Effect of chemical modulation of toll-like receptor 4 in an animal model of ulcerative colitis

Facchini, Fabio A.; Fusco, Davide Di; Barresi, Simona; Luraghi, Andrea; Minotti, Alberto; Granucci, Francesca; Monteleone, Giovanni; Peri, Francesco; Monteleone, Ivan

doi:10.1007/s00228-019-02799-7

Cited by 14 publications

(11 citation statements)

References 47 publications

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“…However, after FPH treatment, the goblet cells in the intestinal mucosa were restored and the columnar cells were arranged regularly, showing that the intestinal permeability and inflammation were ameliorated. The TLR4/MyD88/NF- κ B signaling pathway plays a critical role in the development of UC [ 25 ]. In this study, Western blot and IHC assays were used to evaluate the effect of FPH on the TLR4/MyD88/NF- κ B signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis‐Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity

Dai

Zhan

Peng

et al. 2021

Oxidative Medicine and Cellular Longevity

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Inflammatory bowel disease (IBD), a global disease threatening human health, is commonly accompanied by secondary liver damage (SLD) mediated by the gut-liver axis. Oxidative stress acts a critical role in the onset of IBD, during which excessive oxidation would destroy the tight junctions between intestinal cells, promote proinflammatory factors to penetrate, and thereby damage the intestinal mucosa. Ficus pandurata Hance (FPH) is widely used for daily health care in South China. Our previous study showed that FPH protected acute liver damage induced by alcohol. However, there is no study reporting FPH treating ulcerative colitis (UC). This study is designed to investigate whether FPH could inhibit UC and reveal its potential mechanism. The results showed that FPH significantly alleviated the UC disease symptoms including the body weight loss, disease activity index (DAI), stool consistency changing, rectal bleeding, and colon length loss of UC mice induced by dextran sulfate sodium (DSS) and reversed the influences of DSS on myeloperoxidase (MPO) and diamine oxidase activity (DAO). FPH suppressed UC via inhibiting the TLR4/MyD88/NF-κB pathway and strengthened the gut barrier of mice via increasing the expressions of ZO-1 and occludin and enhancing the colonic antioxidative stress property by increasing the levels of T-SOD and GSH-Px and the expressions of NRF2, HO-1, and NQO1 and reducing MDA level and Keap1, p22-phox, and NOX2 expressions. Furthermore, FPH significantly inhibited SLD related to colitis by reducing the abnormal levels of the liver index, ALT, AST, and cytokines including TNFα, LPS, LBP, sCD14, and IL-18 in the livers, as well as decreasing the protein expressions of NLRP3, TNFα, LBP, CD14, TLR4, MyD88, NF-κB, and p-NF-κB, suggesting that FPH alleviated UC-related SLD via suppressing inflammation mediated by inhibiting the TLR4/MyD88/NF-κB pathway. Our study firstly investigates the anticolitis pharmacological efficacy of FPH, suggesting that it can be enlarged to treat colitis and colitis-associated liver diseases in humans.

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Section: Resultsmentioning

confidence: 99%

Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis‐Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity

Dai

Zhan

Peng

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…16 Very recently, we reported the anti-inflammatory role of FP7 in inflammatory bowel disease (IBD). 25 FP7 strongly reduced LPS-driven release of pro-inflammatory proteins in PBMCs isolated from IBD patients and lamina propria mononuclear cells isolated by biopsy of patients with Crohn’s disease and ulcerative colitis. Additionally, FP7 attenuated colonic inflammation in a mouse model of ulcerative colitis.…”

Section: Discussionmentioning

confidence: 94%

“…13 In this respect, we have already demonstrated the ability of FP7 to prevent LPS-driven TLR4 and CD14 internalisation, suggesting that FP7 can interact with both TLR4/MD-2 and CD14 and prevent activation of MyD88 and TRIF-dependent signalling in PBMC. 25 Furthermore, the small differences in the potential of these small molecules to affect MyD88-dependent and MyD88-independent TLR4 signalling (administered 30 min after LPS) might be affected by internalisation of TLR4 in the cell cytoplasm. In this respect, it has been demonstrated that Rab10 is required for trafficking of TLR4 between the membrane and the Golgi apparatus, and TICAM-1/TICAM-2/TLR4 are essential for endosome localisation of TLR4-mediated IFN signalling.…”

Section: Discussionmentioning

confidence: 99%

Synthetic glycolipid-based TLR4 antagonists negatively regulate TRIF-dependent TLR4 signalling in human macrophages

et al. 2021

Self Cite

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TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.

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“…decreased expression of the pro-inflammatory enzymes: IL-1β, COX-2 and iNOS expression levels, p<0.05 vs control, p<0.05 vs stress only group. Hua et al [89] Cerebral ischemia In vivo: C57Bl/6 mice induced with focal cerebral ischemia/reperfusion Facchini et al [92] Inflammatory bowel disease In vitro: Peripheral blood mononuclear cells and lamina propria mononuclear cells collected from patients with IBD In vivo: BALB/c mice with DSS administered in their water.…”

Section: Tak-242 (Resatorvid)mentioning

confidence: 99%

Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation

Tam

Coller

Hughes

et al. 2021

Indian J Gastroenterol

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Gastrointestinal inflammation is a hallmark of highly prevalent disorders, including cancer treatment-induced mucositis and ulcerative colitis. These disorders cause debilitating symptoms, have a significant impact on quality of life, and are poorly managed. The activation of toll-like receptor 4 (TLR4) has been proposed to have a major influence on the inflammatory signalling pathways of the intestinal tract. Inhibition of TLR4 has been postulated as an effective way to treat intestinal inflammation. However, there are a limited number of studies looking into the potential of TLR4 antagonism as a therapeutic approach for intestinal inflammation. This review surveyed available literature and reported on the in vitro, ex vivo and in vivo effects of TLR4 antagonism on different models of intestinal inflammation. Of the studies reviewed, evidence suggests that there is indeed potential for TLR4 antagonists to treat inflammation, although only a limited number of studies have investigated treating intestinal inflammation with TLR4 antagonists directly. These results warrant further research into the effect of TLR4 antagonists in the intestinal tract.

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Effect of chemical modulation of toll-like receptor 4 in an animal model of ulcerative colitis

Cited by 14 publications

References 47 publications

Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis‐Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity

Ficus pandurata Hance Inhibits Ulcerative Colitis and Colitis‐Associated Secondary Liver Damage of Mice by Enhancing Antioxidation Activity

Synthetic glycolipid-based TLR4 antagonists negatively regulate TRIF-dependent TLR4 signalling in human macrophages

Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation

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