esculetin and Colitis

Aesculetin (6,7-dihydroxy-2H-1-benzopyran-2-one) has been reported to exhibit potent anti-inflammatory property both in vitro and in vivo.. In this study, we evaluated the anti-inflammatory effect and investigated underlying molecular mechanisms of aesculetin in LPS-induced RAW264.7 macrophages and DSS-induced colitis.. In this study, the production of NO, TNF-α, and IL-6 were measured to identify the aesculetin with potent anti-inflammatory effect. Then, the underlying anti-inflammatory mechanisms were explored by western blotting in LPS-induced cells. Next, we verify the anti-inflammatory potential of aesculetin in DSS-induced colitis in vivo. The clinical symptoms of colitis, including weight loss, DAI, colon length and MPO activity, and the secretion of TNF-α and IL-6 were evaluated. Finally, Western blot analysis was applied to further investigate underlying mechanism in DSS-induced colitis model.. Our studies showed that aesculetin exhibited anti-inflammatory potential by inhibiting NO, TNF-α, and IL-6 production and reducing iNOS and NLRP3 expression in LPS-induced RAW264.7 cells. Mechanically, we found that aesculetin significantly inhibited LPS-induced activation of NF-κB and MAPKs signaling pathways. In DSS-induced mouse model, the colitis-related symptoms were relieved by treatment with aesculetin. Besides, aesculetin also inhibited the secretion of TNF-α and IL-6, and the activation of NF-κB and MAPKs signaling pathways in DSS-induced colitis.. The anti-inflammatory effect of aesculetin was connected with its inhibition on the activation of NF-κB and MAPKs signaling pathways both in vitro and in vivo. Therefore, aesculetin was expected to be developed as an anti-inflammatory drug.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Dextran Sulfate; Interleukin-6; Lipopolysaccharides; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Tumor Necrosis Factor-alpha; Umbelliferones

We investigated a potential molecular target for anti-colitic effects of esculetin, 6,7-dihydroxycoumarin. Esculetin administered rectally effectively ameliorated TNBS-induced rat colitis and attenuated the expression of pro-inflammatory mediators in the inflamed colon. In human colon carcinoma HCT116 cells, esculetin induced hypoxia-inducible factor-1α (HIF-1α), leading to secretion of vascular endothelial growth factor, a HIF-1 target gene product involved in ulcer healing of the gastrointestinal mucosa. Esculetin directly inhibited HIF prolyl hydroxylase-2 (HPH-2), an enzyme playing a major role in negatively regulating HIF-1α protein stability. Esculetin inhibition of HPH and consequent induction of HIF-1α were attenuated by escalating dose of either ascorbate or 2-ketoglutarate, the required factors of the enzyme. Structurally, the catechol moiety in esculetin was required for HPH inhibition. Collectively, HPH may be a molecular target for esculetin-mediated anti-colitic effects and the catechol moiety in esculetin is the pharmacophore for HPH inhibition.

Topics: Animals; Colitis; Disease Models, Animal; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Rats; Rats, Sprague-Dawley; Umbelliferones; Vascular Endothelial Growth Factor A

Coumarins comprise a broad class of phenolic compounds that influences the formation and scavenging of reactive oxygen species and the processes involving free radical-mediated injury. In light of the antioxidant and anti-inflammatory properties of esculetin and 4-methylesculetin, the aim of this study was to investigate the effects of these compounds in an experimental model of rat colitis induced by trinitrobenzenesulphonic acid (TNBS). For this purpose, macroscopic (diarrhoea, extension of lesion, colonic weight/length ratio and damage score) and biochemical parameters (myeloperoxidase, alkaline phosphatase and glutathione) were evaluated. Our results reveal that these compounds, particularly 4-methylesculetin, may be effective for the treatment of intestinal inflammatory bowel disease. In the acute colitis model, esculetin promoted a reduction in the extension of the lesion accompanied by a reduction in the incidence of diarrhoea and restoration of the glutathione content. Similar effects were produced by the administration of 4-methylesculetin, which also inhibited the myeloperoxidase and alkaline phosphatase activities in the acute intestinal inflammatory process and in the model of colitis relapse. The effect of the esculetin and 4-methylesculetin on the inflammatory process may be related to their antioxidant and anti-inflammatory properties, as observed in this study. The evidence for better effects of 4-methylesculetin in comparison to those demonstrated by esculetin in both experimental settings could be attributed to the presence of the methyl group at C-4 of 4-methylesculetin.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Colitis; Disease Models, Animal; Glutathione; Male; Peroxidase; Rats; Rats, Wistar; Scopoletin; Structure-Activity Relationship; Sulfasalazine; Trinitrobenzenesulfonic Acid; Umbelliferones