Ulcerative Colitis: Yi WQ

Li Z, Zhang de K, Yi WQ, Ouyang Q, Chen YQ, Gan HT. · Department of Gastroenterology and Geriatric Medicine West China Hospital, Sichuan University, Chengdu, China. · Arch Med Res. · Pubmed #18996285 No free full text.

Abstract: BACKGROUND: Activation of nuclear factor-kappa B (NF-kappaB), which controls transcription of various proinflammatory cytokine genes, has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). The aim of this study was to investigate if NF-kappaB p65 antisense oligonucleotides may affect the expression of NF-kappaB p65 and cytokines in lamina propria mononuclear cells (LPMCs) from patients with UC. METHODS: LPMCs, which were isolated from intestinal mucosal biopsy specimens from patients with UC, were cultured with or without NF-kappaB p65 antisense oligonucleotides, missense oligonucleotides and dexamethasone. NF-kappaB p65 expression was determined by Western blot analysis. The expression of cytokine mRNA was studied by reverse transcription-polymerase chain reaction (RT-PCR). Cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: NF-kappaB p65 antisense oligonucleotides resulted in downregulation of NF-kappaB p65 expression, blocked the expression of IL-1beta mRNA and IL-8 mRNA, and strikingly reduced the production of IL-1beta and IL-8. These effects were greater than those of dexamethasone in cultured LPMCs from patients with UC (p <0.05). CONCLUSIONS: Application of NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with UC.

Yi WQ, Gan HT, Huang XL, Zhang M, Ouyang Q. · Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu 610041, China. · Zhonghua Nei Ke Za Zhi. · Pubmed #18028805 No free full text.

Abstract: OBJECTIVE: To investigate the expression of phosphorylated p38 mitogen activated protein kinase (MAPK) in colonic mucosa of patients with ulcerative colitis (UC) and the effects of SB203580 which is a p38 MAPK inhibitor on the secretion of TNFalpha in colonic mucosa from patients with UC. METHODS: Samples of colonic mucosa were collected from 30 UC patients, 20 males and 10 females, aged (33.50 +/- 10.20) years, during enteroscopy. Samples of normal colonic mucosa 10 cm beyond the tumorous tissue were collected from 15 patients with colonic cancer, 10 males and 5 females, aged (46.64 +/- 10.49) years, as normal controls. The samples underwent pathological and immunohistochemical examination. The remaining samples of the colonic mucosa were cultured and divided into 3 groups: UC + SB203580 group (n = 10, SB203580, an inhibitor of p38 MAPK signal pathway, in a concentration of 20 micromol/L was added), UC control group (n = 10, without addition of SB203580), and peri-cancer normal colonic tissue group (n = 10). 5 hours after the culture, immunohistochemistry was used to detect the expression of phosphorylated p38 MAPK and the expression of phosphorylated transcription of activation factor-2 (ATF(2)), which is a downstream molecule of p38 MAPK. ELISA array was used to detect the content of tumor necrosis factor (TNFalpha) in the supernatant. RESULTS: (1) The A value of phosphorylated p38 MAPK in the colonic mucosa of the UC was 549.22 +/- 32.54, being significantly higher than that of the normal colonic mucosa (143.52 +/- 11.89, P < 0.01). The positive area of the UC group was (1680.61 +/- 115.30) x 10(-5) microm(2), being significantly higher than that of normal colonic mucosa (351.68 +/- 12.73) x 10(-5) microm(2), P < 0.01. (2) The level of TNFalpha in the supernatant of the UC + SB203580 group was (72.07 +/- 20.30) ng/L, being significantly lower than that of the UC control group (549.96 +/- 107.63) ng/L (P < 0.01), but still higher than that of the normal control group (19.44 +/- 3.81) ng/L (P < 0.01). (3) The A value of phosphorylated ATF(2) in the colonic mucosa biopsy specimens of the UC + SB203580 group was 265.82 +/- 40.25, being significantly lower than that of the UC control group (688.32 +/- 47.37, P < 0.01), but still higher than that of the normal control group (120.22 +/- 6.45, P < 0.01). The positive area of phosphorylated ATF(2) in the colonic mucosa biopsy specimens of the UC + SB203580 group was (1213.76 +/- 204.77) x 10(-5) microm(2), being significantly lower than that of the UC control group (2489.02 +/- 193.63) x 10(-5) microm(2), P < 0.01, but no difference in expression of phosphorylated p38 MAPK was found between UC + SB203580 group and UC control group [respectively, A value: 465.64 +/- 38.69 vs 480.34 +/- 38.87, positive area: (1486.26 +/- 165.49) x 10(-5) microm(2) vs (1536.68 +/- 182.16) x 10(-5) microm(2), both P > 0.05]. CONCLUSIONS: p38 MAPK signal transduction pathway plays an important role in the development of UC. Blockade of the signal transduction pathway could ameliorate inflammation, at least in part, by reducing secretion of proinflammatory cytokines, suggesting that p38 MAPK pathway might be a new target for treatment of UC, and SB203580 could be a hopeful novel drug for the treatment of UC.

Huang XL, Yi WQ, Zhang M, Ouyang Q, Gan HT. · Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #17456377 No free full text.

Abstract: OBJECTIVE: To elucidate the role of phosphatidylinositol 3-kinase (PI3K)/Akt in the pathogenesis of ulcerative colitis (UC) and provide experimental evidence that PI3K inhibitor wortmannin can be used as a possible novel approach for treatment of UC. METHODS: Samples of intestinal mucosa were collected from 30 UC patients, 22 males and 8 females, aged 35 +/- 11, during enteroscopy. Samples of normal intestinal mucosa 10 cm beyond the cancerous tissues were collected from 15 patients with intestinal cancer, 9 males and 6 females, aged 40 +/- 9, as normal controls. The samples underwent pathological examination and immunohistochemistry. Another tissues of intestinal mucosa were cultured and divided into 3 groups: UC + wortmannin group, (n = 10, wortmannin, an inhibitor of PI3K/Akt pathway, of the concentration of 0.002 nmol/microl was added), UC control group (n = 10, without addition of wortmannin), and peri-cancer normal intestinal tissue group (n = 10). 4.5 hours after the culture, immunohistochemistry was used to detect the expression of phosphorylated Akt (p-Akt) in the intestinal mucosa and ELISA was used to detect the content of tumor necrosis factor (TNF-alpha) in intestinal mucosa. RESULTS: (1) The A value of p-Akt in the intestinal mucosa of the UC control group was 73.6 +/- 5.2, significantly higher than that of the normal control group (18.0 +/- 2.6, P < 0.05), the positive area of the UC control group was 720 +/- 58, significantly larger than that of the normal control group (133 +/- 29, P < 0.05). (2) The level of TNF-alpha in intestinal mucosa of the UC + wortmannin group was 135 +/- 11, significantly lower than that of the UC control group (296 +/- 39, P < 0.05), however, still significantly higher than that of the normal control group (26 +/- 5, P < 0.05). (3) The A value of p-Akt in the intestinal mucosa biopsy specimens of the UC + wortmannin group was 35.3 +/- 5.6, significantly lower than that of the UC control group (72.3 +/- 6.2, P < 0.05), however, still significantly higher than that of the normal control group (18.0 +/- 2.2, P < 0.05); and the positive area of the UC + wortmannin group was 351 +/- 50, significantly lower than that of the UC control group (716 +/- 94, P < 0.05), however, still significantly higher than that of the normal control group (129 +/- 30, P < 0.05). CONCLUSIONS: (1) PI3K/Akt signal transduction pathway is a critical factor in regulating the expression of pro-inflammatory cytokine, and plays a role in the pathogenesis of UC. (2) Decreasing the levels of relevant cytokines in UC by inhibiting PI3K/Akt signal transduction pathway, wortmannin may be a novel approach for the treatment of UC.