these individuals [24-26]. However, should APN in- crease with exercise training in patients with IBD, then exercise may further augment the inflammatory state associated with IBD, or alternatively prevent the anti- inflammatory effects of exercise training. Evidence does exist that low intensity exercise training is in fact pro- tective against oxidative colonic damage in wild type (WT) rats with dextran sodium sulfate (DSS)-induced colitis , however, given that the greatest overall ben- efits of exercise training observed in both the general population and in other chronic conditions occur when the least active individuals become moderately active , it is unknown whether current moderate intensity exercise recommendations would be beneficial or harm- ful to individuals with IBD. Furthermore, it is unknown whether the presence of APN will impede the benefits typically associated with exercise training. Therefore, the aims of this study were to determine the effect of four weeks of moderate-intensity treadmill running on 1) the clinical and histopathological symptoms asso- ciated with acute colitis, 2) intestinal levels of the cyto- kines IL-1β, IL-6, TNF-α and IL-10 and serum adiponectin, 3) intestinal STAT3 and phosphorylated (p)-STAT3 expression, and 4) colonic epithelial cell pro- liferation in APN deficient mice recovering from chemically-induced acute colitis.
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Case presentation: We report the case of a 64-year-old female patient with a history of long-term NSAID use, who was hospitalized with septic shock caused by Klebsiella pneumoniae bacteremia. Computed tomography revealed multiple renal and splenic abscesses with diffuse colon wall thickening. A colonoscopy confirmed colitis with diffuse ulcers. NSAIDs were discontinued after this hospitalization. The abscesses improved after antibiotic treatment. A short course of balsalazide treatment was given under the suspicion of ulcerative colitis. Balsalazide was discontinued four months later due to a non-compatible clinical course. A follow-up colonoscopy two years later revealed a normal colon mucosa, and NSAID-induced colitis was diagnosed.
Abstract: Objective: To investigate the underlying protective effects of Calycosin on experimental colitis. Methods: The effect of Calycosin on pro-inflammatory genes mRNA expression and production were examined using real-time PCR and ELISA. Flow cytometry was used to determine the effect of Calycosin on LPS-induced ROS production in Raw264.7 cells. Western blot assay was used to determine the effect of Calycosin on NF-κB and MAPK pathway ac- tivation. For in vivo models, 2.5% TNBS was utilized through the catheter to induce experimental colitis. Body weight and DAI were evaluated every day. H&E staining were used to evaluate the effect on Calycosin on TNBS-induced colon damage. Moreover, MPO levels, MDA, GSH and SOD in TNBS-treated colon were determined by assay kits. Results: Calycosin significantly inhibited LPS-induced pro-inflammatory cytokines mRNA expression and produc- tion in Raw264.7 cells. 50 mg/kg Calycosin protect against TNBS-induced experimental colitis in mice, decreased oxidative stress and inhibited TNBS-induced inflammatory cytokine production, which is connected to the inhibition of NF-κB pathway. Conclusion: These findings revealed that Calycosin successfully ameliorated the effect of TNBS- induced colitis in mice.
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DSS induced colitis histologically shows mucosal and submucosal lymphocyte, macrophages, polymorphonuclear leukocyte, tissue mast cell infiltration, destruction of epithelial architecture with loss of epithelial integrity, edema, segmental ulcer, and granuloma. Focal confluent necrosis of muscle fiber with fibroblastic proliferation and phagocytosis along with extravasations of red blood cells. 34 In our study, we successfully produced DSS induced colitis in C57BL/6 mice. Microscopic examination of karanjin (100 mg/kg) low dose treated animal shows decrease in monocyte, lymphocyte infiltration, necrosis and epithelial destruction. High dose of karanjin (200 mg/kg) significantly ameliorated inflammatory infiltration, edema, necrosis, epithelial destruction, colon shortening and ulceration in DSS induced colitis and restores the normal architecture (Fig.2). This is the first study which demonstrates the curative effect of karanjin on DSS induced colitis. CONCLUSION: Karanjin isolated from Pongamia pinnata seed oil prevented progression of DSS induced colitis in mice probably by inhibiting inflammatory cell recruitment and production of oxidant. Thus, these findings suggest that karanjin may be a promising agent for treatment of intestinal inflammation.
The fecal hemoglobin (Figure 1) and ALP (Figure 2) con- centrations in the TNBS group were significantly higher than the ethanol group (P < 0.0001). However, the concentration of these biochemical markers decreased after hemin treat- ment. At the end of experimental period, hemin was able to attenuate the increased fecal hemoglobin (P < 0.0001) in a dose-dependent manner (P < 0.0001). Furthermore, hemin treatment also decreased the ALP concentration in blood (P < 0.0001) in a dose-dependent manner (P < 0.0001). In this case, the administration of hemin 10 mg/kg bw/day (4 days of treatment) was able to abolish the ALP changes promoted by TNBS-induced colitis, since there is no statistical significance with ethanol group, presenting, thus, a protective effect on the enterocyte.
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Procedure: The primary objective is to identify drug for IBD by using Dextran Sodium Sulphate induced colitis. The animals used for the experiment were healthy and active. On the starting day of the experiment the body weights of the animals were checked and fed with feed and drinking water / saline. Animals were divided into 6 groups, according to body weights each group containing 10 animals;
Our present results showed that treatment with mesalazine improved all body, organ, mucosal and bio- chemical alterations induced by intra-colonic administration of acetic acid. Mesalazine, also known as masalamine, is a 5-aminosalicylic acid (5-aminosalicylate) compound and the most commonly used agent for ulcerative colitis therapy. 16 The exact mechanism of action of mesalazine
methanolic extract (PE) loaded 20% pluronic F127 gel was prepared, and its gelation, gel melting temperatures as well as bio-adhesive strength were determined, (v) anti-inflammatory potential of PE against the intestinal inflammatory process induced by TNBS (trinitro-benzesulphonic acid) in rats was evaluated. The protective effects were evaluated as follows: evaluation of intestinal damage (damage score, colon weight) and adherence to adjacent organs, colon malondialdehyde (MDA) estimation. Results: 0.0317% w/w of P-334 with R f value of 0.48 was calculated from the
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In inflammatory diseases HSP70 expression is significantly higher than in a healthy popula- tion. In studies performed on animals, increased expression of HSP70 proteins and HSP40 proteins was detected in the colorectal mucosa of mice with pharmacologically induced colitis. Interestingly, not all HSP families were found to undergo sim- ilar processes – the expression of HSP25, HSP32 and HSP90 remained unchanged . Similar ob- servations were found in studies involving human populations, in which increased HSP70 expres- sion was detected in the mucosa of patients with Crohn’s disease and ulcerative colitis, as compared to the mucosa of healthy volunteers. The evalu- ation included not only biopsies of mucosa with macroscopically evident pathology, but also frag- ments described as intact in endoscopic examina- tion: in both cases HSP70 expression was higher than in the control group .
various carcinomas, yet its pathogenetic role remains unknown. By generating gain- and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer.
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The pleiotropic cytokine granulocyte-colony stimulatory factor (G-CSF) is mainly required for the generation of neutrophils, but its role in macrophage generation has also been reported. In addition, G-CSF is effective for the down-regulation of inflammatory cytokines and ameliorating gut disorders, such as colitis. However, the G-CSF function in macrophage generation and gut immunity remains unclear. The first focus of this thesis was to assess the role of G-CSF in macrophage generation and its contribution to gut immunity. G-CSF was found to promote the generation of Gr-1 high /F4/80 + macrophages in macrophage (M)-CSF-treated bone marrow cells, most likely through suppressing cell death. Gr-1 high macrophages showed anti- inflammatory/regulatory macrophage (M2)-like cytokine and surface marker profiles. G-CSF receptor deficient (G-CSFR -/- ) mice harbored less gut macrophages, but had a similar number of neutrophils in the gut. In addition, adoptive transfer of G-CSF- treated bone marrow-derived macrophages (G-BMDM) showed a dominant gut- homing phenotype. G-CSFR -/- mice were also more susceptible to dextran sulfate sodium (DSS)-induced colitis than wild-type mice and adoptive transfer of G-BMDM protected these mice from DSS-induced colitis. The second focus of this thesis was to explore the signaling mechanism(s) controlling the preferential G-CSF production over inflammatory cytokines in probiotic bacteria-exposed BMDM. Lactobacillus rhamnosus GR-1 (GR-1) renders several immunomodulatory effects, at least in part, through preferentially inducing G-CSF in macrophages. However, the mechanism(s) by which GR-1 induces preferential G-CSF production in macrophages is still unknown. Among 84 genes tested, G-CSF was the cytokine induced at highest levels in GR-1-treated BMDM, but the induction of inflammatory cytokines, such as TNF-α, was minimal. The signaling pathway of GR-1-preferential G-CSF production was TLR2-, NF-κB-, ERKs- and PI3K/Akt-dependent. A secreted protein-like molecule(s) was found to be responsible for GR-1-preferential G-CSF production.
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Until now, there was no study illustrating the role of miR-29a in UC, hence we measured the expression level of miR-29a in the colon tissues of mice with DSS-induced colitis using quantified real-time PCR. As showed in Figure 4B, the expression of miR-29a was significantly increased in the colon tissues of mice with DSS-induced colitis (P < 0.05) compared to the controls. Whether miR-29a regulates the func- tion of Mcl-1 and is involved in apoptosis of the intestinal epithelial cells are still unclear. The regulated genes of miRNA typically have sequence matches with miRNA at 3’-UTR that bind to and be regulated by miRNA. TargetScan and MicroCosm programs were used to search for potential sequence matches between miR- 29a and Mcl-1. As shown in Figure 4A, both human and mouse miR-29a shared perfect sequence matches of seven nucleotides with the 3’-UTR of human and mouse Mcl-1.
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score. This is consistent with the study of Elkatay et al. . These effects could be explained by the fact that DSS could promote inflammation by variable biological pathways including direct cytotoxic effects  and apoptotic damage of colonic epithelial cells . DSS induced colitis is a reproducible model of IBD in mice. It resembles IBD in human morphologically and symptomatic- cally . MOR and/or GIN have the ability to improve disease activity and histological damage score. These results are in accordance with previous studies which showed that GIN improved histological examination in acetic acid induced colitis in rats [33,34]. In addition, GIN extracts ameliorate colonic atrophy in DSS induced colitis in rats . On the other hand, MOR leave extract improved DAI, macroscopic and microscopic lesion in acetic acid induced ulcer in rats . While, MOR seed improves all signs of inflammation, and severity of colitis in acetic acid induced colitis in rats .
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especially tight junction regulation and mucus production, is not very well understood. Se has demonstrated positive effects in reducing inflammation and preserving epithelial cells. In cell models of human breast cancer, Se has enhanced the function of TJs by relocation of ZO-1 proteins to the apical surface, thus decreasing permeability (Martin, 2007). Additionally, rat models examining stress and chemically induced gastric ulcers have found Se to prevent gastric wall mucus depletion. (al-Moutairy, 1996). The current study is focused on how Se alters gut barrier functionality related to the recovery of tight junction regulation and mucin secretion. However, there are currently gaps in our understanding or how Se can impact intestinal barrier function in a mouse model of acute colitis. Thus, we examined Se function with a widely used mouse model of intestinal inflammation, dextran sodium sulfate (DSS) - induced colitis (Perse, 2012). This model has demonstrated acute, chronic, and relapsing experimental inflammation and has been shown to closely resemble human IBD (Okayasu, 1990; Perse, 2012).
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In conclusion, we isolated five diterpenoid alkaloids from A. laciniatum and show that pseudaconitine is the major constituent of the plant. Of the two alkaloids tested in TNBS-induced colitis in mice, one minor compound, 14-O-acetylneoline showed significant anti-colitis activity. This finding corroborates the traditional claim of anti-inflammatory properties of this plant in BTM, however the mechanism by which 14-O-acetylneoline exerts its anti-colitic action cannot be elucidated from our current data. Future work will focus on isolation of larger quantities of this compound from A. laciniatum to facilitate investi- gation into its mechanism of action and detailed pre-clinical studies including toxicity and derivatization analyses to generate synthetic 14-O-acetylneoline.
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reducing the levels of proinflammatory cytokines and recruiting M2 macrophages and eosinophils. In this work we have found different proteins involved in immune responses involved in DSS-induced colitis and ES treat- ment. Firstly, the expression levels of high mobility group box protein 1 (HMGB1) were significantly downreg- ulated after treatment with A. caninum ES in both the LP and IEC layer tissues. Interestingly, this protein was not significantly regulated in the whole gut sample (Supplementary Table 6). This protein is secreted by different immune cells, including macrophages, and it is involved in inflammation and tissue damage via Toll-like recep- tor (TLR)-4 signaling 40,41 . Although this protein was not elevated in the DSS only group, its down-regulation in
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mice with either C. albicans or S. boulardii daily by ga- vages and administered broad-spectrum antibiotics (ABX) for 7 days prior to colitis induction with DSS (Fig. 2a). ABX treatment completely protected the mice from colitis and abrogated the impact of fungi on colitis. Only untreated mice exhibited a strong colitis phenotype with significant weight loss (Fig. 2b), reduced colon length (Fig. 2c), high lipocalin levels (Fig. 2d), and histo- logical damage (Fig. 2e, f ). Analysis of the microbiota by 16S RNA sequencing showed a strong effect of ABX on the biodiversity and composition of the bacterial micro- biota, characterized by a significant reduction of ob- served species (Additional file 1: Figure S1A and B) and dramatically reduced levels of Firmicutes and Bacteroi- detes, along with a dramatic increase in Proteobacteria, which is majorly composed of bacteria from the family Enterobacteriaceae (Additional file 1: Figure S1C and D). These results showed that some components of the bac- terial microbiota are required for the development of DSS-induced colitis. Consequently, in the absence of these bacteria, colitis does not transpire and pro- or anti-inflammatory fungi challenges do not further bring significant changes in the mice phenotype.
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The ulcerogenic activity was determined by the Rainsford's cold stress method, which is used to determine ulcerogenic potency of a drug at a ten times higher dose. Albino rats were distributed in healthy control, standard group and test groups. Doses of each of the synthesized compounds were first calculated on equimolar basis of pure drug and then were converted into ten times higher doses. Formulation of synthesized compounds and standard drug were administered orally. After oral administration of 5 mL of the aqueous drug suspensions (at 10 times the normal dose), the animals were stressed by exposure to -15° for 1 h. The animals were placed in separate cages, to ensure equal cold exposure. After 2 hrs of drug administration, the rats were sacrificed using isoflurane anaesthesia, the stomach and duodenum were dissected out of the body along with the first 5 cm of the intestine, then rinsed with saline and the contents of the stomach were emptied. The stomach and the intestine were then excised open along the greater curvature and gently wiped clean with a swap dripped in saline. The mucosal damage was examined grossly using a magnifier. A score for the ulcer was studies similar to pyloric ligation induced ulcer model. 27
Currently, there is no an effective therapy to cure the disease but the mainstream treatment depends on reduction of the abnormal inflammation in the colon lining and thereby relieves the symptoms of diarrhea, rectal bleeding, and abdominal pain. The treatment depends on the severity of the disease; therefore treatment is adjusted for each individual (Botoman et al., 1998). Most people with mild or moderate ulcerative colitis are treated with corticosteroids (dexamethasone) to reduce inflammation and relieve symptoms (Hanauer et al., 2004). Nearly 25% of patients with UC requiring steroids therapy become steroid-dependent after one year, and virtually all develop steroid-related adverse events (Faubion et al., 2001). Other drugs as immunomodulators (azathioprine and 6-mercapto-purine) that reduce inflammation by affecting the immune system (Bresci et al., 1997) and aminosalicylates (Rachmilewitz, 1989) are available.
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It may be concluded that ethanolic root extract of Argyreia speciosa exerts a significant protection against trinitrobenzene sulfonic acid induced ulcerative colitis in rats. EREAS possesses dose dependent anti-inflammatory and anti-oxidant properties comparable to standard sulfasalazine effects. This effect is due to its anti- inflammatory, anti-oxidant activity and inhibition of lipid peroxidation. Beside the anti-inflammatory and anti-oxidant effect of EREAS, its anti-microbial activity may add to its beneficial effect against ulcerative colitis disorder.
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