend on pro- and anti-apoptotic proteins at mRNA level. Moreover, flow cytometry analysis indicated that the (r)ToTNF-α can induce apoptosis of head kidney leucocytes. Taken together, these characteristics suggest that ToTNF-α can participate in immune response against A. hydrophila and induce apoptosis at mRNA and cellular level, which will help to understand the mechanism of apoptosis and immune response in teleost fish.
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Affiliation(s)
- Linghe Kong
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Kun Qian
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Siwei Wu
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Bingxi Li
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Zheng Guo
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Xiaoxue Yin
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
- Guangdong South China Sea Key Laboratory of Aquaculture for Aquatic Economic Animals, Guangdong Ocean University, Zhanjiang, China
| | - Yu Huang
- Guangdong South China Sea Key Laboratory of Aquaculture for Aquatic Economic Animals, Guangdong Ocean University, Zhanjiang, China
| | - Jianmin Ye
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Xiao Tu
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Shengli Fu
- Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China
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14
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Microbes exploit death-induced nutrient release by gut epithelial cells. Nature 2021; 596:262-267. [PMID: 34349263 DOI: 10.1038/s41586-021-03785-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 06/30/2021] [Indexed: 01/13/2023]
Abstract
Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3-6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host-pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.
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Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease. Nat Med 2021; 27:1212-1222. [PMID: 34183837 DOI: 10.1038/s41591-021-01390-x] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 05/07/2021] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies.
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16
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Liang F, Kang N, Li P, Liu X, Li G, Yang J. Effect of Hyperbaric Oxygen Therapy on Polarization Phenotype of Rat Microglia After Traumatic Brain Injury. Front Neurol 2021; 12:640816. [PMID: 34149591 PMCID: PMC8209338 DOI: 10.3389/fneur.2021.640816] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 04/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The neurological defect caused by secondary damage following traumatic brain injury (TBI) is considered critical for the management of TBI. Microglia (MG) are a resident brain macrophage that could differentiate into M1 type or M2 type in response to injury and repair. It is known that the MG transition from M1 phenotype to anti-inflammatory M2 phenotype might reduce secondary injury of TBI. So, a TBI animal model was established and we compared biomarkers of M1 and M2MG between the controls and experimental animals receiving hyperbaric oxygen therapy (HBOT). This study aimed to explore whether HBOT was an effective method to improve neural functional recovery via promoting the polarization of MG into M2 after TBI. Methods: The rats were randomly divided into four groups: SH (Sham-operated), SH + HBO (hyperbaric oxygen), TBI, and TBI + HBO. Each group included 42 rats, and each of these were divided into the following groups: 1, 6, 12, 24, 72 h, 7, and 14 days. The expression of M1 biomarker inducible nitric oxide synthase (iNOS), M2 biomarker arginase 1 (Arg1), associated cytokine tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1) was evaluated after the observation time. Results: TBI significantly increased the expression levels of M1 marker iNOS and M2 markers Arg1 at different time points. The increased expression of iNOS was suppressed, while the expression level of Arg1 was enhanced by HBOT. Moreover, HBOT suppressed the pro-inflammatory TNF-α secreted by M1, and promoting the anti-inflammatory TGF-1β. Conclusions: In the present study, HBOT showed the effects on shift of M1 toward M2 phenotype with increased expression of M2 biomarkers and decreased expression of M1 biomarkers in the early stage after TBI.
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Affiliation(s)
- Fang Liang
- Department of Hyperbaric Oxygen, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Nan Kang
- Department of Orthopedics, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Pinpin Li
- Department of Hyperbaric Oxygen, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xuehua Liu
- Department of Hyperbaric Oxygen, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Ge Li
- Department of Hyperbaric Oxygen, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jing Yang
- Department of Hyperbaric Oxygen, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Al-Sadi R, Engers J, Haque M, King S, Al-Omari D, Ma TY. Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation. PLoS One 2021; 16:e0249544. [PMID: 33826658 PMCID: PMC8026081 DOI: 10.1371/journal.pone.0249544] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/20/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. AIMS The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. RESULTS MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. CONCLUSION Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
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Affiliation(s)
- Rana Al-Sadi
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
- * E-mail:
| | - Jessica Engers
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Mohammad Haque
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Steven King
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Deemah Al-Omari
- Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Thomas Y. Ma
- Department of Medicine, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
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18
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Ahlawat S, Kumar P, Mohan H, Goyal S, Sharma KK. Inflammatory bowel disease: tri-directional relationship between microbiota, immune system and intestinal epithelium. Crit Rev Microbiol 2021; 47:254-273. [PMID: 33576711 DOI: 10.1080/1040841x.2021.1876631] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human gut microbiota contributes to host nutrition and metabolism, sustains intestinal cell proliferation and differentiation, and modulates host immune system. The alterations in their composition lead to severe gut disorders, including inflammatory bowel disease (IBD) or inflammatory bowel syndrome (IBS). IBD including ulcerative colitis (UC) and Crohn's disease (CD) are gamut of chronic inflammatory disorders of gut, mediated by complex interrelations among genetic, environmental, and internal factors. IBD has debateable aetiology, however in recent years, exploring the central role of a tri-directional relationship between gut microbiota, mucosal immune system, and intestinal epithelium in pathogenesis is getting the most attention. Increasing incidences and early onset explains the exponential rise in IBD burden on health-care systems. Industrialization, hypersensitivity to allergens, lifestyle, hygiene hypothesis, loss of intestinal worms, and gut microbial composition, explains this shifted rise. Hitherto, the interventions modulating gut microbiota composition, microfluidics-based in vitro gastrointestinal models, non-allergic functional foods, nutraceuticals, and faecal microbiota transplantation (FMT) from healthy donors are some of the futuristic approaches for the disease management.
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Affiliation(s)
- Shruti Ahlawat
- Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Pramod Kumar
- Ministry of Health and Family Welfare, Government of India, Indian Council of Medical Research, New Delhi, India
| | - Hari Mohan
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Sandeep Goyal
- Department of Medicine, Pt. BD Sharma Post-graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Krishna Kant Sharma
- Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
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Ye Y, Zhang L, Hu T, Yin J, Xu L, Pang Z, Chen W. CircRNA_103765 acts as a proinflammatory factor via sponging miR-30 family in Crohn's disease. Sci Rep 2021; 11:565. [PMID: 33436852 PMCID: PMC7804428 DOI: 10.1038/s41598-020-80663-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/23/2020] [Indexed: 01/08/2023] Open
Abstract
Increasing evidence suggests that circular RNAs (circRNAs) play critical roles in various pathophysiological activities. However, the role of circRNAs in inflammatory bowel disease (IBD) remains unclear. Here we report the potential roles of hsa_circRNA_103765 in regulating cell apoptosis induced by TNF-α in Crohn’s disease (CD). We identify that CircRNA_103765 expression was significantly upregulated in peripheral blood mononuclear cells (PBMCs) of patients with active IBD. A positive correlation with TNF-α significantly enhanced circRNA_103765 expression in CD, which was significantly reversed by anti-TNF-α mAb (infliximab) treatment. In vitro experiments showed that TNF-α could induce the expression of circRNA_103765, which was cell apoptosis dependent, while silencing of circRNA_103765 could protect human intestinal epithelial cells (IECs) from TNF-α-induced apoptosis. In addition, circRNA_103765 acted as a molecular sponge to adsorb the miR-30 family and impair the negative regulation of Delta-like ligand 4 (DLL4). Collectively, CircRNA_103765 is a novel important regulator of the pathogenesis of IBD via sponging miR-30 family-mediated DLL4 expression changes. Blockade of circRNA_103765 could serve as a novel approach for the treatment of IBD patients.
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Affiliation(s)
- Yulan Ye
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, China.,Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Liping Zhang
- Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Tong Hu
- Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Juan Yin
- Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Lijuan Xu
- Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Zhi Pang
- Department of Gastroenterology, The North District of the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, Jiangsu, China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, China.
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20
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Rapa SF, Di Paola R, Cordaro M, Siracusa R, D’Amico R, Fusco R, Autore G, Cuzzocrea S, Stuppner H, Marzocco S. Plumericin Protects against Experimental Inflammatory Bowel Disease by Restoring Intestinal Barrier Function and Reducing Apoptosis. Biomedicines 2021; 9:biomedicines9010067. [PMID: 33445622 PMCID: PMC7826791 DOI: 10.3390/biomedicines9010067] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with a potential activity for UC treatment, this study evaluated the effects of plumericin, a spirolactone iridoid, present as one of the main bioactive components in the bark of Himatanthus sucuuba (Woodson). Plumericin was evaluated for its ability to improve barrier function and to reduce apoptotic parameters during inflammation, both in intestinal epithelial cells (IEC-6), and in an animal experimental model of 2, 4, 6-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Our results indicated that plumericin increased the expression of adhesion molecules, enhanced IEC-6 cells actin cytoskeleton rearrangement, and promoted their motility. Moreover, plumericin reduced apoptotic parameters in IEC-6. These results were confirmed in vivo. Plumericin reduced the activity of myeloperoxidase, inhibited the expression of ICAM-1, P-selectin, and the formation of PAR, and reduced apoptosis parameters in mice colitis induced by DNBS. These results support a pharmacological potential of plumericin in the treatment of UC, due to its ability to improve the structural integrity of the intestinal epithelium and its barrier function.
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Affiliation(s)
- Shara Francesca Rapa
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Marika Cordaro
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Ramona D’Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Giuseppina Autore
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (R.D.P.); (R.S.); (R.D.); (R.F.); (S.C.)
| | - Hermann Stuppner
- Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria;
| | - Stefania Marzocco
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (S.F.R.); (G.A.)
- Correspondence: ; Tel.: +89-969159
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21
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Faria RS, Silva HD, Mello-Andrade F, Pires WC, de Castro Pereira F, de Lima AP, de Fátima Oliveira Santos S, Teixeira TM, da Silva PFF, Naves PLF, Batista AA, da Silva Oliveira RJ, Reis RM, de Paula Silveira-Lacerda E. Ruthenium(II)/Benzonitrile Complex Induces Cytotoxic Effect in Sarcoma-180 Cells by Caspase-Mediated and Tp53/p21-Mediated Apoptosis, with Moderate Brine Shrimp Toxicity. Biol Trace Elem Res 2020; 198:669-680. [PMID: 32266641 DOI: 10.1007/s12011-020-02098-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022]
Abstract
Ruthenium(II)/benzonitrile complexes have demonstrated promising anticancer properties. Considering that there are no specific therapies for treating sarcoma, we decided to evaluate the cytotoxic, genotoxic, and lethal effects of cis-[RuCl(BzCN)(phen)(dppb)]PF6 (BzCN = benzonitrile; phen = 1,10-phenanthroline; dppb = 1,4-bis-(diphenylphosphino)butane), as well as the mechanism of cell death induction that occurs against murine sarcoma-180 tumor. Thus, MTT assay was applied to assess the ruthenium cytotoxicity, showing that the compound is a more potent inhibitor for the sarcoma-180 tumor cell viability than normal cells (lymphocytes). The comet assay indicated low genotoxic for normal cells. cis-[RuCl(BzCN)(phen)(dppb)]PF6 also showed moderate lethality in Artemia salina. The complex induced cell cycle arrest in the G0/G1 phase in sarcoma-180 cells. In addition, the complex caused S180 cells to die by apoptosis by an increase in Annexin-V-positive cells and morphological changes typical of apoptotic cells. Additionally, cis-[RuCl(BzCN)(phen)(dppb)]PF6 increased the gene expression of Bax, Casp3, and Tp53 in S180 cells. By using a western blot, we observed an increased protein level of TNF-R2, Bax, and p21. In conclusion, cis-[RuCl(BzCN)(phen)(dppb)]PF6 is active and selective for sarcoma-180 cells, leading to cell cycle arrest at the G0/G1 and cell death through a caspases-mediated and Tp53/p21-mediated pathway.
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Affiliation(s)
- Raquel Santos Faria
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | - Hugo Delleon Silva
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
- Uni-Anhanguera University Center of Goias, Goiania, Goiás, 74423-115, Brazil
| | - Francyelli Mello-Andrade
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
- Department of Chemistry, Federal Institute of Education, Science and Technology of Goiás, Goiania, Goiás, 74055-110, Brazil
| | - Wanessa Carvalho Pires
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | - Flávia de Castro Pereira
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | - Aliny Pereira de Lima
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
- Faculty of Brazil Institute (FIBRA), Anapolis, Goiás, 75133-050, Brazil
| | - Sônia de Fátima Oliveira Santos
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | - Thallita Monteiro Teixeira
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | - Paula Francinete Faustino da Silva
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil
| | | | - Alzir Azevedo Batista
- Department of Chemistry, Federal University of São Carlos, Sao Carlos, São Paulo, 13565-905, Brazil
| | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, 14784-400, Brazil
| | - Elisângela de Paula Silveira-Lacerda
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil.
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22
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Sato N, Garcia-Castillo V, Yuzawa M, Islam MA, Albarracin L, Tomokiyo M, Ikeda-Ohtsubo W, Garcia-Cancino A, Takahashi H, Villena J, Kitazawa H. Immunobiotic Lactobacillus jensenii TL2937 Alleviates Dextran Sodium Sulfate-Induced Colitis by Differentially Modulating the Transcriptomic Response of Intestinal Epithelial Cells. Front Immunol 2020; 11:2174. [PMID: 33042131 PMCID: PMC7527445 DOI: 10.3389/fimmu.2020.02174] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/10/2020] [Indexed: 12/11/2022] Open
Abstract
Immunobiotics have emerged as a promising intervention to alleviate intestinal damage in inflammatory bowel disease (IBD). However, the beneficial properties of immunobiotics are strain dependent and, therefore, each strain has to be evaluated in order to demonstrate its potential application in IBD. Our previous in vitro and in vivo studies demonstrated that Lactobacillus jensenii TL2937 attenuates gut acute inflammatory response triggered by Toll-like receptor 4 activation. However, its effect on colitis has not been evaluated before. In this work, we studied whether the TL2937 strain was able to protect against the development of colitis in a dextran sodium sulfate (DSS)-induced mouse model and we delved into the mechanisms of action by evaluating the effect of the immunobiotic bacteria on the transcriptomic response of DSS-challenged intestinal epithelial cells. L. jensenii TL2937 was administered to adult BALB/c mice before the induction of colitis by the administration of DSS. Colitis and the associated inflammatory response were evaluated for 14 days. Mice fed with L. jensenii TL2937 had lower disease activity index and alterations of colon length when compared to control mice. Reduced myeloperoxidase activity, lower production of pro-inflammatory (TNF-α, IL-1, CXCL1, MCP-1, IL-15, and IL-17), and higher levels of immunoregulatory (IL-10 and IL-27) cytokines were found in the colon of TL2937-treated mice. In addition, the treatment of porcine intestinal epithelial (PIE) cells with L. jensenii TL2937 before the challenge with DSS differentially regulated the activation of the JNK pathway, leading to an increase in epithelial cell integrity and to a differential immunotranscriptomic response. TL2937-treated PIE cells had a significant reduction in the expression of inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6, IL-15), chemokines (CCL2, CCL4, CCL8, CXCL4, CXCL5, CXCL9, CXCL10), adhesion molecules (SELE, SELL, EPCAM), and other immune factors (NCF1, NCF2, NOS2, SAA2) when compared to control cells after the challenge with DSS. The findings of this work indicate that (a) L. jensenii TL2937 is able to alleviate DSS-induced colitis suggesting a potential novel application for this immunobiotic strain, (b) the modulation of the transcriptomic response of intestinal epithelial cells would play a key role in the beneficial effects of the TL2937 strain on colitis, and (c) the in vitro PIE cell immunoassay system could be of value for the screening and selection of new immunobiotic strains for their application in IBD.
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Affiliation(s)
- Nana Sato
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Valeria Garcia-Castillo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepción, Chile
| | - Mao Yuzawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Md. Aminul Islam
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Department of Medicine, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Leonardo Albarracin
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Laboratory of Immunobiotechnology, Reference Center for Lactobacilli (CERELA-National Council for Scientific and Technological Research), San Miguel de Tucumán, Argentina
- Laboratory of Computing Science, Faculty of Exact Sciences and Technology, Tucuman University, San Miguel de Tucumán, Argentina
| | - Mikado Tomokiyo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Wakako Ikeda-Ohtsubo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Apolinaria Garcia-Cancino
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepción, Chile
| | - Hideki Takahashi
- Laboratory of Plant Pathology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Plant Immunology Unit, International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Julio Villena
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Department of Medicine, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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23
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Sato N, Yuzawa M, Aminul MI, Tomokiyo M, Albarracin L, Garcia-Castillo V, Ideka-Ohtsubo W, Iwabuchi N, Xiao JZ, Garcia-Cancino A, Villena J, Kitazawa H. Evaluation of Porcine Intestinal Epitheliocytes as an In vitro Immunoassay System for the Selection of Probiotic Bifidobacteria to Alleviate Inflammatory Bowel Disease. Probiotics Antimicrob Proteins 2020; 13:824-836. [PMID: 32779098 DOI: 10.1007/s12602-020-09694-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The use of in vitro systems that allow efficient selection of probiotic candidates with immunomodulatory properties could significantly minimize the use of experimental animals. In this work, we generated an in vitro immunoassay system based on porcine intestinal epithelial (PIE) cells and dextran sodium sulfate (DSS) administration that could be useful for the selection and characterization of potential probiotic strains to be used in inflammatory bowel disease (IBD) patients. Our strategy was based on two fundamental pillars: on the one hand, the capacity of PIE cells to create a monolayer by attaching to neighboring cells and efficiently mount inflammatory responses and, on the other hand, the use of two probiotic bifidobacteria strains that have been characterized in terms of their immunomodulatory capacities, particularly in mouse IBD models and patients. Our results demonstrated that DSS administration can alter the epithelial barrier created in vitro by PIE cells and induce a potent inflammatory response, characterized by increases in the expression levels of several inflammatory factors including TNF-α, IL-1α, CCL4, CCL8, CCL11, CXCL5, CXCL9, CXCL10, SELL, SELE, EPCAM, VCAM, NCF2, and SAA2. In addition, we demonstrated that Bifidobacterium breve M-16V and B. longum BB536 are able to regulate the C-jun N-terminal kinase (JNK) intracellular signalling pathway, reducing the DSS-induced alterations of the in vitro epithelial barrier and differentially regulating the inflammatory response in a strain-dependent fashion. The good correlation between our in vitro findings in PIE cells and previous studies in animal models and IBD patients shows the potential value of our system to select new probiotic candidates in an efficient way.
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Affiliation(s)
- Nana Sato
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Mao Yuzawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Md Islam Aminul
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Mikado Tomokiyo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Leonardo Albarracin
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), San Miguel de Tucuman, Tucuman, Argentina.,Laboratory of Computing Science, Faculty of Exact Sciences and Technology, Tucuman University, San Miguel de Tucuman, Tucuman, Argentina
| | - Valeria Garcia-Castillo
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Wakako Ideka-Ohtsubo
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Noriyuki Iwabuchi
- Food Science and Technology Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - Jin-Zhong Xiao
- Food Science and Technology Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - Apolinaria Garcia-Cancino
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Julio Villena
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan. .,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), San Miguel de Tucuman, Tucuman, Argentina.
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan. .,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
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24
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Zhang J, Xu M, Zhou W, Li D, Zhang H, Chen Y, Ning L, Zhang Y, Li S, Yu M, Chen Y, Zeng H, Cen L, Zhou T, Zhou X, Lu C, Yu C, Li Y, Sun J, Kong X, Shen Z. Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53. J Biol Chem 2020; 295:4237-4251. [PMID: 32075910 PMCID: PMC7105307 DOI: 10.1074/jbc.ra119.010143] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 02/11/2020] [Indexed: 12/31/2022] Open
Abstract
Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1-/- mice, DJ-1-/-p53-/- mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1-/- mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Min Xu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Weihua Zhou
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Dejian Li
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yi Chen
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Longgui Ning
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuwei Zhang
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Sha Li
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Mengli Yu
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yishu Chen
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Hang Zeng
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Li Cen
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Tianyu Zhou
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xinxin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chao Lu
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Youming Li
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Jing Sun
- Department of Gastroenterology, Rui Jin Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
| | - Xiaoni Kong
- Institute of Clinical Immunology, Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.
| | - Zhe Shen
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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25
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Faria DRD, Barbieri LC, Koh CC, Machado PRL, Barreto CC, Lima CMFD, Lessa MM, Carvalho E, Gollob KJ, Dutra WO. In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline. Am J Trop Med Hyg 2020; 101:392-401. [PMID: 31219000 DOI: 10.4269/ajtmh.19-0139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.
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Affiliation(s)
- Daniela Rodrigues de Faria
- Centro Universitário de Formiga - UNIFOR-MG, Formiga, Brazil.,Laboratory of Cell-Cell Interactions, Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiza Cenizio Barbieri
- Laboratory of Cell-Cell Interactions, Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Carolina Cattoni Koh
- Laboratory of Cell-Cell Interactions, Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Paulo Roberto Lima Machado
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais - INCT-DT, Salvador, Brazil.,Immunology Service, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Carolina Cincurá Barreto
- Immunology Service, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Brazil
| | | | - Marcus Miranda Lessa
- Immunology Service, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Edgar Carvalho
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais - INCT-DT, Salvador, Brazil.,Immunology Service, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Kenneth J Gollob
- International Research Center, ACCamargo Cancer Center, São Paulo, Brazil.,Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais - INCT-DT, Salvador, Brazil
| | - Walderez Ornelas Dutra
- Laboratory of Cell-Cell Interactions, Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais - INCT-DT, Salvador, Brazil
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26
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Gröschel C, Prinz-Wohlgenannt M, Mesteri I, Karuthedom George S, Trawnicek L, Heiden D, Aggarwal A, Tennakoon S, Baumgartner M, Gasche C, Lang M, Marculescu R, Manhardt T, Schepelmann M, Kallay E. Switching to a Healthy Diet Prevents the Detrimental Effects of Western Diet in a Colitis-Associated Colorectal Cancer Model. Nutrients 2019; 12:E45. [PMID: 31877961 PMCID: PMC7019913 DOI: 10.3390/nu12010045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 01/19/2023] Open
Abstract
Inflammatory bowel disease increases the odds of developing colitis-associated cancer. We hypothesized that Western-style diet (WD) aggravates azoxymethane (AOM)/dextran sulfate sodium salt (DSS)-induced colitis-associated tumorigenesis and that switching to the standard AIN93G diet will ameliorate disease symptoms even after cancer initiation. Female BALB/c mice received either WD (WD group) or standard AIN93G diet (AIN group) for the whole experimental period. After five weeks, the mice received 12.5 mg/kg AOM intraperitoneally, followed by three DSS cycles. In one group of mice, the WD was switched to AIN93G the day before starting the first DSS cycle (WD/AIN group). Feeding the WD during the whole experimental period aggravated colitis symptoms, shortened the colon (p < 0.05), changed microbiota composition and increased tumor promotion. On molecular level, the WD reduced proliferation (p < 0.05) and increased expression of the vitamin D catabolizing enzyme Cyp24a1 (p < 0.001). The switch to the AIN93G diet ameliorated this effect, reflected by longer colons, fewer (p < 0.05) and smaller (p < 0.01) aberrant colonic crypt foci, comparable with the AIN group. Our results show that switching to a healthy diet, even after cancer initiation is able to revert the deleterious effect of the WD and could be an effective preventive strategy to reduce colitis symptoms and prevent tumorigenesis.
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Affiliation(s)
- Charlotte Gröschel
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Maximilian Prinz-Wohlgenannt
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Ildiko Mesteri
- Institute of Pathology Überlingen, 88662 Überlingen, Germany;
| | - Sobha Karuthedom George
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Lena Trawnicek
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Denise Heiden
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Abhishek Aggarwal
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Samawansha Tennakoon
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Maximilian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Michaela Lang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (C.G.); (M.L.)
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria;
| | - Teresa Manhardt
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Martin Schepelmann
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
| | - Enikö Kallay
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (M.P.-W.); (S.K.G.); (L.T.); (D.H.); (A.A.); (S.T.); (T.M.); (M.S.)
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27
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Chu FF, Esworthy RS, Shen B, Gao Q, Doroshow JH. Dexamethasone and Tofacitinib suppress NADPH oxidase expression and alleviate very-early-onset ileocolitis in mice deficient in GSH peroxidase 1 and 2. Life Sci 2019; 239:116884. [PMID: 31689440 PMCID: PMC6898790 DOI: 10.1016/j.lfs.2019.116884] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/15/2019] [Accepted: 09/16/2019] [Indexed: 12/25/2022]
Abstract
C57BL6/J (B6) mice lacking Se-dependent GSH peroxidase 1 and 2 (GPx1/2-DKO) develop mild to moderate ileocolitis around weaning. These DKO mice have a disease resembling human very-early-onset inflammatory bowel disease (VEOIBD), which is associated with mutations in NADPH oxidase genes. Drugs including dexamethasone (Dex), Tofacitinib (Tofa; a Janus kinase/JAK inhibitor) and anti-TNF antibody are effective to treat adult, but not pediatric IBD. AIMS To test the efficacy of hydrophobic Dex and hydrophilic Dex phosphate (Dex phos), Tofa, anti-Tnf Ab, Noxa1ds-TAT and gp91ds-TAT peptides (inhibiting NOX1 and NOX2 assembly respectively), antioxidant MJ33 and ML090, and pifithrin-α (p53 inhibitor) on alleviation of gut inflammation in DKO weanlings. MAIN METHODS All treatments began on 22-day-old GPx1/2-DKO mice. The mouse intestine pathology was compared between the drug- and vehicle-treated groups after six or thirteen days of treatment. KEY FINDINGS Among all drugs tested, Dex, Dex phos and Tofa were the strongest to suppress ileocolitis in the DKO weanlings. Dex, Dex phos and Tofa inhibited crypt apoptosis and increased crypt density. Dex or Dex phos alone also inhibited cell proliferation, exfoliation and crypt abscess in the ileum. Dex, but not Tofa, retarded mouse growth. Both Dex and Tofa inhibited ileum Nox1, Nox4 and Duox2, but not Nox2 gene expression. Noxa1ds-TAT and gp91ds-TAT peptides as well as MJ33 had subtle effect on suppressing pathology, while others had negligible effect. SIGNIFICANCE These findings suggest that NADPH oxidases can be novel drug targets for pediatric IBD therapy, and Tofa may be considered for treating VEOIBD.
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Affiliation(s)
- Fong-Fong Chu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, China; Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
| | - R Steven Esworthy
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
| | - Binghui Shen
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
| | - Qiang Gao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, China; Department of Gastroenterology and Hepatology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, China.
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD, USA.
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Zheng JH, Lin SR, Tseng FJ, Tsai MJ, Lue SI, Chia YC, Woon M, Fu YS, Weng CF. Clerodane Diterpene Ameliorates Inflammatory Bowel Disease and Potentiates Cell Apoptosis of Colorectal Cancer. Biomolecules 2019; 9:biom9120762. [PMID: 31766534 PMCID: PMC6995628 DOI: 10.3390/biom9120762] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/20/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is general term for ulcerative colitis and Crohn's disease, which is chronic intestinal and colorectal inflammation caused by microbial infiltration or immunocyte attack. IBD is not curable, and is highly susceptible to develop into colorectal cancer. Finding agents to alleviate these symptoms, as well as any progression of IBD, is a critical effort. This study evaluates the anti-inflammation and anti-tumor activity of 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) in in vivo and in vitro assays. The result of an IBD mouse model induced using intraperitoneal chemical azoxymethane (AOM)/dextran sodium sulfate (DSS) injection showed that intraperitoneal HCD adminstration could ameliorate the inflammatory symptoms of IBD mice. In the in vitro assay, cytotoxic characteristics and retained signaling pathways of HCD treatment were analyzed by MTT assay, cell cycle analysis, and Western blotting. From cell viability determination, the IC50 of HCD in Caco-2 was significantly lower in 2.30 μM at 48 h when compared to 5-fluorouracil (5-FU) (66.79 μM). By cell cycle and Western blotting analysis, the cell death characteristics of HCD treatment in Caco-2 exhibited the involvement of extrinsic and intrinsic pathways in cell death, for which intrinsic apoptosis was predominantly activated via the reduction in growth factor signaling. These potential treatments against colon cancer demonstrate that HCD could provide a promising adjuvant as an alternative medicine in combating colorectal cancer and IBD.
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Affiliation(s)
- Jia-Huei Zheng
- Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan; (J.-H.Z.); (S.-R.L.); (F.-J.T.); (S.-I.L.)
| | - Shian-Ren Lin
- Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan; (J.-H.Z.); (S.-R.L.); (F.-J.T.); (S.-I.L.)
| | - Feng-Jen Tseng
- Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan; (J.-H.Z.); (S.-R.L.); (F.-J.T.); (S.-I.L.)
- Department of Orthopedics, Hualien Armed Force General Hospital, Hualien 97144, Taiwan
| | - May-Jywan Tsai
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei City 11217, Taiwan;
| | - Sheng-I Lue
- Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan; (J.-H.Z.); (S.-R.L.); (F.-J.T.); (S.-I.L.)
- Department of Physiology & Master’s Program, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Chen Chia
- Department of Food Science & Technology, Tajen University, Pingtung 90741, Taiwan;
| | - Mindar Woon
- Department of Radiation Oncology, Yeezen Hospital, Taoyuan 32645, Taiwan;
| | - Yaw-Syan Fu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China
| | - Ching-Feng Weng
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China
- Correspondence: or ; Tel.: +886-3-8903609
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29
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Jozawa H, Inoue-Yamauchi A, Arimura S, Yamanashi Y. Loss of C/EBPδ enhances apoptosis of intestinal epithelial cells and exacerbates experimental colitis in mice. Genes Cells 2019; 24:619-626. [PMID: 31233664 DOI: 10.1111/gtc.12711] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 06/08/2019] [Accepted: 06/19/2019] [Indexed: 01/01/2023]
Abstract
Inflammatory bowel diseases (IBDs) are characterized by chronic inflammation involving intestinal tissue damage, which include ulcerative colitis and Crohn's disease as major entities. Accumulating evidence suggests that excessive apoptosis of intestinal epithelial cells (IECs) contributes to the development of IBD. It was recently reported that the transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) is involved in inflammation; however, its role in colitis remains unclear. Here, we found that C/EBPδ knockout mice showed enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis, a mouse model of IBD, which was associated with severe colonic inflammation and mucosal damage with increased IEC apoptosis. Additionally, DSS stimulation induced increased expression of pro-apoptotic BH3-only protein Bim in the colon of C/EBPδ knockout mice. Collectively, our findings demonstrate that C/EBPδ plays an essential role in suppressing DSS-induced colitis, likely by attenuating IEC apoptosis.
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Affiliation(s)
- Hiroki Jozawa
- Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akane Inoue-Yamauchi
- Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Sumimasa Arimura
- Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yuji Yamanashi
- Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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30
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Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis. Biochem Pharmacol 2019; 166:264-273. [PMID: 31170375 DOI: 10.1016/j.bcp.2019.05.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 05/30/2019] [Indexed: 12/14/2022]
Abstract
Semaphorin 3E (SEMA3E) has emerged as an axon-guiding molecule that regulates various biological processes including the immune responses and apoptosis. However, its role in the pathophysiology of colitis remains elusive. We investigated the role of SEMA3E in intestinal epithelial cells (IECs) activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of SEMA3E is reduced significantly in patients with UC and demonstrated a negative linear association between SEMA3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e resulted in an increase onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant SEMA3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant SEMA3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes. Together, these findings identify SEMA3E as a novel regulator in intestinal inflammation that regulates IECs apoptosis and suggest a potential novel approach to treat UC.
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31
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Imbalance of Controlled Death in Peripheral Blood Lymphocytes in Crohn's Disease and Ulcerative Colitis. ACTA ACUST UNITED AC 2019; 55:medicina55060231. [PMID: 31159239 PMCID: PMC6632058 DOI: 10.3390/medicina55060231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 05/30/2019] [Accepted: 05/30/2019] [Indexed: 02/06/2023]
Abstract
Background and objectives: Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Both conditions are associated with an exacerbated intestinal immune response to harmless stimuli, leading to upregulation of pro-inflammatory mediators. Materials and Methods: The subjects of the study were 55 patients with IBD. The control group consisted of 35 healthy subjects. The researched material consisted of peripheral blood lymphocytes collected from the subjects. Expression of the genes BAX, BCL2, CASP3 and CASP9 was assessed at the mRNA level in the peripheral blood lymphocytes of patients with ulcerative colitis and Crohn's disease relative to the healthy subjects. The expression of the genes was determined by rtPCR using TaqMan probes specific for these genes. Results: The group of patients diagnosed with CD had statistically significantly higher expression of the genes BAX (p = 0.012), BCL2 (p = 0.022), CASP3 (p = 0.003) and CASP9 (p = 0.029) than healthy subjects. Expression of BAX, BCL2, CASP3 and CASP9 in UC patients in the active phase of the disease was significantly lower than in patients in remission: BAX (p = 0.001), BCL2 (p = 0.038) and CASP9 (p = 0.007). In patients with UC, the BAX/BCL2 ratio was significantly correlated (r = 0.473) with the duration of the disease. In the group of CD patients treated biologically, a significantly lower BAX/BCL2 ratio was demonstrated than in patients that were not biologically treated. Conclusions: Our research has shown a simultaneous increase in the expression of the anti-apoptotic BCL2 gene and the proapoptotic BAX gene, which suggests the dysregulation of apoptosis mechanisms in IBD. Significantly higher expression of BAX and BCL2 in UC patients in remission as compared to CD may suggest differences in these diseases in terms of prognosis and treatment. Our results may suggest that an underlying imbalance in factors controlling apoptosis in peripheral blood lymphocytes may be the response of the immune system to inflammation of the intestinal mucosa. Modulation of apoptosis may become an important therapeutic mechanism in IBD.
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32
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Kawamoto A, Nagata S, Anzai S, Takahashi J, Kawai M, Hama M, Nogawa D, Yamamoto K, Kuno R, Suzuki K, Shimizu H, Hiraguri Y, Yui S, Oshima S, Tsuchiya K, Nakamura T, Ohtsuka K, Kitagawa M, Okamoto R, Watanabe M. Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients. J Crohns Colitis 2019; 13:495-509. [PMID: 30395194 DOI: 10.1093/ecco-jcc/jjy180] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The intestinal epithelium of inflammatory bowel disease [IBD] patients is exposed to various pro-inflammatory cytokines, most notably tumour necrosis factor alpha [TNF-α]. We have previously shown that the Notch signalling pathway is also upregulated in such an epithelium, contributing to intestinal epithelial cell [IEC] proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved. METHODS Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-α-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D [UBD] in various patient-derived intestinal tissues. RESULTS In human IEC cell lines, we found that Notch signalling and TNF-α-induced NFκB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly upregulated genes, due to synergy of Notch and TNF-α. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-α-dependent expression of UBD. Notably, post-infliximab [IFX] downregulation of UBD reflected favourable outcome in IBD patients. CONCLUSION We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.
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Affiliation(s)
- Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayaka Nagata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sho Anzai
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junichi Takahashi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mao Kawai
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minami Hama
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daichi Nogawa
- Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kouhei Yamamoto
- Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Reiko Kuno
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kohei Suzuki
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yui Hiraguri
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shiro Yui
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeru Oshima
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuya Nakamura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Advanced Therapeutics in GI Diseases, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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33
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Qiao YQ, Cai CW, Shen J, Zheng Q, Ran ZH. Circular RNA expression alterations in colon tissues of Crohn's disease patients. Mol Med Rep 2019; 19:4500-4506. [PMID: 30896837 DOI: 10.3892/mmr.2019.10070] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 02/18/2019] [Indexed: 12/26/2022] Open
Abstract
Genetic factors are crucial in the development of Crohn's disease (CD). Circular RNAs (circRNAs) are known to function as microRNA (miRNA) sponges and regulate a number of signalling pathways via circRNA‑miRNA interactions. As competing endogenous RNAs, the functions of circRNAs in CD should be investigated. In the present study, colon biopsy tissues were collected from ileocolon (L3)‑active CD patients and healthy controls. circRNA microarrays were performed with colon tissues from 3 CD patients and 3 controls. Subsequently, the candidate circRNAs were verified via reverse transcription‑quantitative polymerase chain reaction using colon tissues from a further 10 CD patients and 10 controls. Targeted miRNAs, genes and pathways of candidate circRNAs were predicted and analysed. Arraystar circRNA microarrays demonstrated that there were 163 upregulated circRNAs targeting 435 miRNAs and 55 downregulated circRNAs targeting 207 miRNAs (fold‑change >2 and P<0.01) in CD patients. As a candidate circRNA, hsa‑circRNA‑102685 was observed to putatively target hsa‑miR‑146b‑5p, hsa‑miR‑182‑5p and hsa‑miR‑146a‑5p. Furthermore, Kyoto Encyclopaedia of Genes and Genomes pathway analysis predicted that hsa‑circRNA‑102685 potentially participated in apoptosis, and in the Toll‑like receptor and p53 signalling pathways. Overall, the current study suggested that circRNA alterations serve an important role in the pathogenesis of CD. circRNAs, such as hsa‑circRNA‑102685, are involved in certain important signalling pathways of CD, and may be novel targets for diagnosis or treatment in this disease.
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Affiliation(s)
- Yu Qi Qiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Centre, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Chen Wen Cai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Centre, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Centre, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Qing Zheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Centre, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Zhi Hua Ran
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Centre, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
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34
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Chae JM, Chang MH, Heo W, Cho HT, Lee DH, Hwang BB, Kim JW, Yoon SM, Yang S, Lee JH, Kim YJ. LB-9, Novel Probiotic Lactic Acid Bacteria, Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice by Inhibiting TNF-α-Mediated Apoptosis of Intestinal Epithelial Cells. J Med Food 2019; 22:271-276. [DOI: 10.1089/jmf.2018.4236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jung Min Chae
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Moon Han Chang
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Wan Heo
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Hyung Taek Cho
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Dong Hun Lee
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Bo Byeol Hwang
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Jin Woo Kim
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | | | | | - Jin Hyup Lee
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Young Jun Kim
- Department of Food and Biotechnology, Korea University, Sejong, Korea
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35
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Kikut J, Konecka N, Ziętek M, Szczuko M. Inflammatory Bowel Disease Etiology: Current Knowledge. Pteridines 2018. [DOI: 10.1515/pteridines-2018-0020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Non-specific inflammatory bowel diseases (IBD) include Crohn’s disease (CD) and ulcerative colitis (UC). Both diseases are characterized by chronic inflammation of unclear etiology. The inflammatory bowel diseases incidence is continuously observed to rise. Colon inflammatory response is a physiological process which occurrence is indispensable as an organisms’ defense reaction. The inflammation may be caused by internal factors associated with body’s cells as well as external factors, such as infections and exposition for inflammatory agents. Until recently, IBD have been classified as autoimmune diseases, today they seem to be associated with gut barrier disorders or dysbiosis. Factors that predispose to inflammatory bowel diseases include: genetic factors, dysbiosis and so called western-type diet, natural components such as gluten and lactose. In addition, the development of the disease is favored by: cigarette smoking, phosphate, nanomolecules, sodium chloride, emulgents, carrageenan, carboxymethylcellulose, pollution, maltodextrin. IBD affects whole the body, causing serious medical consequences. Symptoms like anxiety and chronic stress, that occur commonly, can lead to depressive disorders. Quantitative and qualitative dietary deficiency caused by absorption disorders, may promote the occurrence of osteoporosis and osteopenia. In addition, dysbiosis coexisting with alterations in intestinal permeability can lead to the development of nonalcoholic fatty liver disease. IBD medical consequences include also systemic complications, associated with the extra gastrointestinal manifestations’ occurrence.
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Affiliation(s)
- Justyna Kikut
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University in Szczecin , Poland
| | - Nina Konecka
- Department of Applied Neurocognitivistic, Pomeranian Medical University in Szczecin , Poland
| | - Maciej Ziętek
- Department of Perinatology, Obstetrics and Gynecology Pomeranian Medical University in Szczecin , Poland
| | - Małgorzata Szczuko
- Departament of Biochemistry and Human Nutrition, Pomeranian Medical University in Szczecin , Poland
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36
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Christodoulou-Vafeiadou E, Ioakeimidis F, Andreadou M, Giagkas G, Stamatakis G, Reczko M, Samiotaki M, Papanastasiou AD, Karakasiliotis I, Kontoyiannis DL. Divergent Innate and Epithelial Functions of the RNA-Binding Protein HuR in Intestinal Inflammation. Front Immunol 2018; 9:2732. [PMID: 30532756 PMCID: PMC6265365 DOI: 10.3389/fimmu.2018.02732] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/06/2018] [Indexed: 12/17/2022] Open
Abstract
HuR is an abundant RNA-binding protein acting as a post-transcriptional regulator of many RNAs including mRNAs encoding inflammatory mediators, cytokines, death signalers and cell cycle regulators. In the context of intestinal pathologies, elevated HuR is considered to enhance the stability and the translation of pro-tumorigenic mRNAs providing the rationale for its pharmacological targeting. However, HuR also possesses specific regulatory functions for innate immunity and cytokine mRNA control which can oppose intestinal inflammation and tumor promotion. Here, we aim to identify contexts of intestinal inflammation where the innate immune and the epithelial functions of HuR converge or diverge. To address this, we use a disease-oriented phenotypic approach using mice lacking HuR either in intestinal epithelia or myeloid-derived immune compartments. These mice were compared for their responses to (a) Chemically induced Colitis; (b) Colitis- associated Cancer (CAC); (c) T-cell mediated enterotoxicity; (d) Citrobacter rodentium-induced colitis; and (e) TNF-driven inflammatory bowel disease. Convergent functions of epithelial and myeloid HuR included their requirement for suppressing inflammation in chemically induced colitis and their redundancies in chronic TNF-driven IBD and microbiota control. In the other contexts however, their functions diversified. Epithelial HuR was required to protect the epithelial barrier from acute inflammatory or infectious degeneration but also to promote tumor growth. In contrast, myeloid HuR was required to suppress the beneficial inflammation for pathogen clearance and tumor suppression. This cellular dichotomy in HuR's functions was validated further in mice engineered to express ubiquitously higher levels of HuR which displayed diminished pathologic and beneficial inflammatory responses, resistance to epithelial damage yet a heightened susceptibility to CAC. Our study demonstrates that epithelial and myeloid HuR affect different cellular dynamics in the intestine that need to be carefully considered for its pharmacological exploitation and points toward potential windows for harnessing HuR functions in intestinal inflammation.
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Affiliation(s)
| | - Fotis Ioakeimidis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Margarita Andreadou
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Giorgos Giagkas
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - George Stamatakis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Martin Reczko
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Martina Samiotaki
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | | | - Ioannis Karakasiliotis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Dimitris L Kontoyiannis
- Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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37
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Moulahoum H, Boumaza BMA, Ferrat M, Bounaama A, Djerdjouri B. Arsenic trioxide ameliorates murine colon inflammation through inflammatory cell enzymatic modulation. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:259-270. [PMID: 30415273 DOI: 10.1007/s00210-018-1578-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/02/2018] [Indexed: 12/20/2022]
Abstract
Arsenic trioxide (As2O3) is a trending subject in recent therapy approaches despite its described toxicity. In this work, we have investigated the use of arsenic trioxide in a murine model of chemically induced inflammatory bowel disease "colitis." Male mice were randomly separated into four different groups. Controls received vehicle, arsenic group had a daily injection of As2O3 (2.5 mg/kg, i.p.) for 2 days. Colitis was induced through intra-rectal instillation of 4% (v/v) solution of acetic acid in the second day. The treatment group (As2O3 + acetic acid) received the same treatment as the two previous groups. Twenty-four hours after colitis challenge, animals were sacrificed and organs (colons, livers, and kidneys) were taken for analysis. Disease-related macroscopic and microscopic symptoms, as well as histologic observations, showed a high index in the colitis group, which was greatly reduced by the As2O3 pretreatment. Similarly, colon length was reduced during colon inflammation, which was prevented in the presence of As2O3. Inflammatory cells and oxidative stress markers significantly increased during inflammation accompanied by a considerable reduction of antioxidants. As2O3 treatment managed to reverse these observations to normal levels. Mitochondrial implication was observed through mPTP opening phenomena and semi-quantitative cell death estimation. Low-dose As2O3 use as a mean of preventing the acute phase of colitis can be seen as an interesting approach which counts as a great addition to IBD available treatments.
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Affiliation(s)
- Hichem Moulahoum
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria. .,Faculty of Science, Biochemistry Department, Ege University, Bornova, 35100, İzmir, Turkey.
| | - Belkacem Mohamed Amine Boumaza
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Meriem Ferrat
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Abdelkader Bounaama
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Bahia Djerdjouri
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
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38
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Gu J, Liu J, Huang T, Zhang W, Jia B, Mu N, Zhang K, Hao Q, Li W, Liu W, Zhang W, Zhang Y, Xue X, Zhang C, Li M. The protective and anti-inflammatory effects of a modified glucagon-like peptide-2 dimer in inflammatory bowel disease. Biochem Pharmacol 2018; 155:425-433. [PMID: 30040929 DOI: 10.1016/j.bcp.2018.07.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/20/2018] [Indexed: 12/26/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent, and remitting inflammatory disease resulting from immune dysregulation in the gut. As a clinically frequent disease, it can affect individuals throughout their lives, with multiple complications. Glucagon-like peptide 2 (GLP-2) is a potent epithelium-specific intestinal growth factor. However, native GLP-2 has a relatively short half-life in human circulation because of extensive renal clearance and rapid degradation by the proteolytic enzyme dipeptidyl peptidase-IV (DPP-IV). Previously, We prepared a recombinant GLP-2 variant (GLP-2②), which has increased half-life and activity as compared to the [Gly2]GLP-2 monomer. The aim of the present study was to investigate the protective potential of GLP-2② in IBD models. LPS-induced in vitro model and dextran sulfate sodium (DSS)-induced in vivo model were used to study the anti-inflammatory and therapeutic effect of GLP-2②. We found that treated with GLP-2② showed a significantly reduction in the secretion of inflammatory cytokines. Furthermore, GLP-2② alleviated symptoms of DSS-induced colitis. GLP-2② treated mice displayed an increase in body weight, lower colitis scores, and fewer mucosal damage compared with GLP-2 treated mice. MPO activities, protein expression of NLRP3 and COX2 in the colon tissues were significantly reduced in GLP-2② groups. Importantly, the ameliorative effect of GLP-2② was related to anti-apoptosis effect in colon tissues. These findings demonstrated that GLP-2② may offer a superior therapeutic benefit over [Gly2]GLP-2 monomer for treatment of IBD.
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Affiliation(s)
- Jintao Gu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Jun Liu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Tonglie Huang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Bo Jia
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Nan Mu
- Department of Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Wei Liu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Xiaochang Xue
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
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Nakanishi Y, Sato T, Takahashi K, Ohteki T. IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo. Mucosal Immunol 2018; 11:871-880. [PMID: 29364866 DOI: 10.1038/mi.2017.104] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 10/23/2017] [Indexed: 02/04/2023]
Abstract
Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C+ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ-signal transducer and activator of transcription 1 (IFN-γ-Stat1) pathway was required for generating colitogenic macrophages, given that Stat1-/- mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.
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Affiliation(s)
- Y Nakanishi
- Department of Biodefense Research, Tokyo Medical and Dental University, Tokyo, Japan.,IBD project, Laboratory for Integrated Research Projects on Intractable Diseases, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - T Sato
- Department of Biodefense Research, Tokyo Medical and Dental University, Tokyo, Japan.,Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, Japan
| | - K Takahashi
- College of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - T Ohteki
- Department of Biodefense Research, Tokyo Medical and Dental University, Tokyo, Japan
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40
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Eissa N, Hussein H, Kermarrec L, Ali AY, Marshall A, Metz-Boutigue MH, Hendy GN, Bernstein CN, Ghia JE. Chromogranin-A Regulates Macrophage Function and the Apoptotic Pathway in Murine DSS colitis. J Mol Med (Berl) 2017; 96:183-198. [PMID: 29274006 DOI: 10.1007/s00109-017-1613-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 10/24/2017] [Accepted: 11/22/2017] [Indexed: 12/27/2022]
Abstract
Chromogranin-A (CHGA) is elevated in inflammatory bowel disease (IBD), but little is known about its role in colonic inflammation. IBD is associated with impaired functions of macrophages and increased apoptosis of intestinal epithelial cells. We investigated CHGA expression in human subjects with active ulcerative colitis (UC) and the underlying mechanisms in Chga -/- mice. In UC, CHGA, classically activated macrophage (M1) markers, caspase-3, p53, and its associated genes were increased, while alternatively activated macrophage (M2) markers were decreased without changes in the extrinsic apoptotic pathway. CHGA correlated positively with M1 and the apoptotic pathway and negatively with M2. In the murine dextran sulfate sodium (DSS)-induced colitis, Chga deletion reduced the disease severity and onset, pro-inflammatory mediators, M1, and p53/caspase-3 activation, while it upregulated anti-inflammatory cytokines and M2 markers with no changes in the extrinsic apoptotic markers. Compared to Chga +/+ , M1 and p53/caspase-3 activation in Chga -/- macrophages were decreased in vitro, while M2 markers were increased. CHGA plays a critical role during colitis through the modulation of macrophage functions via the caspase-3/p53 pathway. Strategies targeting CHGA to regulate macrophage activation and apoptosis might be developed to treat UC patients. KEY MESSAGES • Chromogranin-A (CHGA) is pro-hormone and is secreted in the gut. CHGA is elevated in colitis and is associated with the disease severity. The lack of GHGA has beneficial immunomodulatory properties during the development of intestinal inflammation. The lack of CHGA regulates the plasticity of macrophages and p53/caspase activation in colitis. Functional analysis of CHGA may lead to a novel therapy for IBD.
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Affiliation(s)
- Nour Eissa
- Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada
- Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Hayam Hussein
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, OH, USA
| | - Laëtitia Kermarrec
- Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada
| | - Ahmed Y Ali
- Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada
- Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada
| | - Aaron Marshall
- Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada
- Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada
| | - Marie-Helene Metz-Boutigue
- Inserm UMR112, Biomatériaux et ingéniérie tissulaire, Institut Leriche 2éme étage, Hôpital Civil, Porte de l'Hôpital, BP 426, 67091, Strasbourg, France
| | - Geoffrey N Hendy
- Metabolic Disorders and Complications, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University, Montreal, QC, Canada
| | - Charles N Bernstein
- Internal Medicine Section of Gastroenterology, University of Manitoba, Winnipeg, MB, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Jean-Eric Ghia
- Immunology Department, College of Medicine, University of Manitoba, 431 Apotex Centre, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada.
- Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.
- Internal Medicine Section of Gastroenterology, University of Manitoba, Winnipeg, MB, Canada.
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada.
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JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation. Stem Cell Reports 2017; 10:17-26. [PMID: 29276155 PMCID: PMC5768934 DOI: 10.1016/j.stemcr.2017.11.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 11/16/2017] [Accepted: 11/17/2017] [Indexed: 01/26/2023] Open
Abstract
The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.
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MiR-3202 protects smokers from chronic obstructive pulmonary disease through inhibiting FAIM2: An in vivo and in vitro study. Exp Cell Res 2017; 362:370-377. [PMID: 29208459 DOI: 10.1016/j.yexcr.2017.11.038] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/27/2017] [Accepted: 11/29/2017] [Indexed: 12/14/2022]
Abstract
Previous study found the variable miR-3202 as a potential biomarker in smoker with or without chronic obstructive pulmonary disease (COPD). This study aims to identify the molecular involvement of miR-3202 in the pathophysiology of COPD. Level of miR-3202 in blood sample of non-smoker non-COPD(C), smoker without COPD(S), smoker with stable COPD(S-COPD) and smoker with acute exacerbation COPD(AE-COPD) was observed by quantitative real-time PCR. By bioinformatics prediction, Fas apoptotic inhibitory molecule 2 (FAIM2) was identified as a potential target of miR-3202. In vitro, human bronchial epithelial (HBE) cells and cigarette smoke extract (CSE) stimulated T lymphocytes were co-cultured. Cell proliferation and apoptosis of HBE cells were determinated. In vivo, rats were exposed in cigarette smoke for 30 days and expression of miR-3202 and FAIM2 in bronchia were detected. Results showed that The miR-3202 was down-regulated in S, S-COPD and AE-COPD group when compared with C group. Decreased level of miR-3202 was also observed in CSE treated T lymphocyte. Additionally, CSE stimulation increased INF-γ and TNF-α levels and FAIM2 expression whereas inhibited Fas and FasL expressions in T lymphocytes. However, these effects were significantly suppressed by miR-3202 overexpression and enhanced by miR-3202 inhibitor. Likely to exogenous miR-3202, FAIM2 knockdown significantly inhibited HBE cells apoptosis, as well as inhibited INF-γ and TNF-α levels. In COPD rats model, miR-3202 was reduced while FAIM2 was up-regulated accordingly. Here, results suggest that high level miR-3202 in T lymphocytes may protect epithelial cells through targeting FAIM2. MiR-3202 might be used as a notable biomarker of COPD.
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43
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Huang L, Hou Q, Ye L, Yang Q, Yu Q. Crosstalk between H9N2 avian influenza virus and crypt-derived intestinal organoids. Vet Res 2017; 48:71. [PMID: 29096712 PMCID: PMC5667514 DOI: 10.1186/s13567-017-0478-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 10/02/2017] [Indexed: 12/30/2022] Open
Abstract
The spread of Avian influenza virus via animal feces makes the virus difficult to prevent, which causes great threat to human health. Therefore, it is imperative to understand the survival and invasion mechanism of H9N2 virus in the intestinal mucosa. In this study, we used mouse threedimensional intestinal organoids that contained intestinal crypts and villi differentiated from intestinal stem cells to explore interactions between H9N2 avian influenza virus and the intestinal mucosa. The HA, NA, NP and PB1 genes of H9N2 viruses could be detected in intestinal organoids at 1 h, and reached peak levels at 48 h post-infection. Moreover, the HA and NP proteins of H9N2 virus could also be detected in organoids via immunofluorescence. Virus invasion caused damage to intestinal organoids with reduced mRNA transcript expression of Wnt3, Dll1 and Dll4. The abnormal growth of intestinal organoids may be attributed to the loss of Paneth cells, as indicated by the low mRNA transcript levels of lyz1 and defcr1. This present study demonstrates that H9N2 virus could invade intestinal organoids and then cause damage, as well as affect intestinal stem cell proliferation and differentiation, promoting the loss of Paneth cells.
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Affiliation(s)
- Lulu Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, Jiangsu, China
| | - Qihang Hou
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, Jiangsu, China
| | - Lulu Ye
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, Jiangsu, China
| | - Qian Yang
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, Jiangsu, China
| | - Qinghua Yu
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, Jiangsu, China.
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Besson JCF, de Carvalho Picoli C, Matioli G, Natali MRM. Methyl jasmonate: a phytohormone with potential for the treatment of inflammatory bowel diseases. ACTA ACUST UNITED AC 2017; 70:178-190. [PMID: 29072315 DOI: 10.1111/jphp.12839] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 09/21/2017] [Indexed: 12/30/2022]
Abstract
OBJECTIVES The phytohormone methyl jasmonate (MeJA) has been identified as a vital cell regulator in plants. This substance is analogous to eicosanoids and similar to that of anti-inflammatory prostaglandins. In animals and in animal cells, it displayed an efficient neuroprotective, anti-inflammatory and antioxidant action; while in tumoral strains, it demonstrates a potentially highly attractive mechanism of apoptosis induction through various cellular and molecular mechanisms. The aim of the present review was to explore two new hypotheses that explain the action of MeJA, a lipid phytohormone and its potentially anti-apoptotic mechanism for use as a therapeutic target for future treatment of Inflammatory bowel diseases (IBDs). KEY FINDINGS Methyl jasmonate is a new candidate for the treatment of IBDs, modulating the expression of the major classes of caspase-type protease families that selectively act on the extrinsic and intrinsic pathways of the apoptotic process. Its action is based on the reduction of the expression in tumour necrosis factor tissue levels and the modulating action of reactive oxygen species production, acting only on the destruction of cells that express the diseased phenotype, and preserving cells that are not transformed. CONCLUSIONS Methyl jasmonate may represent an alternative for the transduction processes of important signals in the cellular renewal of the intestinal mucosa.
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Affiliation(s)
| | | | - Graciette Matioli
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, Brazil
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45
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Bradford EM, Ryu SH, Singh AP, Lee G, Goretsky T, Sinh P, Williams DB, Cloud AL, Gounaris E, Patel V, Lamping OF, Lynch EB, Moyer MP, De Plaen IG, Shealy DJ, Yang GY, Barrett TA. Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease. THE JOURNAL OF IMMUNOLOGY 2017; 199:1886-1897. [PMID: 28747340 DOI: 10.4049/jimmunol.1601066] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 06/27/2017] [Indexed: 12/28/2022]
Abstract
TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient (Tnf-/-) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→Tnfr1/2-/- BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.
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Affiliation(s)
- Emily M Bradford
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.,Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | - Stacy H Ryu
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.,Driskill Graduate Program in Life Sciences, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Ajay Pal Singh
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Goo Lee
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Tatiana Goretsky
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.,Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | - Preetika Sinh
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - David B Williams
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Amber L Cloud
- Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | - Elias Gounaris
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Vihang Patel
- Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | - Olivia F Lamping
- Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | - Evan B Lynch
- Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
| | | | - Isabelle G De Plaen
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | | | - Guang-Yu Yang
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Terrence A Barrett
- Department of Internal Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; .,Division of Gastroenterology, University of Kentucky, Lexington, KY 40536
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Aseer KR, Silvester AJ, Kumar A, Choi MS, Yun JW. SPARC paucity alleviates superoxide-mediated oxidative stress, apoptosis, and autophagy in diabetogenic hepatocytes. Free Radic Biol Med 2017; 108:874-895. [PMID: 28499910 DOI: 10.1016/j.freeradbiomed.2017.05.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 05/05/2017] [Accepted: 05/08/2017] [Indexed: 12/14/2022]
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is known to play a previously unappreciated role in diabetes, but its precise mechanism in liver/hepatocyte pathology remains unknown. Inhibition of SPARC is critical in resolving candidate pathogenic events such as production of reactive oxygen species (ROS), which are broadly considered for their roles in diabetes, and is capable of protecting functional hepatocytes. Here, we provide in vitro and in vivo evidence demonstrating pathological correlations between SPARC and streptozotocin (STZ)-induced diabetic rat livers as well as cultured hepatocytes induced by diabetogenic stimuli. Under these conditions, transient SPARC silencing was carried out to investigate the role of SPARC in the pathogenesis of pro-diabetic hepatocyte damage and dysfunction. The constitutive expression of SPARC in hepatocytes was up-regulated under a diabetic environment. In addition, Nox4-dependent superoxide generation contributed to increased expression of SPARC, and this was inhibited by tiron and pharmacological or genetic inactivation of Nox4-containing NADPH oxidase. Remarkably, SPARC deficiency inhibited diabetic stimuli-induced elevation of superoxide production and resolved salient features of hepatocyte damage such as impaired cytoprotection, inflammation, apoptosis, and autophagy. At the same time, links between SPARC, integrin-β1, Nox4-derived superoxide, and JNK signaling provide a basis for these phenotypes. Taken together with the observations that SPARC deficiency had protective effects on hepatocytes via a favorable inhibition profile, functional knowledge of SPARC may offer a unique therapeutic approach to preserve hepatocellular fate decisions in diabetes.
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Affiliation(s)
- Kanikkai Raja Aseer
- Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk 712-714, Republic of Korea
| | | | - Anuj Kumar
- Bioinformatics and Documentation Laboratory, Uttarakhand Council for Biotechnology, Dehradun 248007, India
| | - Myung-Sook Choi
- Department of Food Science and Nutrition & Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Jong Won Yun
- Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk 712-714, Republic of Korea.
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47
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Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia. Br J Cancer 2017; 117:136-143. [PMID: 28524162 PMCID: PMC5520210 DOI: 10.1038/bjc.2017.148] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma. METHODS Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma. RESULTS Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects. CONCLUSIONS Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.
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Lim KJ, Lee SJ, Kim S, Lee SY, Lee MS, Park YA, Choi EJ, Lee EB, Jun HK, Cho JM, Lee S, Kwon KS, Lim BP, Jeon MS, Shin EC, Choi YS, Fudim E, Picard O, Yavzori M, Ben-Horin S, Chang SJ. Comparable Immune Function Inhibition by the Infliximab Biosimilar CT-P13: Implications for Treatment of Inflammatory Bowel Disease. J Crohns Colitis 2017; 11:593-602. [PMID: 28453766 DOI: 10.1093/ecco-jcc/jjw183] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS CT-P13 is the first biosimilar monoclonal antibody to infliximab, and was recently approved in the European Union, Japan, Korea, and USA for all six indications of infliximab. However, studies directly assessing the biologic activity of CT-P13 versus inflximab in the context of inflammatory bowel disease [IBD] are still scanty. In the present study, we aimed to compare the biological activities of CT-P13 and infliximab with specific focus on intestinal cells so as to gain insight into the potential biosimilarity of these two agents for treatment of IBD. METHODS CT-P13 and infliximab were investigated and compared by in vitro experiments for their neutralisation ability of soluble tumour necrosis factor alpha [sTNFα] and membrane-bound tumour necrosis factor alpha [mTNFα], suppression of cytokine release by reverse signalling, induction of regulatory macrophages and wound healing, and antibody-dependent cell cytotoxicity [ADCC]. RESULTS CT-P13 showed similar biological activities to infliximab as gauged by neutralisation of soluble TNFα, as well as blockade of apoptosis and suppression of pro-inflammatory cytokines in intestinal Caco-2 cells. Infliximab and CT-P13 equally induced apoptosis and outside-to-inside signals through transmembrane TNFα [tmTNFα]. Moreover, regulatory macrophage induction and ensuing wound healing were similarly exerted by CT-P13 and infliximab. However, neither CT-P13 nor infliximab exerted any significant ADCC of ex vivo-stimulated peripheral blood monocytes or lamina propria mononuclear cells from IBD patients. CONCLUSIONS These findings indicate that CT-P13 and infliximab exert highly similar biological activities in intestinal cells, and further support a mechanistic comparability of these two drugs in the treatment of IBD.
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Affiliation(s)
- Ki Jung Lim
- R&D Division, Celltrion Inc., Incheon, Korea
| | - So Jung Lee
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | - Su Yeon Lee
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | - Yoon A Park
- R&D Division, Celltrion Inc., Incheon, Korea
| | | | | | | | | | | | | | | | - Myung-Shin Jeon
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon, Korea
| | - Eui Cheol Shin
- Laboratory of Immunology and Infectious Disease, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Yong Sung Choi
- Department of Gastroenterology, Daehang Hospital, Seoul, Korea
| | - Ella Fudim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Orit Picard
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Miri Yavzori
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
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49
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Lamb CA, Mansfield JC, Tew GW, Gibbons D, Long AK, Irving P, Diehl L, Eastham-Anderson J, Price MB, O'Boyle G, Jones DEJ, O'Byrne S, Hayday A, Keir ME, Egen JG, Kirby JA. αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. J Crohns Colitis 2017; 11:610-620. [PMID: 28453768 PMCID: PMC5815571 DOI: 10.1093/ecco-jcc/jjw189] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 09/28/2016] [Accepted: 10/19/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions. METHODS αEβ7+ and αEβ7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. RESULTS CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7- T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7- lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. CONCLUSION αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology.
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Affiliation(s)
- Christopher A Lamb
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
| | - John C Mansfield
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
| | - Gaik W Tew
- Research & Early Development, Genentech, South San Francisco, CA 94080, USA
| | - Deena Gibbons
- Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK
- London Research Institute, Cancer Research UK, London WC2, UK
| | - Anna K Long
- Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
| | - Peter Irving
- Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK
- Department of Gastroenterology, Guys and St Thomas' NHS Foundation Trust, London SE1 7EH, UK
| | - Lauri Diehl
- Research & Early Development, Genentech, South San Francisco, CA 94080, USA
| | | | - Maria B Price
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
| | - Graeme O'Boyle
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - David E J Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Sharon O'Byrne
- Research & Early Development, Genentech, South San Francisco, CA 94080, USA
| | - Adrian Hayday
- Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK
- London Research Institute, Cancer Research UK, London WC2, UK
| | - Mary E Keir
- Research & Early Development, Genentech, South San Francisco, CA 94080, USA
| | - Jackson G Egen
- Research & Early Development, Genentech, South San Francisco, CA 94080, USA
| | - John A Kirby
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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50
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Rychlik A, Gonkowski S, Nowicki M, Calka J. Inflammatory bowel disease affects density of nitrergic nerve fibers in the mucosal layer of the canine gastrointestinal tract. CANADIAN JOURNAL OF VETERINARY RESEARCH = REVUE CANADIENNE DE RECHERCHE VETERINAIRE 2017; 81:129-136. [PMID: 28408781 PMCID: PMC5370539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 10/18/2016] [Indexed: 06/07/2023]
Abstract
The objective of this study was to determine the effect of inflammatory bowel disease (IBD) on the density of nitrergic nerve fibers in the mucosal layer of different sections of the gastrointestinal tract of dogs. Twenty-eight German shepherd hybrid dogs of both sexes, weighing from 15 to 25 kg and aged 6 to 10 y, were studied. The dogs were divided into 4 groups with 7 animals in each group: healthy animals, as well as dogs suffering from mild, moderate, and severe IBD. Immunoreactivity to neuronal isoform of nitric oxide synthase, which is a marker of nitrergic neurons, in samples of the mucosal layer in the duodenum, jejunum, and descending colon was studied using the single immunofluorescence method and the number of nerve fibers was evaluated in each observation field. The obtained results showed that IBD causes an increase in the number of nitrergic nerve fibers in all intestinal segments studied and these changes are directly proportional to the intensity of the disease process. These observations may be useful in diagnostic evaluation of the stage of canine inflammatory bowel disease in veterinary practice. The pathological mechanisms of these observed changes and the specific reasons for them are still not completely explained, however, and further study is required.
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Affiliation(s)
- Andrzej Rychlik
- Address all correspondence to Prof. Andrzej Rychlik; telephone: +48 895233746; fax: +48 895233744; e-mail:
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