Asmaa Al-Failakawi

We investigated the roles and regulation of contractile and sodium ion transporter proteins in the pathogenesis of diarrhea in the acute ulcerative colitis. Acute ulcerative colitis was induced in male Sprague-Dawley rats using dextran sulfate sodium (DSS) in drinking water for seven days. The effects of nobiletin, a citrus flavonoid, were also examined. Increased myeloperoxidase activity, colon mass, and inflammatory cell infiltration were associated with damage to goblet cells and the epithelial cell lining indicating the development of acute ulcerative colitis. SERCA-2 calcium pump expression remained unchanged, whereas the phospholamban (PLN) regulatory peptide was reduced and its phosphorylated form (PLN-P) increased, suggesting a post-translational increase in SERCA-2 activity in the inflamed colon. Higher levels of IP3 were associated with a decrease in the Gαq protein levels without altering phospholipase C expression, suggesting that IP3 regulation is independent of Gαq protein signaling. In addition, the expression of sodium/hydrogen exchanger isoforms NHE-1, NHE-3 and carbonic anhydrase-1 and sodium pump activity were decreased in the inflamed colon. Nobiletin treatment of colitis selectively reversed the inflammatory and oxidative stress markers, including superoxide dismutase and catalase without restoring the expression of ion transporters. This study highlights alterations in the expression of ion transporters and their regulatory proteins in acute ulcerative colitis. These changes in the ion transporters are likely to reduce NaCl absorption and alter contractility, thereby contributing to the pathogenesis of diarrhea in the present model of acute ulcerative colitis. Nobiletin selectively ameliorates acute colitis in this model.

Background: We investigated the roles and regulation of contractile and sodium ion transporter proteins in the pathogenesis of diarrhea in acute ulcerative colitis. Methods: Acute ulcerative colitis was induced in male Sprague-Dawley rats using dextran sulfate sodium (DSS) in drinking water for seven days. The effects of nobiletin, a citrus flavonoid, were also examined. Results: Increased myeloperoxidase activity, colon mass, and inflammatory cell infiltration associated with damage to goblet cells and the epithelial cell lining indicated the development of acute ulcerative colitis. SERCA-2 calcium pump expression remained unchanged, whereas the phospholamban (PLN) regulatory peptide was reduced and its phosphorylated form (PLN-P) increased, suggesting a post-translational enhancement of SERCA-2 activity in the inflamed colon. Higher levels of IP3 were associated with a decrease in the Gαq protein levels without altering phospholipase C expression, suggesting that IP3 regulation is independent of Gαq protein signaling. In addition, the expression of sodium/hydrogen exchanger isoforms NHE-1, NHE-3 and carbonic anhydrase-1 and sodium pump activity were decreased in the inflamed colon. Nobiletin treatment of colitis selectively reversed the inflammatory and oxidative stress markers, including superoxide dismutase and catalase without restoring the expression of ion transporters. Conclusions: This study highlights alterations in the expression of ion transporters and their regulatory proteins in acute ulcerative colitis. These changes in the ion transporters are likely to reduce NaCl absorption and alter contractility, thereby contributing to the pathogenesis of diarrhea in the present acute model of ulcerative colitis. Nobiletin selectively ameliorates acute colitis in this model.

Background: The pathogenesis of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease is not well understood. This study investigated the roles and regulation of the claudin-1, -2, -3, and -4 isoforms in the pathogenesis of ulcerative colitis, and the potential therapeutic effects of nobiletin. Methods: Colitis was induced in rats by administering dextran sulfate sodium [DSS] in drinking water for seven days. Animals were treated daily with nobiletin [oral, 60 mg/Kg body weight] and studied in four groups, C [non-colitis control], D [DSS-induced colitis], CN [nobiletin-treated non-colitis control], and DN [nobiletin-treated DSS-induced colitis]. On day seven, the animals were sacrificed, and colonic tissues were collected and analyzed. Results: Both macroscopic and microscopic findings suggest the progression of colitis. In the inflamed colon, claudin-1 and -4 proteins were decreased, claudin-2 increased, while the claudin-3 protein remained unchanged. Except for claudin-1, these changes were not paralleled by mRNA expression, indicating a complex regulatory mechanism. Uniform β-actin expression along with consistent quality and yield of total RNA indicated selectivity of these changes. Nobiletin treatment reversed these changes. Conclusions: Altered expression of the claudin isoforms -1, -2, and -4 disrupts tight junctions, exposing the lamina propria to microflora, leading to electrolyte disturbance and the development of ulcerative colitis. Nobiletin with its anti-inflammatory properties may be useful in IBD.