Curcumin Inhibits 5-Fluorouracil-induced Up-regulation of CXCL1 and CXCL2 of the Colon Associated with Attenuation of Diarrhoea Development.

The compound 5-fluorouracil (5-FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5-FU in mice. Curcumin has anti-inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5-FU-induced diarrhoea development and CXCL1 and CXCL2 up-regulation in the colon. Mice were given 5-FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5-FU and administered 30 min. before the administration of 5-FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real-time RT-PCR. Curcumin reduced the 5-FU-induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up-regulated by 5-FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5-FU application in vitro. The 5-FU-induced up-regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay-117082 and bortezomib, nuclear factor kappa B (NF-κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element-binding protein-histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF-κB and HAT activation.

Anti-inflammatory effect of enzymatic hydrolysate of corn gluten in an experimental model of colitis.

OBJECTIVES: Intestinal bacteria are thought to be involved in the initiation and perpetuation of inflammatory bowel diseases. Prebiotics (non-digestable dietary carbohydrate) have beneficial properties that alter the intestinal flora and contain glutamine-rich protein. Glutamine significantly decreases indices of inflammation. In this study, an enzymatic hydrolysate of corn gluten (EHCG) was administered by gavage to Sprague-Dawley rats fed an elemental diet to determine whether EHCG can ameliorate experi- mental colitis. METHODS: Colitis was induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid after 10 days' daily oral administration of EHCG at 100 and 300 mg/kg. Macroscopic damage was assessed using a scoring system. The mucosa homogenate was sonicated and myeloperoxidase activity and histamine levels measured. KEY FINDINGS: Treatment with EHCG significantly decreased the severity of injury and reduced myeloperoxidase activity and histamine levels in the distal colon mucosa. CONCLUSIONS: EHCG may have therapeutic benefit as a supplement in enteral nutrition for patients with inflammatory bowel diseases.

Membrane permeability and antipyrine absorption in a rat model of ischemic colitis.

The aim of this study was to determine whether the duration of ischemia affects antipyrine absorption in the large intestine. This was carried out in a rat model of ischemic colitis in which ischemia and associated inflammation was induced by marginal vessel ligation. Blood flow was disrupted by positioning an o-ring around the distal rectum and ligating the marginal vessel at two locations in the hind-gut ligament artery region. Ligation was performed for 1, 2, 3, and 5h. We assessed large intestine damage by measuring key indicators of inflammation, myeloperoxidase (MPO) activity and thiobarbituric acid reactant substrates (TBARS) in the mucosa and by histological staining with hematoxylin-eosin stain. Antipyrine membrane permeability was assessed in Ussing-type diffusion chambers, and related pharmacokinetics were calculated from antipyrine plasma concentration measurements following colon administration of the drug. Vessel ligation caused some sloughing of epithelial cells and elevated the MPO and TBARS levels. Prolonged ligation failed to affect the apparent permeability coefficient (P(app)) of antipyrine. Prolonged ligation, however, gradually increased plasma antipyrine concentrations to near control levels. This increase was paralleled by increases in the absorption rate constant AUC and antipyrine bioavailability. Taken together, these results suggest that the absorption kinetics of antipyrine may depend on blood flow changes in the large intestine that occur with inflammation.

A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice.

In this study, we have evaluated the efficacy of dosmalfate, a new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1 beta, prostaglandins (PG)E(2) and (PG)D(2) concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800 mg/kg body weight, p.o.) ameliorated severe colitis reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 beta levels. (PG)E(2) and (PG)D(2) synthesis were significantly reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude that dosmalfate is protective in acute DSS-induced colitis. The beneficial effects seem to be related to a decrease of neutrophil infiltration, absence of up-regulation of IL-1 beta and increase of PG production in colon mucosa.