Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation

Khare, Vineeta; Krnjic, Anita; Frick, Adrian; Gmainer, Christina; Asboth, Mario; Jimenez, Kristine; Lang, Michaela; Baumgartner, Maximilian; Evstatiev, Rayko; Gasché, Christoph

doi:10.1038/s41598-019-39401-0

Cited by 53 publications

(60 citation statements)

References 48 publications

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“…Damaged epithelial cells interact with macrophages, which are the first responders to encounter gut microbes. Macrophages secrete pro-inflammatory mediators, such as IL-6 and TNF-α, which delay healing of colon epithelial cells (Khare et al, 2019). Safranal suppressed the production of IL-6 and TNF-α in colon tissue ( Figures 7A, B ).…”

Section: Resultsmentioning

confidence: 99%

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation

et al. 2019

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Introduction: Crocus sativus (saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties.Objective: In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice.Methods: Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. The in vivo anti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis.Results: Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.

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Section: Resultsmentioning

confidence: 99%

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation

et al. 2019

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“…However, our own unpublished data suggest that IBD medication does not affect cytokine production in pregnant IBD patients. 5-ASA and azathioprine are considered of low risk during pregnancy and therefore often used in clinical practice Studies investigating the effect of these treatments on the epithelial barrier function have indicated a positive effect in an intestinal organoids model [47]. Furthermore, 5-ASA was able to inhibit IFN-gamma induced impairment of the epithelial barrier [48].…”

Section: Discussionmentioning

confidence: 99%

A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models

Giessen¹,

Woude²,

Peppelenbosch³

et al. 2019

Cells

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Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. Methods: We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. Results: Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. Conclusion: Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining.

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“…Inflammatory bowel syndrome and IBD cause frequent diarrhea, which reduces the quality of life . The kampo medicine KST has long been used for the treatment of abdominal pain caused by diarrhea.…”

Section: Discussionmentioning

confidence: 99%

“…97) exceeded 160 000 in 2013, and the number of IBD patients is increasing . Corticosteroids, 5‐aminosalicylic acid, immune modulators, such as thiopurine and methotrexate , biological drugs, and anti‐tumor necrosis factor (TNF) antibody are used for the treatment of IBD in both CD and UC patients. We previously reported that Swertia japonica extract and its main compound swertiamarine, and Atractylodes lancea rhizome extract and a volatile component β‐eudesmol stimulated gastric emptying and/or small intestine motility by inhibiting the dopamine D 2 and/or 5‐HT receptor .…”

Section: Introductionmentioning

confidence: 99%

Effects of kampo medicine keishikashakuyakuto on large intestine disease in mice

Kimura

2019

Traditional & Kampo Medicine

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Aim The aim of this study was to examine the effects of keishikashakuyakuto (KST) on large intestine diarrhea and inflammation in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) mouse models. Methods This study examined the effects of KST on diarrhea and inflammatory bowel syndrome using 5‐hydroxytryptamine (5‐HT)‐induced diarrhea and 3% dextran sulfate sodium (DSS)‐treated colitis models. Results Keishikashakuyakuto (200 and/or 500 mg/kg) and ramosetron (5 μg/kg) prolonged the onset‐time of 5‐HT‐induced diarrhea in mice. KST and ramosetron prevented diarrhea and the stool score was decreased 60 min after 5‐HT treatment. The disease activity index in the 3% DSS‐treated mice was lower after oral KST than in mice given 3% DSS only. Furthermore, KST inhibited the decreases in red cells and platelets, and in hemoglobin and hematocrit that were observed in DSS‐treated mice. On colon histology using hematoxylin–eosin and direct fast scarlet staining, KST prevented the mucosa membrane ulceration and eosinophil infiltration of the mucosa membrane caused by DSS treatment. The increase in colonic monocyte chemoattractant protein 1, interleukin‐1β and tumor necrosis factor‐α in DSS‐treated mice was reduced by oral KST. Conclusion Keishikashakuyakuto may be effective for IBS and IBD.

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Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation

Cited by 53 publications

References 48 publications

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation

A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models

Effects of kampo medicine keishikashakuyakuto on large intestine disease in mice

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