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Rebamipide Promotes the Regeneration of Aspirin-Induced Small-Intestine Mucosal Injury through Accumulation of β-Catenin.

Lai Y, Zhong W, Yu T, Xia ZS, Li JY, Ouyang H, Shan TD, Yang HS, Chen QK - PLoS ONE (2015)

Bottom Line: The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively.COX expression was significantly down-regulated in aspirin induced SII (P < 0.05).In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT

Background: The effect of rebamipide on repairing intestinal mucosal damage induced by nonsteroidal anti-inflammatory drugs and its mechanism remain unclear. In this study, we sought to explore the mechanism whereby rebamipide could promote the regeneration of aspirin-induced intestinal mucosal damage.

Methods: BALB/c mice were administered aspirin (200 mg/kg/d) for 5 days to induce acute small intestinal injury (SII). Subsequently, SII mice were treated with rebamipide (320 mg/kg/d) for 5 days. The structure of intestinal barrier was observed with transmission electron microscope, and Zo-1 and occludin expressions were detected. The proliferative index was indicated by the percentage of proliferating cell nuclear antigen positive cells. The prostaglandin E2 (PGE2) levels in the small intestine tissues were measured by an enzyme immunoassay. The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively.

Results: COX expression was significantly down-regulated in aspirin induced SII (P < 0.05). In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly. The proliferative index increased after rebamipide treatment when compared with that in the control mice. The expressions of COX-2, β-catenin, and c-myc and the PGE2 concentrations in small intestinal tissues were significantly increased in mice with rebamipide treatments (P < 0.05).

Conclusion: Rebamipide administration in aspirin-induced SII mice could improve the intestinal barrier structure and promote the regeneration of small intestinal epithelial injury through up-regulating COX-2 expression and the accumulation of β-catenin.

No MeSH data available.


Related in: MedlinePlus

Expression changes of COX-1, COX-2, and PGE2 after rebamipide administration.(A-B) The mRNA expressions of COX-1 (A) and COX-2 (B) in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (C) Immunohistochemistry staining for COX-1 and COX-2 in small intestinal epithelium of the SII-Reb and SII-Sal groups was shown. COX-1 and COX-2 positive cells were detected in the subepithelial area (black arrowheads; bar indicates 25μm). (D) Protein levels of COX-1, COX-2, and PGE2 indicated by Western blots analysis. (G-I) The integrated intensities of bands for COX-1, COX-2, and PGE2 (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (H) The concentrations of PGE2 in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups).
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pone.0132031.g004: Expression changes of COX-1, COX-2, and PGE2 after rebamipide administration.(A-B) The mRNA expressions of COX-1 (A) and COX-2 (B) in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (C) Immunohistochemistry staining for COX-1 and COX-2 in small intestinal epithelium of the SII-Reb and SII-Sal groups was shown. COX-1 and COX-2 positive cells were detected in the subepithelial area (black arrowheads; bar indicates 25μm). (D) Protein levels of COX-1, COX-2, and PGE2 indicated by Western blots analysis. (G-I) The integrated intensities of bands for COX-1, COX-2, and PGE2 (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (H) The concentrations of PGE2 in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups).

Mentions: The mRNA abundances of COX-1 and COX-2 in the small intestine of the four groups of mice at day 0, day 5, and day 10 relative to the Con-Sal group at day 0 were detected. The relative abundances of COX-1 and COX-2 in the SII-Reb and SII-Sal groups were significantly lower at day 5 when compared with those in the Con-Reb and Con-Sal groups (P < 0.05; Fig 4A and 4B). After rebamipide administration, COX-2 mRNA levels in the small intestines of SII-Reb mice were increased significantly at day 10 (P < 0.05; Fig 4B). However, down-regulated expression of COX-1 by aspirin in the SII-Reb group was sustained at a low level after rebamipide administration.


Rebamipide Promotes the Regeneration of Aspirin-Induced Small-Intestine Mucosal Injury through Accumulation of β-Catenin.

Lai Y, Zhong W, Yu T, Xia ZS, Li JY, Ouyang H, Shan TD, Yang HS, Chen QK - PLoS ONE (2015)

Expression changes of COX-1, COX-2, and PGE2 after rebamipide administration.(A-B) The mRNA expressions of COX-1 (A) and COX-2 (B) in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (C) Immunohistochemistry staining for COX-1 and COX-2 in small intestinal epithelium of the SII-Reb and SII-Sal groups was shown. COX-1 and COX-2 positive cells were detected in the subepithelial area (black arrowheads; bar indicates 25μm). (D) Protein levels of COX-1, COX-2, and PGE2 indicated by Western blots analysis. (G-I) The integrated intensities of bands for COX-1, COX-2, and PGE2 (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (H) The concentrations of PGE2 in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups).
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pone.0132031.g004: Expression changes of COX-1, COX-2, and PGE2 after rebamipide administration.(A-B) The mRNA expressions of COX-1 (A) and COX-2 (B) in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (C) Immunohistochemistry staining for COX-1 and COX-2 in small intestinal epithelium of the SII-Reb and SII-Sal groups was shown. COX-1 and COX-2 positive cells were detected in the subepithelial area (black arrowheads; bar indicates 25μm). (D) Protein levels of COX-1, COX-2, and PGE2 indicated by Western blots analysis. (G-I) The integrated intensities of bands for COX-1, COX-2, and PGE2 (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups). (H) The concentrations of PGE2 in the small intestine of the four groups were shown (n = 6, *P < 0.05 when compared with Con-Reb and Con-Sal groups; &P < 0.05 when compared with SII-Sal, Con-Reb, and Con-Sal groups).
Mentions: The mRNA abundances of COX-1 and COX-2 in the small intestine of the four groups of mice at day 0, day 5, and day 10 relative to the Con-Sal group at day 0 were detected. The relative abundances of COX-1 and COX-2 in the SII-Reb and SII-Sal groups were significantly lower at day 5 when compared with those in the Con-Reb and Con-Sal groups (P < 0.05; Fig 4A and 4B). After rebamipide administration, COX-2 mRNA levels in the small intestines of SII-Reb mice were increased significantly at day 10 (P < 0.05; Fig 4B). However, down-regulated expression of COX-1 by aspirin in the SII-Reb group was sustained at a low level after rebamipide administration.

Bottom Line: The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively.COX expression was significantly down-regulated in aspirin induced SII (P < 0.05).In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT

Background: The effect of rebamipide on repairing intestinal mucosal damage induced by nonsteroidal anti-inflammatory drugs and its mechanism remain unclear. In this study, we sought to explore the mechanism whereby rebamipide could promote the regeneration of aspirin-induced intestinal mucosal damage.

Methods: BALB/c mice were administered aspirin (200 mg/kg/d) for 5 days to induce acute small intestinal injury (SII). Subsequently, SII mice were treated with rebamipide (320 mg/kg/d) for 5 days. The structure of intestinal barrier was observed with transmission electron microscope, and Zo-1 and occludin expressions were detected. The proliferative index was indicated by the percentage of proliferating cell nuclear antigen positive cells. The prostaglandin E2 (PGE2) levels in the small intestine tissues were measured by an enzyme immunoassay. The mRNA and protein expression levels of cyclooxygenase (COX) and β-catenin signal were detected in the small intestine using quantitative PCR and Western blot, respectively.

Results: COX expression was significantly down-regulated in aspirin induced SII (P < 0.05). In SII mice treated with rebamipide, histopathological findings of aspirin-induced intestinal inflammation were significantly milder and tight junctions between intestinal epithelial cells were improved significantly. The proliferative index increased after rebamipide treatment when compared with that in the control mice. The expressions of COX-2, β-catenin, and c-myc and the PGE2 concentrations in small intestinal tissues were significantly increased in mice with rebamipide treatments (P < 0.05).

Conclusion: Rebamipide administration in aspirin-induced SII mice could improve the intestinal barrier structure and promote the regeneration of small intestinal epithelial injury through up-regulating COX-2 expression and the accumulation of β-catenin.

No MeSH data available.


Related in: MedlinePlus