Posttranslational modifications as therapeutic targets for intestinal disorders.

A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.

The Effect of FR167653, p38 Mitogen-Activated Protein Kinase (MAPK) Inhibitor, on the Expression of Slit Diaphragm-Associated Proteins in Experimental Diabetic Nephropathy / 대한신장학회지

PURPOSE: This study was undertaken to investigate the effect of a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, FR167653, on urinary albumin excretion and on the expression of slit diaphragm-associated proteins in diabetic rats. METHODS: Thirty-two Sprague-Dawley rats were injected with diluent [control (C), N=16] or streptozotocin intraperitoneally (DM, N=16). Eight rats from each group were treated with 5 mg/kg/day FR 167653 (C+FR, DM+FR) for 6 weeks. At the time of sacrifice, 24-hour urinary albumin excretion was determined by ELISA. Glomerular nephrin, P-cadherin, and ZO-1 mRNA and protein expression were determined by real-time PCR and Western blot, respectively, with sieved glomeruli. RESULTS: Urinary albumin excretion was significantly higher in DM compared to C rats, and this increase in albuminuria was significantly inhibited by the administration of FR167653 in DM rats. Glomerular phospho-p38 MAPK protein expression was significantly increased in DM rats compared to C rats, and FR167653 treatment significantly attenuated the increase in phospho-p38 MAPK expression in DM glomeruli. Nephrin mRNA and protein expression were higher in 6-week DM compared to C glomeruli, and these increases were significantly abrogated with FR167653 treatment in DM rats. In contrast, FR167653 had no effects on the decrease in P-cadherin expression and the increase in ZO-1 expression observed in DM glomeruli. CONCLUSION: These findings suggest that FR167653, a p38 MAPK inhibitor, reduce the amount of albuminuria in early diabetic nephropathy, and this anti-proteinuric effect seems to be related with the change of glomerular nephrin expression.

The Effects of FR-167653 on Postoperative Intimal Hyperplasia of the Interposition Vein Graft in Rat: 2nd Report / 日本心臓血管外科学会雑誌

Recently we reported that the inhibitor of <i>p</i>38 mitogen-activated protein kinase, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) may suppress postoperative intimal hyperplasia. In this study we evaluated the best dosage and phase for administration of FR-167653, in order to clarify its mechanism in the postoperative treatment of intimal hyperplasia. Twenty-one Lewis male rats (484±5g) were studied. The epigastric vein graft was interposed into the common femoral artery. The rats were divided into four groups according to the dosage and phase of administration of FR-167653: group I (<i>n</i>=5) with 2.0μg/g of FR-167653 immediately before bypass, group T (<i>n</i>=5) with 2.0μg/g immediately before bypass and 2 weeks after bypass, group D (<i>n</i>=5) with 4.0μg/g immediately before bypass, and the control group (<i>n</i>=6) with the same dose of saline. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal areas in group I, T and D were significantly decreased compared with the control group, especially in group D (0.05±0.02mm² vs. 0.43±0.05mm², <i>p</i><0.001). These results suggest that FR-167653 can suppress the postoperative intimal hyperplasia that occurs with interposition of vein grafts in rats.

The Effect of FR-167653 on Postoperative Intimal Hyperplasia of the Interposition Vein Graft in Rat / 日本心臓血管外科学会雑誌

Recently we reported that tumor necrosis factor-α (TNF-α) mRNA expression and the development of postoperative intimal hyperplasia (IH) is different in rat epigastric vein interposition graft, compared to femoral artery re-anastomosis. We evaluated whether a TNF-α suppressive agent, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) could suppress IH or not. Eleven Lewis male rats (480±8g) were studied. The epigastric vein graft was interposed into the common femoral artery. They were divided into two groups: group FR (<i>n</i>=5) with 2.0μg/g of FR-167653, and group C (<i>n</i>=6) with same dose of saline instead of FR-167653. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal area in group FR was significantly decreased, compared with group C (0.160±0.057mm² vs. 0.434±0.045mm², <i>p</i><0.01). These results suggest that the TNF-α suppressive agent FR-167653 may suppress the postoperative intimal hyperplasia that occurs on the interposition vein graft in rats.