Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis

Witaicenis, Aline; Seito, Leonardo Noboru; Stasi, Luiz Cláudio Di

doi:10.1016/j.cbi.2010.03.045

Cited by 111 publications

(76 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Various antioxidant flavonoids and coumarin derivatives have been reported as protective products to prevent and treat intestinal inflammatory processes induced by different chemical inductors of experimental colitis (Galvez et al, 2001;Distasi et al, 2004;Luchini et al, 2008;Witaicenis et al, 2010) Codonopsis lanceolata were active compounds in experimental colitis .…”

Section: Discussionmentioning

confidence: 99%

Potential antioxidant and anti-inflammatory effects of Hyphaena thebaica in experimentally induced inflammatory bowel disease

Shalaby¹

2013

Afr. J. Pharm. Pharmacol.

View full text Add to dashboard Cite

Ulcerative colitis and Crohn's disease are chronic recurrent inflammatory bowel disease (IBD) of unknown origin. Oxidative stress is believed to be a key factor in the pathogenesis of the mucosal damage in IBD. The aqueous extract of Hyphaena thebaica fruits showed an antioxidant activity; this is due to the substantial amount of their water-soluble phenolic contents. This study was undertaken to study the effect of H. thebaica in experimentally induced IBD. Sprague Dawley rats were pretreated orally for 5 days with distilled water in control, H. thebaica 500 mg/kg in acetic acid + H. thebaica group and 5-aminosalisylic acid (5-ASA) 100 mg/kg in acetic acid + 5ASA groups. Colitis was induced by transrectal administration of 4% acetic acid on 5th day. All the animals were sacrificed with ether overdose 48 h after colitis induction, and 10 cm colon segment was resected from distal end. Colon was weighed (for disease activity index) and scored macroscopically and microscopically after histological staining. Biochemical assessments included myeloperoxidase (MPO) and tissue catalase (CAT), glutathione (GSH) and superoxide dismutase (SOD) measurements. H. thebaica showed significant prevention of increase in colon weight and disease activity index along with decrease in macroscopic and microscopic lesion score as compared to control group. Significant improvement was observed in the levels of MPO, CAT and SOD, except GSH. However, the effect of H. thebaica was significantly less than 5-ASA. H. thebaica at 500 mg/kg showed significant amelioration of experimentally induced IBD, which may be attributed to its antioxidant and anti-inflammatory properties.

show abstract

Section: Discussionmentioning

confidence: 99%

Potential antioxidant and anti-inflammatory effects of Hyphaena thebaica in experimentally induced inflammatory bowel disease

Shalaby¹

2013

Afr. J. Pharm. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…All these effects clearly contribute to the different pharmacological activities of esculetin, including analgesic effects (11), anti-carcinogenic properties (12,13) and immunomodulatory functions (14). With regard to the latter activity, a previous study demonstrated the intestinal anti-inflammatory activity of this coumarin in an experimental model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats (15). Based on this finding, our objective was to evaluate the effects of esculetin on the intestinal inflammatory process to further clarify the mechanism of action of this compound.…”

mentioning

confidence: 98%

Mechanism and Effect of Esculetin in an Experimental Animal Model of Inflammatory Bowel Disease

et al. 2013

View full text Add to dashboard Cite

Esculetin is a coumarin derivative with high antioxidant activity. In a rat experimental model of inflammatory bowel disease induced by trinitrobenzenesulfonic acid, esculetin at the dose of 5mg/Kg displayed intestinal anti-inflammatory activity; however, its mechanism of action needs to be elucidated. Our objective was to evaluate the effects of esculetin on the intestinal inflammatory process and to clarify the mechanism of action of this compound. We also compared its effects with prednisolone and sulphasalazine. Our results demonstrate that treatment with esculetin prevented an increase in malondialdehyde content, counteracted the depletion of glutathione content, reduced epithelial cell apoptosis, reduced the secretion of pro-inflammatory cytokines, such as IL-lP, IL-2 and IFN-y, in vitro, and reduced the colonic levels of TNF-a and IL-IP in vivo. Additionally, esculetin treatment inhibited MPO and AP activities. These results demonstrated that esculetin produced a more effective intestinal anti-inflammatory effect than sulphasalazine because it was used at a lO-fold lower dose, and it produced effects similar to those created by prednisolone. We suggest that esculetin exerts its activity by inhibiting pro-inflammatory cytokine secretion and increasing the defences against reactive oxygen species. This leads to less migration and/or activation of inflammatory cells, resulting in the improvement of lesions and functions in the intestinal epithelium. This study confirms the intestinal anti-inflammatory activity of esculetin and demonstrates that this compound has both antioxidative and immunomodulatory properties. Therefore, esculetin may be an interesting new anti-inflammatory drug for the treatment of inflammatory bowel disease.Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. IBD is divided into two major categories, ulcerative colitis (UC) and Crohn's disease (CD). The cause of IBD is not known; however, the actual development of disease reflects the contributions of host genetics, an environmental trigger and the consequent immune response (l). Current drugs for IBD

show abstract

“…Esculetin exhibits a variety of bioactivities, including inhibitory activity on lipoxygenase extracted from ground soybean (Lee and Lillard, 1997), inhibitory activity with mushroom tyrosinase, free radical scavenging activity (Payá et al, 1992), calf thymus DNA protective activity (Tahara et al, 2005), chemopreventive activity in mammary carcinogenesis in female Sprague-Dawley rats (Matsunaga et al, 1998), and inhibitory activity on cell cycle progression of human leukemia HL-60 . 4-ME has exhibited enhanced intestinal anti-inflammatory activity in rat colitis (Witaicenis et al, 2010), and 4-PE is a potent rat lens aldose reductase 2 inhibitor (Kato et al, 2010). Recently, owing to the easy accessibility of the structural modification in this position (Garazd et al, 2005), various substitution groups such as aryl groups and heterocyclic rings have been introduced to C-4 position to obtain products with potentially enhanced or new activities (Mashelka and Audi, 2006;Kini et al, 2012;Sokmen et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins

Xia

Wang

et al. 2015

Drug Metab Dispos

View full text Add to dashboard Cite

Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacologic activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human UDPglucuronosyltransferase (UGT) enzymes remain unclear. This study was aimed at exploring the structure-glucuronidation relationship of esculetin and its C-4 derivatives, including 4-methyl esculetin, 4-phenyl esculetin, and 4-hydroxymethyl esculetin as well as 4-acetic acid esculetin. It was achieved by identifying the main human UGTs responsible for the different reactions and by careful characterization of the reactions kinetics. These catechols, with the exception of 4-acetic acid esculetin, are selectively metabolized to the corresponding 7-O-glucuronides. UGT1A6 and UGT1A9 are the two major UGTs involved in the 7-O-glucuronidation of 4-methyl esculetin and esculetin. UGT1A6 was the major contributor for 7-O-glucuronidation of 4-hydroxymethyl esculetin, and UGT1A9 played a significant role in the 7-O-glucuronidation of 4-phenyl esculetin. The results of the kinetic analyses revealed that the K m values of the compounds, in both UGT1A9 and human liver microsomes, decreased with increasing hydrophobicity of the C-4 substitutions. The outcome of this was that C-4 hydrophobic and hydrophilic groups on 6,7-dihydroxycoumarin exhibited contrasting effects on UGT affinity. All of these findings provide helpful guidance for further structural modification of 6,7-dihydroxycoumarins with improved metabolic stability.

show abstract

Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis

Cited by 111 publications

References 51 publications

Potential antioxidant and anti-inflammatory effects of Hyphaena thebaica in experimentally induced inflammatory bowel disease

Potential antioxidant and anti-inflammatory effects of Hyphaena thebaica in experimentally induced inflammatory bowel disease

Mechanism and Effect of Esculetin in an Experimental Animal Model of Inflammatory Bowel Disease

Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins

Contact Info

Product

Resources

About