Project description:Colitis is the common pathological lesion of inflammatory bowel diseases, the major chronic inflammatory diseases of intestinal tracts in humans. In this study, we investigated the therapeutic effects of ginger extract and its component zingerone in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mice were administered with TNBS and/or various amounts of ginger and zingerone by an intrarectal route. The severity of colitis was evaluated by colonic weight/length ratio, macroscopic lesion, and histological examination. The mechanisms of ginger and zingerone were further elucidated by DNA microarray, ex vivo imaging, and immunohistochemical staining. Our data showed that treatment with ginger extract and zingerone ameliorated TNBS-induced colonic inflammation and injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF-κB activation and decreased the NF-κB and IL-1β protein levels in the colon. In conclusion, our data showed that ginger improved the TNBS-induced colitis in mice via modulation of NF-κB activity and IL-1β signaling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. A total of 24 mice was randomly divided into four groups of six mice: mock, mice were given with 0.1 ml of 50% ethanol; TNBS, mice were given with 250 mg/kg TNBS in 0.1 ml of 50% ethanol; TNBS/ginger, mice were administered with mixtures containing 250 mg/kg TNBS and various amounts of ginger extract in 0.1 ml of 50% ethanol; TNBS/zingerone, mice were given with mixtures containing 250 mg/kg TNBS and various amounts of zingerone in 0.1 ml of 50% ethanol. Mice were sacrificed seven days later for histochemical staining, RNA extraction, and ex vivo imaging.

Project description:Analysis of mechano-regulation of tenocyte metabolism at gene expression level. The hypothesis tested in the present study was that cyclic tensile strain influence the balance of anabolism/catabolism of tenocytes. Forkhead box O (FoxO) proteins are a family of transcription factors implicated in many biological processes including immune regulation. In this study, we found that mice null for Foxo4, a member of the FoxO family, are more susceptible to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis than wild type controls. To understand the mechanism of elevated colitis susceptibility and the nature of the TNBS-induced colitis in Foxo4-null mice, we performed microarray analysis with mucosal cDNA samples from large intestines of untreated, ethanol and TNBS-treated wild type and Foxo4 KO mice. Unexpectedly, we found that cytokine CCL5, CXCL9, TNFalpha, and IFNgamma were already significantly upregulated in untreated Foxo4-null mice compared to WT controls despite lack of visible colonic phenotypes. Consistent with the exacerbated inflammatory phenotype in TNBS-treated Foxo4 KO mice, expressions of these inflammatory cytokines are further upregulated after TNBS-treatment. In addition, we observed many more inflammatory cytokines that were upregulated in TNBS-treated Foxo4 KO mice, including chemokines (CCL3, 4, 7, 8, 11, 12, 21b and CXCL1, 12, 14), chemokine receptors (CCR7, CCRl2, 8,CXC3CR1), cytokines (IL-1, IL-6, IL-11, IFI205), and cytokine receptors (TNFrsf). Interestingly, many of the anti-bacterial peptides were also up-regulated in TNBS treated Foxo4 KO mice including defensin related cryptdin (Defcr3,5,6, 9,13) and Defcr related sequence (Defcr-cr1,2,10,12). Up-regulation of basal level of IFNgamma, TNFalpha, CCL5, and CXCL9 expression in Foxo4 KO mice is specific to colonic tissues, as no significant difference of these gene transcript levels between wild type and Foxo4 KO mice was observed in other tissues including thymus . IFNgamma, TNFalpha, and IL-1ï¢which are upregulated in TNBS-treated Foxo4 KO mice, are Th1 type cytokines. This is consistent with the Th1 inflammatory phenotype observed in TNBS-treated Foxo4-KO mice. We also tested whether the expression of Th2 cytokines (IL-4, IL-5, and IL-13) is altered in TNBS-treated WT and Foxo4-null mice in comparison to ethanol-treated mice and observed no significant differences suggesting that the TNBS-induced colitis in Foxo4-null FVB mice is predominantly Th1 in nature. Colonic mucosal tissues from five mice per treatment group (untreated, two days after ethanol or TNBS-treatment) were pooled. Total RNA obtained from colon mucosa isolated tendon fascicles subjected to 1 or 24 hours in vitro cyclic tensile strain compared to unstrained control fascicles.

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