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klf, cells, expression, intestinal, epithelial, caco, fig, mice, pubmed, colitis, article, barrier, protein, ibd, mrna, cell, google, scholar, dss, treatment, shklfadv, levels, gse, cas, apoptosis, alkbh, data, colon, mettl, tnfαifnγ, modification, disease, staining, apto, tnbs, inflammatory, mesalazine, knockdown, overexpression, ythdf, ecadherin, tissues, central, function, patients, wang, analysis, occludin, healthy, proteins,

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$$ \begin{gathered} {\text{treatment}} nf-kappab-mediated antiapoptotic pathway $$ \begin{gathered} {\text{ tnf-α/ifn-γ mixture compared tnf-α/ifn-γ mixtures tnf-α/ifn-γ mixture apgl3-basic-luciferase reporter vectors 100 ng/ml tnf-α/ifn-γ pgl3-basic-luciferase reporter vector banf1-nf-kappab pathway {\delta ct tnf-α/ifn-γ stimulation pg-mnase enzyme mixture nf-κb pathway [51] tnf-α/ifn-γ {\text{group}} apical junction complex article download pdf dual-luciferase reporter assays cell-magnetic bead complex cell-magnetic bead compound trans-epithelium electrical resistance mis-localised cytoplasmic protein utilizing spike dna cell-magnetic bead combination enzyme‑linked immunosorbent assays 5ʹ-tagagggtcaccgcgtctat-3ʹ reverse 5ʹ-cctgctggatggcaactaa-3ʹ reverse 5ʹ-tgtttagcaaagccgtca-3ʹ reverse 5ʹ- ctggggtgatgatgtctccag-3ʹ reverse reducing tnf-induced apoptosis inflammatory bowel disease ct values 2−△△ct values dextran sulfate sodium intestinal epithelial-specific knockdown pgl3-e-cadherin vectors shklf4-adv significantly increased normal rabbit igg merip-pcr assay showed stem cell induction dss-induced colitis model tnbs-induced acute colitis fluorescein isothiocyanate-dextran scrna-seq dataset gse164985 future qrt‒pcr tests spike dna inflammatory bowel diseases intestinal epithelial barrier merip-pcr analysis revealed

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         headline:Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel disease
         description:Krüppel-like factor 4 (KLF4), a transcription factor, is involved in various biological processes. However, the role of KLF4 in regulating the intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) and its mechanism have not been extensively studied. KLF4 expression in IBD patients and colitis mice was analyzed using Gene Expression Omnibus(GEO) database, immunohistochemistry (IHC) and Western blot. The roles of KLF4 in IEB and colitis symptoms were verified in dextran sulfate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model mice using an adenovirus carrying KLF4 shRNA (shKLF4-Adv). Furthermore, the influence of KLF4 on trans-epithelium electrical resistance (TEER), paracellular permeability, apical junction complex (AJC) protein expression and apoptosis was assessed in vitro and in vivo. MeRIP and RIP assays were used to verify the effects of m6A modification on KLF4 expression. KLF4 expression was significantly decreased in IBD patients and was negatively associated with inflammatory features. KLF4 deletion aggravated colitis symptoms and IEB injuries by reducing AJC protein expression and increasing apoptosis in mice with colitis. Furthermore, KLF4 transcriptionally regulated the expression of AJC proteins and inhibited apoptosis by reducing cellular ROS levels and proinflammatory cytokine expression. Moreover, we observed that METTL3/ALKBH5/YTHDF2-mediated m6A modification led to a decrease in KLF4 expression in Caco-2 cells. In addition, APTO-253, an inducer of KLF4, exhibited a synergistic effect with mesalazine on IEB function. Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD.
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            KLF4
            Intestinal epithelial barrier
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            Biomedicine
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      headline:Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel disease
      description:Krüppel-like factor 4 (KLF4), a transcription factor, is involved in various biological processes. However, the role of KLF4 in regulating the intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) and its mechanism have not been extensively studied. KLF4 expression in IBD patients and colitis mice was analyzed using Gene Expression Omnibus(GEO) database, immunohistochemistry (IHC) and Western blot. The roles of KLF4 in IEB and colitis symptoms were verified in dextran sulfate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model mice using an adenovirus carrying KLF4 shRNA (shKLF4-Adv). Furthermore, the influence of KLF4 on trans-epithelium electrical resistance (TEER), paracellular permeability, apical junction complex (AJC) protein expression and apoptosis was assessed in vitro and in vivo. MeRIP and RIP assays were used to verify the effects of m6A modification on KLF4 expression. KLF4 expression was significantly decreased in IBD patients and was negatively associated with inflammatory features. KLF4 deletion aggravated colitis symptoms and IEB injuries by reducing AJC protein expression and increasing apoptosis in mice with colitis. Furthermore, KLF4 transcriptionally regulated the expression of AJC proteins and inhibited apoptosis by reducing cellular ROS levels and proinflammatory cytokine expression. Moreover, we observed that METTL3/ALKBH5/YTHDF2-mediated m6A modification led to a decrease in KLF4 expression in Caco-2 cells. In addition, APTO-253, an inducer of KLF4, exhibited a synergistic effect with mesalazine on IEB function. Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD.
      datePublished:2024-11-29T00:00:00Z
      dateModified:2024-11-29T00:00:00Z
      pageStart:1
      pageEnd:23
      license:http://creativecommons.org/licenses/by-nc-nd/4.0/
      sameAs:https://doi.org/10.1007/s00018-024-05514-7
      keywords:
         Inflammatory bowel disease
         KLF4
         Intestinal epithelial barrier
         Apical junction complex
         Apoptosis
         m6A Modification
         Cell Biology
         Biomedicine
         general
         Life Sciences
         Biochemistry
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         name:Department of Gastroenterology, The Yancheng School of Clinical Medicine of Nanjing Medical University (Yancheng Third People’s Hospital), Yancheng, China
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         name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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         name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
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         name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
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            name:The First Affiliated Hospital of Soochow University
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               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
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               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
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            address:
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            address:
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            name:The First Affiliated Hospital of Soochow University
            address:
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            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
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      name:Qinhua Xi
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            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Tongguo Shi
      url:http://orcid.org/0000-0002-5382-2775
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The Yancheng School of Clinical Medicine of Nanjing Medical University (Yancheng Third People’s Hospital), Yancheng, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

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