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1.
Acta Pharmacol Sin ; 45(7): 1451-1465, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38491161

RÉSUMÉ

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg-1·d-1) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 µM) promoted wound healing and reduced cell apoptosis. NGR1 (100 µM) also increased Lgr5+ cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5+ ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5+ stem cells and intestinal reconstruction, at least partially via activation of the Wnt/ß-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5+ ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/ß-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/ß-Catenin signaling pathway.


Sujet(s)
Colite , Ginsénosides , Muqueuse intestinale , Souris de lignée C57BL , Récepteurs couplés aux protéines G , Voie de signalisation Wnt , Animaux , Ginsénosides/pharmacologie , Ginsénosides/usage thérapeutique , Voie de signalisation Wnt/effets des médicaments et des substances chimiques , Colite/traitement médicamenteux , Colite/induit chimiquement , Colite/métabolisme , Colite/anatomopathologie , Souris , Récepteurs couplés aux protéines G/métabolisme , Muqueuse intestinale/effets des médicaments et des substances chimiques , Muqueuse intestinale/métabolisme , Mâle , Cellules souches/effets des médicaments et des substances chimiques , Cellules souches/métabolisme , Humains
2.
World J Gastroenterol ; 26(30): 4378-4393, 2020 Aug 14.
Article de Anglais | MEDLINE | ID: mdl-32874052

RÉSUMÉ

The rapid development of metagenomics, metabolomics, and metatranscriptomics provides novel insights into the intestinal microbiota factors linked to inflammatory bowel disease (IBD). Multiple microorganisms play a role in intestinal health; these include bacteria, fungi, and viruses that exist in a dynamic balance to maintain mucosal homeostasis. Perturbations in the intestinal microbiota disrupt mucosal homeostasis and are closely related to IBD in humans and colitis in mice. Therefore, preventing or correcting the imbalance of microbiota may serve as a novel prevention or treatment strategy for IBD. We review the most recent evidence for direct or indirect interventions targeting intestinal microbiota for treatment of IBD in order to overcome the current limitations of IBD therapies and shed light on personalized treatment options.


Sujet(s)
Colite , Microbiome gastro-intestinal , Maladies inflammatoires intestinales , Microbiote , Animaux , Maladies inflammatoires intestinales/thérapie , Intestins , Souris
3.
Molecules ; 23(6)2018 Jun 07.
Article de Anglais | MEDLINE | ID: mdl-29880739

RÉSUMÉ

Fargesin is a bioactive lignan from Flos Magnoliae, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly attenuated the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration and myeloperoxidase (MPO) activity, reducing tumor necrosis factor (TNF)-α secretion, and inhibiting nitric oxide (NO) production in colitis mice. The degradation of inhibitory κBα (IκBα), phosphorylation of p65, and mRNA expression of nuclear factor κB (NF-κB) target genes were inhibited by fargesin treatment in the colon of the colitis mice. In vitro, fargesin blocked the nuclear translocation of p-p65, downregulated the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and dose-dependently inhibited the activity of NF-κB-luciferase in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Taken together, for the first time, the current study demonstrated the anti-inflammatory effects of fargesin on chemically induced IBD might be associated with NF-κB signaling suppression. The findings may contribute to the development of therapies for human IBD by using fargesin or its derivatives.


Sujet(s)
Anti-inflammatoires/usage thérapeutique , Benzodioxoles/usage thérapeutique , Maladies inflammatoires intestinales/traitement médicamenteux , Lignanes/usage thérapeutique , Animaux , Anti-inflammatoires/pharmacologie , Benzodioxoles/pharmacologie , Inhibiteurs de la cyclooxygénase 2/pharmacologie , Sulfate dextran/administration et posologie , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Médiateurs de l'inflammation/métabolisme , Maladies inflammatoires intestinales/induit chimiquement , Lignanes/pharmacologie , Luciferases/antagonistes et inhibiteurs , Souris , Facteur de transcription NF-kappa B/génétique , Facteur de transcription NF-kappa B/métabolisme , Monoxyde d'azote/antagonistes et inhibiteurs , Monoxyde d'azote/biosynthèse , Nitric oxide synthase type II/antagonistes et inhibiteurs , Myeloperoxidase/antagonistes et inhibiteurs , Protéolyse , Cellules RAW 264.7 , Facteur de nécrose tumorale alpha/antagonistes et inhibiteurs
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