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Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p

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Background: The association between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. It is also well known that a high fat diet (HFD) promotes insulin resistance which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP4) inhibitors are used clinically in diabetes therapy to prolong the effects of glucagon-like peptide-1 (GLP-1). However, because another derivative from proglucagon, the intestinotrophic hormone GLP-2, is also a substrate for DPP-4, DPP-4 inhibitionmay enhance intestinal carcinogenesis by increasing endogenous active GLP-2. We therefore conducted this study to investigate the influence of a DPP-4 inhibitor on intestinal tumorigenesis in Apc Min/+ mice fed a HFD. Material and Methods: Segmental differences in DPP-4, 8, and 9 mRNA expression and DPP enzyme activity were determined in the mice. The DPP-4 inhibitor, sitagliptin (0.3, 1 or 3 mg/kg), was given orally. Mucosal DPP activity and GLP concentrations were measured 24 hr after administration. Six-week-old male Apc Min/+ mice were randomized to either a HFD (60 kcal fat) group or control diet (10 kcal fat) group for 9 weeks. Each group was divided into two groups, which were either treated or not treated with sitagliptin (3 mg/kg/day, i.g.). The mice were sacrificed 9 weeks after the initiation of treatment. The small intestine was coiled up into a Swiss roll, which was used to determine the number, size, and localization of tumors. Results: DPP-4 mRNA was expressed at high levels in the jejunum and ileum, with high DPP-4 activity also being detected. Oral sitagliptin caused a dose-dependent suppression in mucosal DPP-4 activity. Although the mucosal concentration of total GLP-2 was not affected, the concentration of GLP-1(7-36) was significantly elevated in the mucosa of the ileum. From seven to eight weeks after the initiation of sitagliptin treatment, bloody and inconsistent stools were observed mainly in the control diet and sitagliptin-treated mice. These mice also showed significantly lower body weight gains. In the control diet group, daily treatment with sitagliptin caused a significant increase in the number of intestinal tumors compared with mice not treated with sitagliptin. Daily treatment with sitagliptin suppressed the number of intestinal tumors in the HFD group, although this change was not statistically significant. Conclusion: This study demonstrated that chronic treatment with sitagliptin increased endogenous mucosal GLPs in the intestine and promoted intestinal tumorigenesis in lean mice, whereas sitagliptin treatment tended to suppress tumorigenesis in mice fed a HFD. Because a HFD promotes insulin resistance and intestinal neoplasia, DPP-4 inhibition may also be useful as an agent for preventing cancer in obese or diabetic patients.

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

and then had received scheduled maintenance IFX. Similarly, in the Re-set IFX group, patients received scheduled maintenance IFX immediately following surgery to eliminate active CD lesions. Both groups were followed for 3 to 5 years during which patients’ disease profiles were monitored with a keen interest in mucosal healing. Results: During 1, 2 and 5 years of follow up, remission maintenance rates were 58.3%, 37.5%, and 16.2%, respectively in the RIFX group. The corresponding maintenance remission rates in the Re-set IFX group were 91.7%, 69.5% and 51.7%. Likewise, complete mucosal healing rate at 3 years was 29.6% in the RIFX group and 75.0% in the Re-set IFX group, reflecting vastly better maintenance efficacy rates in the Re-set IFX group vs RIFX group. Readmission rate was 50.0% in the RIFX group vs 21.2% in the Re-set IFX group, while re-operation rate was 23.3% in the RIFX group and 12.1% in the Re-set IFX group. Conclusions: In the clinical settings described above, scheduled maintenance IFX therapy appeared to produce improved efficacy outcomes when initiated immediately after resections of active CD lesions. More notably, the efficacy of IFX to induce mucosal healing was better in the Re-set treatment setting vs routine setting.

G A A b st ra ct s inflammatory cells, and submucosal edema. [Result] Serum CyA levels were significantly less elevated after oral administration of CyA-MS than only CyA (CyA, 44.7±0.8ng/ml; CyAMS, 7.7±1.3ng/ml). The differences between CyA (0) and CyA (0)-MS was not significant in body weight, the histological score, MPO activity, and realtime RT-PCR. The body weight were significantly recovered in the mice group treated with CyA (0.2)-MS, CyA (2), and CyA (2)-MS compared with CyA (0)-MS. The percent body weight at day 10 compared with day 0 were as follows: CyA (0)-MS, -26.17±3.48%; CyA (0.2), -16.763±2.52%; CyA (0.2)-MS, -8.8±2.01%; CyA (2), -13.99±3.81%; and CyA (2)-MS, -7.53±1.97%, respectively. The histological score in CyA(0.2)-MS, CyA(2), and CyA(2)-MS were significantly less than CyA(0)-MS (78.2%, 83.9%, and 80.4%, respectively). The mice group treated with CyA (0.2)-MS was equally effective in histologically compared with that of CyA (2) and CyA (2)MS. MPO activity of the group treated with CyA-MS was also significantly lower than of those treated with vehicle, and data were as follows: CyA (0)-MS, 1.22±0.17unit/mg tissue; CyA (0.2)-MS, 0.73±0.17unit/mg tissue; and CyA (2)-MS, 0.67±0.17unit/mg tissue, respectively. Gene expressions of IL-1β, IL-6, and CXCL1, in the mice treated with CyA (0.2)-MS and CyA (2)-MS were down-regulated compared with the mice treated with CyA (0)-MS (37% and 24%, 11% and 13%, 11% and 14%, respectively). [Conclusion] CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.

Background: Colorectal cancer is one of the most serious complications of ulcerative colitis (UC) and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. As we have shown previously, the selective cyclooxygenase (COX)-2 inhibitor is effective in diminishing carcinogenesis in an murine model of UC (DDW 2006).1 However, this might exacerbate dextran sulfate sodium (DSS) colitis in mice. The selective COX-2 inhibitor Etodolac is marketed as a racemic mixture of the Rand Senantiomers that are not metabolically interconvertible. The biochemical and pharmacological effects of Etodolac are due to the S-enantiomer, while R-enantiomer lacks COX-inhibitory activity. Therefore, R-Etodolac has potential advantage of avoiding COX-2 inhibitory adverse effects. In this study, we evaluated the effect of R-Etodolac on colitis-related mouse colon carcinogenesis. Methods: The mice received 1,2-dimethlhydrazine (DMH) at a dose of 20mg/kg body wt subcutaneously three times within 1 week of reaching 6 weeks of age. Starting 1 week after the DMH injection, chronic colitis was induced in mice by administration of 2 cycles of DSS (each cycle: 3% DSS for 7 days and then distilled water for 14 days). The mice were killed 28 days after the completion of the 2 cycles. The mice were divided into the following groups: group A served as a disease control; group B received low (2mg/kg) dose of REtodolac every 3 days by oral gavage during the whole period; group C received high (10mg/ kg) dose of R-Etodolac every 3 days by oral gavage during the whole period; group D received no agents including DSS and served as a normal control. Results: The administration of R-Etodolac decreased the disease activity index during the administration cycle of DSS. The mean number of tumors was 17.8 in group A, 15.2 in group B and 6.0 in group C. In group C, R-Etodolac significantly suppressed the occurrence of neoplasia (p