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Sample records for acid induced colitis

  1. Inflammatory cells’ role in acetic acid-induced colitis

    PubMed Central

    Sanei, Mohammad H.; Hadizadeh, Fatemeh; Adibi, Peyman; Alavi, Sayyed Ali

    2014-01-01

    Background: Free radicals are the known mechanisms responsible for inducing colitis with two origins: Inflammatory cells and tissues. Only the inflammatory cells can be controlled by corticosteroids. Our aim was to assess the importance of neutrophils as one of the inflammatory cells in inducing colitis and to evaluate the efficacy of corticosteroids in the treatment of inflammatory bowel disease (IBD). Materials and Methods: Thirty-six mice were divided into six groups of six mice each. Colitis was induced in three groups by exposing them to acetic acid through enema (group 1), ex vivo (group 3), and enema after immune suppression (group 5). Each group had one control group that was exposed to water injection instead of acetic acid. Tissue samples were evaluated and compared based on macroscopic damages and biochemical and pathological results. Results: Considering neutrophilic infiltration, there were significant differences between groups 1, 3, 5, and the control of group 1. Groups 3, 5, and their controls, and group 1 and the control of group 3 had significant differences in terms of goblet depletion. Based on tissue originated H2O2, we found significant differences between group 1 and its control and group 3, and also between groups 5 and the control of group 3. All the three groups were significantly different from their controls based on Ferric Reducing Ability of Plasma (FRAP) and such differences were also seen between group 1 with two other groups. Conclusion: Neutrophils may not be the only cause of oxidation process in colitis, and also makes the effectiveness of corticosteroids in the treatment of this disease doubtful. PMID:25337523

  2. Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Kuśnierz-Cabala, Beata; Konturek, Peter; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1β. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa. PMID:26798415

  3. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-01-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. PMID:27598133

  4. Relationship between Mast Cells and the Colitis with Relapse Induced by Trinitrobenzesulphonic Acid in Wistar Rats

    PubMed Central

    Luchini, Ana Carolina; Costa de Oliveira, Déborah Mara; Pellizzon, Cláudia Helena; Di Stasi, Luiz Claudio; Gomes, José Carlos

    2009-01-01

    The present study aimed to clarify the role of mast cells in colitis with relapse induced in Wistar rats by trinitrobenzenosulphonic acid. Colitis induction increased the histamine concentration in the colon, which peaked on day 26. The number of mast cells, probably immature, was ten times higher on day 8. Different from animals infected with intestinal parasites, after colitis remission, mast cells do not migrate to the spleen, showing that mast cell proliferation presents different characteristics depending on the inflammation stimuli. Treatment with sulfasalazine, doxantrazole, quercetin, or nedocromil did not increase the histamine concentration or the mast cell number in the colon on day 26, thereby showing absence of degranulation of these cells. In conclusion, although mast cell proliferation is associated with colitis, these cells and their mediators appear to play no clear role in the colitis with relapses. PMID:19436763

  5. Vitamin D treatment attenuates 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis but not oxazolone-induced colitis.

    PubMed

    Liu, Tianjing; Shi, Yongyan; Du, Jie; Ge, Xin; Teng, Xu; Liu, Lu; Wang, Enbo; Zhao, Qun

    2016-01-01

    Crohn's disease (CD) and ulcerative colitis (UC) have different immunological mechanisms, while both of them are potential targets of vitamin D treatment. In this study, we have tried to address the role of vitamin D in CD and UC using two mouse models. Mice of C57B6L were given vitamin D before the induction of colitis. Our results showed that vitamin D attenuated 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis but not oxazolone-induced colitis. Vitamin D could preserve the local histology, alleviate inflammation, suppress apoptosis, maintain tight junction function and decrease permeability. Interestingly, it has more of an effect on local structure preservation and inflammation inhibition in CD than in UC mice. Vitamin D blocked the increase of helper T-cell type 1 (Th1)- and helper T-cell type 17 (Th17)-related cytokines in TNBS-induced colitis. But the increase of helper T-cell type 2 (Th2)- and regulatory T cells (Treg)-related cytokines was augmented at the same time in oxazolone-induced colitis which counteracted each other. Our study helps elucidate the differential protective effects of vitamin D on CD and UC patients, as reported in literature. PMID:27620138

  6. Tauroursodeoxycholate improves 2,4,6-trinitrobenzenesulfonic acid-induced experimental acute ulcerative colitis in mice.

    PubMed

    Yang, Yang; He, Jiao; Suo, Yuan; Zheng, Zongwei; Wang, Jingjing; Lv, Le; Huo, Chuanchuan; Wang, Ziye; Li, Jing; Sun, Wenji; Zhang, Yongmin

    2016-07-01

    Ulcerative colitis is a chronic nonspecific inflammatory disease of unknown cause. The aim of this study was to evaluate the anti-inflammatory effect of tauroursodeoxycholate in 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in mice. After the induction of colitis for 24h, the mice were administrated orally with tauroursodeoxycholate (20, 40 and 60mg/kg) and sulfasalazine (500mg/kg) by gavage for 7 consecutive days. The inhibition effects were evaluated by the body of weight change, survival rate, macroscopical and histological evaluations. Besides, myeloperoxidase (MPO) activity, interleukin (IL)-1β, interferon (IFN)-γ and tumour necrosis factor-α (TNF-α) in colon tissue were also determined by enzyme-linked immunosorbent assay. Treatment with different doses of tauroursodeoxycholate (20, 40 and 60mg/kg) significantly improved the body weight change, decreased the macroscopic and histopathological scores. Compared with the model group, the accumulation of MPO activity, the colonic tissue levels of IL-1β, IFN-γ and TNF-α were significantly reduced in the tauroursodeoxycholate treated groups. Moreover, tauroursodeoxycholate assuaged the symptoms of colitis. These results suggested that tauroursodeoxycholate has an anti-inflammatory effect in TNBS-induced ulcerative colitis in mice. PMID:27179450

  7. Loss of n-6 fatty acid induced pediatric obesity protects against acute murine colitis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary influences may affect microbiome composition and host immune responses, thereby modulating propensity toward inflammatory bowel diseases: Crohn disease and ulcerative colitis. Dietary n-6 fatty acids have been associated with ulcetative colitis in prospective studies. However, the critical d...

  8. Effects of trimetazidine in ethanol- and acetic acid-induced colitis: oxidant/anti-oxidant status.

    PubMed

    Girgin; Karaoglu; Tüzün; Erkus; Ozütemiz; Dinçer; Batur; Tanyalçin

    1999-11-01

    There is overwhelming evidence in favour of a significant role of reactive oxygen metabolites (ROM) in the pathophysiology of inflammatory bowel disease (IBD) in man and in experimental animal models. This study was undertaken to investigate the possible protective effects of pretreatment with trimetazidine (TMZ) on the oxidant-anti-oxidant balance in ethanol- and acetic acid-induced colonic damage in rats. TMZ was chosen because of its various cytoprotective features (preserving cellular ATP levels, limiting intracellular acidosis and limiting inorganic phosphate, Na(+) and Ca(2+) accumulation) and anti-oxy characteristics which were previously reported. A total of 80 rats were randomized into eight major groups each consisting of 10 animals. Animals in groups 1, 2 and 3 served as models of ethanol-induced colitis (0.25 ml of 30% (v/v) ethanol), while group 4 served as their control. Animals in groups 5, 6 and 7 served as models of acetic acid-induced colitis (1 ml of 4% (v/v) acetic acid), while group 8 served as their control. TMZ was administered 5 mg/kg by intrarectal (i.r.) and intraperitoneal (i.p.) routes to groups 1, 2, 5 and 6. Intraperitoneal administration of TMZ was used in order to evaluate its systemic effect while i.r. administration was used to determine its local effect. After decapitation, colon mucosa samples were obtained and evaluated macroscopically and microscopically. Myeloperoxidase (MPO) activities as markers for inflammation, malondialdehyde (MDA) levels as markers for oxidant stress and reduced glutathione (GSH) and oxidized glutathione (GSSG) levels as markers for anti-oxidant status were determined. Acute colitis was observed in macroscopic and microscopic evaluation in ethanol- and acetic acid-administered groups compared with controls (P = 0.000). The macroscopic and microscopic scores in colitis groups were correlated with MPO activities (r = 0.5365, P = 0.000 and r = 0.5499, P = 0.000, respectively). MDA

  9. Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model

    PubMed Central

    2013-01-01

    Background Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. Methods Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. Results Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary

  10. Protective effect of taurohyodeoxycholic acid from Pulvis Fellis Suis on trinitrobenzene sulfonic acid induced ulcerative colitis in mice.

    PubMed

    He, Jiao; Liang, Jinru; Zhu, Sha; Zhao, Wenna; Zhang, Yongmin; Sun, Wenji

    2011-11-16

    Ulcerative colitis is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and up-regulation of pro-inflammatory cytokines. The aim of this study is to evaluate the effect of taurohyodeoxycholic acid (THDCA) isolated from Pulvis Fellis Suis on acute ulcerative colitis model induced by trinitrobenzene sulfonic acid (TNBS) in mice. The efficacy of THDCA was studied by macroscopical and histological scoring systems as well as myeloperoxidase (MPO) activity. Serum levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-6 were assayed by enzyme-linked immunoassay. The expression of cyclooxygenase (COX)-2 in the colons was assessed by immunohistochemical analysis. Treatment with THDCA in doses of 25, 50 and 100mg/kg/day and sulfasalazine in a dose of 500 mg/kg/day used as reference for 7 consecutive days after the induction of colitis, significantly decreased colonic MPO activity, TNF-α, IL-6 serum levels and the expression of COX-2 in colon compared with TNBS induced ulcerative colitis model group. Moreover, THDCA attenuated the macroscopic colonic damage and the histopathological changes induced by TNBS. All the effects of these parameters were comparable to that of the standard sulfasalazine, especially at the highest dose level. The results suggested that THDCA from Pulvis Fellis Suis has a protective effect in TNBS-induced ulcerative colitis which might be due to its anti-inflammatory activities, and that it may have therapeutic value in the setting of inflammatory bowel disease. PMID:21925164

  11. Effect of taurine on oxidative stress and apoptosis-related protein expression in trinitrobenzene sulphonic acid-induced colitis

    PubMed Central

    Giriş, M; Depboylu, B; Doğru-Abbasoğlu, S; Erbil, Y; Olgaç, V; Alış, H; Aykaç-Toker, G; Uysal, M

    2008-01-01

    Ulcerative colitis (UC) is a multi-factorial inflammatory disease of the colon and rectum. The present study was undertaken to investigate the effect of taurine, an anti-oxidant amino acid, on oxidative stress and the expression of apoptosis-related proteins, pro-apoptotic Bax and anti-apoptotic B cell lymphoma-2 (Bcl-2) in colon tissue in rats with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Rats received taurine (1·5% w/v) in drinking water for 15 days before and 15 days after administration of TNBS solution. Then, colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) and glutathione (GSH) levels, and Bax and Bcl-2 expression were measured. TNBS-induced colitis caused significantly increased MPO activity and MDA levels and decreased GSH levels in colon tissue compared to controls. Increase in Bax expression and decrease in Bcl-2 expression were detected in colon of rats with TNBS-induced colitis. Taurine treatment was associated with amelioration in macroscopic and microscopic colitis scores, decreased colonic MPO activity and MDA levels and increased GSH levels in TNBS-induced colitis. In addition, taurine reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of rats with TNBS-induced colitis. The results of this study show that taurine administration may exert beneficial effects in UC by decreasing inflammatory reactions, oxidative stress and apoptosis. PMID:18241224

  12. Healing Effect of Pistacia Atlantica Fruit Oil Extract in Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Tanideh, Nader; Masoumi, Samira; Hosseinzadeh, Massood; Safarpour, Ali Reza; Erjaee, Hoda; Koohi-Hosseinabadi, Omid; Rahimikazerooni, Salar

    2014-01-01

    Background: Considering the anti-oxidant properties of Pistacia atlantica and lack of data regarding its efficacy in the treatment of ulcerative colitis, this study aims at investigating the effect of the Pistacia atlantica fruit extract in treating experimentally induced colitis in a rat model. Methods: Seventy male Sprague-Dawley rats (weighing 220±20 g) were used. All rats fasted 24 hours before the experimental procedure. The rats were randomly divided into 7 groups, each containing 10 induced colitis with 2ml acetic acid (3%). Group 1 (Asacol), group 2 (base gel) and group 7 (without treatment) were assigned as control groups. Group 3 (300 mg/ml) and group 4 (600 mg/ml) received Pistacia atlantica fruit orally. Group 5 (10% gel) and group 6 (20% gel) received Pistacia atlantica in the form of gel as enema. Macroscopic, histopathological examination and MDA measurement were carried out. Results: All groups revealed significant macroscopic healing in comparison with group 7 (P<0.001). Regarding microscopic findings in the treatment groups compared with group 7, the latter group differed significantly with groups 1, 2, 4 and 6 (P<0.001). There was a significant statistical difference in MDA scores of the seven treatment groups (F(5,54)=76.61, P<0.001). Post-hoc comparisons indicated that the mean±SD score of Asacol treated group (1.57±0.045) was not significantly different from groups 4 (1.62±0.024) and 6 (1.58±0.028). Conclusion: Our study showed that a high dose of Pistacia atlantica fruit oil extract, administered orally and rectally can improve colitis physiologically and pathologically in a rat model, and may be efficient for ulcerative colitis. PMID:25429174

  13. Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in BALB/c mice

    PubMed Central

    Pandurangan, Ashok Kumar; Mohebali, Nooshin; Norhaizan, Mohd Esa; Looi, Chung Yeng

    2015-01-01

    Gallic acid (GA) is a polyhydroxy phenolic compound that has been detected in various natural products, such as green tea, strawberries, grapes, bananas, and many other fruits. In inflammatory bowel disease, inflammation is promoted by oxidative stress. GA is a strong antioxidant; thus, we evaluated the cytoprotective and anti-inflammatory role of GA in a dextran sulfate sodium (DSS)-induced mouse colitis model. Experimental acute colitis was induced in male BALB/c mice by administering 2.5% DSS in the drinking water for 7 days. The disease activity index; colon weight/length ratio; histopathological analysis; mRNA expressions of IL-21 and IL-23; and protein expression of nuclear erythroid 2-related factor 2 (Nrf2) were compared between the control and experimental mice. The colonic content of malondialdehyde and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity were examined as parameters of the redox state. We determined that GA significantly attenuated the disease activity index and colon shortening, and reduced the histopathological evidence of injury. GA also significantly (P<0.05) reduced the expressions of IL-21 and IL-23. Furthermore, GA activates/upregulates the expression of Nrf2 and its downstream targets, including UDP-GT and NQO1, in DSS-induced mice. The findings of this study demonstrate the protective effect of GA on experimental colitis, which is probably due to an antioxidant nature of GA. PMID:26251571

  14. Dual Role of Endogenous Serotonin in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis

    PubMed Central

    Rapalli, Alberto; Bertoni, Simona; Arcaro, Valentina; Saccani, Francesca; Grandi, Andrea; Vivo, Valentina; Cantoni, Anna M.; Barocelli, Elisabetta

    2016-01-01

    Background and Aims: Changes in gut serotonin (5-HT) content have been described in Inflammatory Bowel Disease (IBD) and in different experimental models of colitis: the critical role of this monoamine in the pathogenesis of chronic gastrointestinal inflammation is gradually emerging. Aim of the present study was to evaluate the contribution of endogenous 5-HT through the activation of its specific receptor subtypes to the local and systemic inflammatory responses in an experimental model of IBD. Materials and Methods: Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT1A (WAY100135), 5-HT2A (Ketanserin), 5-HT3 (Ondansetron), 5-HT4 (GR125487), 5-HT7 (SB269970) receptors and with 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino)tetralin. Results: Blockade of 5-HT1A receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT1A agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT2A receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT3, 5-HT4, and 5-HT7 receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it. Conclusion: The prevailing deleterious contribution given by endogenous 5-HT to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT2A and, to a lesser extent, by 5-HT4 receptors and coexists with the weak beneficial effect elicited by 5-HT1A stimulation. These findings suggest how only a selective interference with 5-HT pro-inflammatory actions may represent an additional potential therapeutic option for intestinal inflammatory disorders. PMID:27047383

  15. Protective effect of royal jelly in 2,4,6 trinitrobenzene sulfonic acid-induced colitis in rats

    PubMed Central

    Karaca, Turan; Uz, Yesim Hulya; Demirtas, Selim; Karaboga, Ihsan; Can, Guray

    2015-01-01

    Objective(s): In the present study, we evaluated immunological and immunomodulatory properties of royal jelly (RJ) in 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Materials and Methods: Eighteen adult female Wistar albino rats were divided into three groups of six animals each: a control group that received only saline solution, a TNBS-induced colitis group, and a TNBS-colitis+RJ group that received 250 mg/kg/day of RJ for seven days before the induction of colitis, following by the same treatment for an additional seven days. At the end of the experiment, cardiac blood and colon samples were obtained under deep anaesthesia from the animals in all groups. Serum interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α) and IL-10 levels were analyzed with an enzyme-linked immunosorbent assay (ELISA). Five-micrometre-thick sections were stained with haematoxylin-eosin (H&E) for microscopic evaluations. For immunohistochemical evaluations, the paraffin sections were stained with anti-CD3 (cluster of differentiation), anti-CD5, anti-CD8 and anti-CD45. Results: The results showed that the oral RJ treatment inhibited proinflammatory cytokines, IL-1β and TNF-α secretion, while increasing anti-inflammatory cytokine IL-10 production in the TNBS-induced colitis+RJ group compared with the colitis group not treated with RJ. The colitis was not as severe in the colitis+RJ group, with ulcerative damage, weight loss and inflammatory scores suggesting that impaired CD3-, CD5-, CD8- and CD45-positive T cell immune responses likely mediated the anti-inflammatory effect. Conclusion: The antioxidant and anti-inflammatory properties of RJ protected colon mucosa against TNBS-induced colitis in rats orally treated with RJ. PMID:26019800

  16. Protective effect of Dillenia indica L. on acetic acid induced colitis in mice.

    PubMed

    Somani, S J; Badgujar, L B; Sutariya, B K; Saraf, M N

    2014-09-01

    The inflammatory bowel disease (IBD) is an idiopathic, immune mediated and chronic inflammation of the intestine. The study aimed to elucidate the ameliorative effect of methanolic extract of Dillenia indica (DIME), hexane fraction (HFDI) and chloroform fraction (CFDI) of Dillenia indica in acetic acid induced experimental colitis in mice. Macroscopic score, colon weight, colonic catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor (TNF-alpha), and histological changes were recorded after the treatment regimen of 7 days. Intra-rectal instillation of acetic acid caused enhanced macroscopic score, colon weight, colonic MPO, MDA, and TNF-alpha level. It caused significant decreased level of CAT, SOD and GSH. DIME (800 mg/kg), HFDI (200 mg/kg) and CFDI (200 mg/kg) treatment exhibited significant effect in lowering macroscopic score, colon weight, MPO, MDA, TNF-alpha levels and elevation of CAT, GSH and SOD levels. The results suggest that D. indica has ameliorating effects on experimental colitis by inhibiting the proinflammatory mediators like TNF-alpha production. PMID:25241587

  17. Pretreatment of Gymnema sylvestre revealed the protection against acetic acid-induced ulcerative colitis in rats

    PubMed Central

    2014-01-01

    Background Overproduction of free radicals and decreased antioxidant capacity are well-known risk factors for inflammatory bowel diseases. Gymnema sylvestre (GS) leaves extract is distinguished for its anti-diabetic, antioxidant and anti-inflammatory properties. Present study is designed to evaluate the preventative activities of GS against acetic acid (AA)-induced ulcerative colitis in Wistar rats. Methods Experimentally ulcerative colitis (UC) was induced by AA in animals pretreated with three different doses of GS leaves extract (50, 100, 200 mg/kg/day) and a single dose of mesalazine (MES, 300 mg/kg/day) for seven days. Twenty four hours later, animals were sacrificed and the colonic tissues were collected. Colonic mucus content was determined using Alcian blue dye binding technique. Levels of thiobarbituric acid reactive substances (TBARS), total glutathione sulfhydryl group (T-GSH) and non-protein sulfhydryl group (NPSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were estimated in colon tissues. Colonic nucleic acids (DNA and RNA) and total protein (TP) concentrations were also determined. Levels of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in colonic tissues. The histopathological changes of the colonic tissues were also observed. Results In AA administered group TBARS levels were increased, while colonic mucus content, T-GSH and NP-SH, SOD and CAT were reduced in colon. Pretreatment with GS inhibited TBARS elevation as well as mucus content, T-GSH and NP-SH reduction. Enzymatic activities of SOD and CAT were brought back to their normal levels in GS pretreated group. A significant reduction in DNA, RNA and TP levels was seen following AA administration and this inhibition was significantly eliminated by GS treatment. GS pretreatment also inhibited

  18. Protective Effect of the Methanolic Extract of Malva parviflora L. leaves on Acetic Acid-induced Ulcerative Colitis in Rats

    PubMed Central

    Dugani, Aisha; Dakhil, Bushra; Treesh, Soad

    2016-01-01

    Background/Aims: Inflammatory bowel disease (IBD) is a general term describing chronic, idiopathic relapsing, inflammatory conditions of the gastrointestinal tract of unknown etiology. Previous studies have indicated that Malva parviflora leaf extract possesses anti-inflammatory, antioxidant, and antiulcerogenic activity. activity. This work aimed to investigatee the anti-inflammatory effect of the methanolic (MEMP) and aqueous (AEMP) extracts of M. parviflora leaves on acetic acid-induced colitis in rats. Materials and Methods: 42 male Wistar albino rats were divided into seven groups (n = 6). Group I: Normal saline control group with no colitis; Group II: Acetic acid colitis group; Group III: 100 mg/kg/5 d MEMP; Group IV: 200 mg/kg/5 d.MEMP; Group V: 100 mg/kg/5 d AEMP; Group VI: 200 mg/kg/5 d AEMP; Group VII: Prednisolone group (2 mg/kg/5 d). Treatments were followed by induction of colitis using intrarectal instillation of 2 mL of 4% acetic acid. Colon damage was evaluated macroscopically (spleen weight/body weight, colon weight/length ratio) and the histological changes were also recorded. Results: The results of this study showed that acetic acid caused severe inflammation of the colon and a significant increase in spleen weight/body weight, and an increase in colon weight/length ratio compared with normal control group. Pretreatment with MEMP and AEMP for 5 days followed by induction of colitis resulted in a significant attenuation of spleen weight and colon weight/length ratio compared with acetic acid control group. Methanolic extract provided better anticolitic effect than aqueous extract; the effect was prominent at the dose of 200 mg/kg. Histopathological findings confirmed the protective effect of the MEMP. Conclusion: In conclusion, MEMP could ameliorate mucosal damage in experimentally induced colitis when given orally. PMID:27184642

  19. Effect of royal jelly on experimental colitis induced by acetic acid and alteration of mast cell distribution in the colon of rats

    PubMed Central

    Karaca, T.; Bayiroglu, F.; Yoruk, M.; Kaya, M.S.; Uslu, S.; Comba, B.; Mis, L.

    2010-01-01

    This study investigated the effects of royal jelly (RJ) on acetic acid-induced colitis in rats. Twenty adult female Wistar albino rats were divided into four treatment groups of 5 animals each, including a control group (Group I); Group II was treated orally with RJ (150 mg kg−1 body weight); Group III had acetic acid-induced colitis; and Group IV had acetic acid-induced colitis treated orally with RJ (150 mg kg−1 body weight) for 4 weeks. Colitis was induced by intracolonic instillation of 4% acetic acid; the control group received physiological saline (10 mL kg−1). Colon samples were obtained under deep anaesthesia from animals in all groups. Tissues were fixed in 10% formalin neutral buffer solution for 24 h and embedded in paraffin. Six-micrometre-thick sections were stained with Mallory’s triple stain and toluidine blue in 1% aqueous solution at pH 1.0 for 5 min (for Mast Cells). RJ was shown to protect the colonic mucosa against the injurious effect of acetic acid. Colitis (colonic damage) was confirmed histomorphometrically as significant increases in the number of mast cells (MC) and colonic erosions in rats with acetic acid-induced colitis. The RJ treatment significantly decreased the number of MC and reduced the area of colonic erosion in the colon of RJ-treated rats compared with rats with untreated colitis. The results suggest that oral treatment with RJ could be used to treat colitis. PMID:21263740

  20. Melatonin reduces bacterial translocation and apoptosis in trinitrobenzene sulphonic acid-induced colitis of rats

    PubMed Central

    Akcan, Alper; Kucuk, Can; Sozuer, Erdogan; Esel, Duygu; Akyildiz, Hizir; Akgun, Hulya; Muhtaroglu, Sabahattin; Aritas, Yucel

    2008-01-01

    AIM: To investigate the effects of exogenous melatonin on bacterial translocation and apoptosis in a rat ulcerative colitis model. METHODS: Rats were randomly assigned to three groups: groupI: control, group II: experimental colitis, group III: colitis plus melatonin treatment. On d 11 after colitis, plasma tumor necrosis factor-α, portal blood endotoxin levels, colon tissue myeloperoxidase and caspase-3 activity were measured. Bacterial translocation was quantified by blood, lymph node, liver and spleen culture. RESULTS: We observed a significantly reduced incidence of bacterial translocation to the liver, spleen, mesenteric lymph nodes, portal and systemic blood in animals treated with melatonin. Treatment with melatonin significantly decreased the caspase-3 activity in colonic tissues compared to that in trinitrobenzene sulphonic acid- treated rats (16.11 ± 2.46 vs 32.97 ± 3.91, P < 0.01). CONCLUSION: Melatonin has a protective effect on bacterial translocation and apoptosis. PMID:18240350

  1. Effect of marine mangrove Avicennia marina (Forssk.) Vierh against acetic acid-induced ulcerative colitis in experimental mice.

    PubMed

    Rise, C L Victoria; Prabhu, V Vinod; Guruvayoorappan, Chandrasekharan

    2012-01-01

    Ulcerative colitis and Crohn's disease are two conditions that have many features in common and are referred as inflammatory bowel disease (IBD). Patients with IBD are predisposed to colorectal cancer. This investigation evaluates the effect of marine mangrove Avicennia marina against acetic acid-induced colitis. The treatment of A marina extract significantly decreased the colonic lipid peroxides, glutathione peroxidase, and serum nitric oxide and significantly increased the colonic and erythrocyte superoxide dismutase and glutathione levels compared with colitis control. In addition, A marina extract significantly decreased the lesion score and wet colon weight compared with colitis control. Treatment with A marina extract reflects its therapeutic activity against UC by minimal damage of colonic epithelial cells compared with colitis control during histopathologic examination. These protective role of A marina extract against UC could be attributed to the presence of higher levels of decanoic acid, diethylhydroxylamine (DEHA), pentanoic acid, pyrrolidine, 4-chlorophenyl, thiazolidinones, and arabinopyranoside (flavonoid). These findings suggest that A marina extract could be useful as a potential (natural) therapeutic agent for IBD. PMID:23216642

  2. Myrrh attenuates oxidative and inflammatory processes in acetic acid-induced ulcerative colitis

    PubMed Central

    Fatani, Amal Jamil; Alrojayee, Fatima Salih; Parmar, Mihir Yogeshkumar; Abuohashish, Hatem Mustafa; Ahmed, Mohammed Mahboobuddin; Al-Rejaie, Salim Salih

    2016-01-01

    The pathogenesis of ulcerative colitis (UC) has been associated with a weakened antioxidant capacity and increased inflammatory processes. Myrrh is traditionally used for the treatment of inflammatory diseases due to its antioxidant and anti-inflammatory properties. The present study aimed to evaluate the effects of myrrh on an experimental rat model of UC. UC was induced in rats using acetic acid (AA) after pre-treatment with myrrh (125, 250 or 500 mg/kg/day) or mesalazine (MES; 300 mg/kg/day) for 7 days. The levels of various inflammatory cytokines, prostaglandin E2 (PGE2) and nitric oxide (NO) in the rat colon tissues were assessed. In addition, the colonic levels of thiobarbituric acid reactive substances (TBARS) and non-protein sulfhydryl groups (NP-SH), as well as the activities of superoxide dismutase (SOD) and catalase (CAT), were estimated. Furthermore, total protein (TP) contents and the levels of DNA and RNA were measured, and histopathological changes in colonic tissues were analyzed. The results indicated that the levels of pro-inflammatory cytokines, PGE2, NO and TBARS were markedly increased. By contrast, the levels of interleukin-10, NP-SH, TP and nucleic acids, and the enzymatic activities of SOD and CAT were significantly decreased in the AA model group. In addition, pretreatment with myrrh and MES was able to attenuate the impaired oxidative stress response and upregulation of inflammatory biomarkers. Furthermore, the enzymatic activities of SOD and CAT were near to normal in the myrrh and MES pretreated groups. The ability of myrrh to protect against UC was further confirmed by histopathological analysis, and the high dose of myrrh exerted an effect comparable to MES. In conclusion, the results of the present study suggested that myrrh has potent therapeutic value in the amelioration of experimental colitis in laboratory animals by downregulating the expression of proinflammatory mediators and improving endogenous antioxidative activities. PMID

  3. Effect of ethanolic extract of leaves of Paederia foetida Linn. on acetic acid induced colitis in albino rats

    PubMed Central

    Das, Swarnamoni; Kanodia, Lalit; Mukherjee, Apurba; Hakim, Abdul

    2013-01-01

    Objectives: To evaluate the effect of ethanolic extract of leaves of Paederia foetida on acetic acid induced colitis in albino rats. Materials and Methods: Ethanolic extract of Paederia foetida (EEPF) was prepared by percolation method. Acute toxicity test was done by using Organization for Economic Cooperation and Development guidelines. Albino rats were divided into four groups of five animals each. Groups A and B received 3% gum acacia. Groups C and D received EEPF 500 mg/kg body weight (BW) and 5-aminosalisylic acid 100 mg/kg BW respectively. Colitis was induced by transrectal administration of 4% acetic acid on 5th day. All animals were sacrificed after 48 h of colitis induction and distal 10 cm of the colon was dissected. Colon was weighed for disease activity index (DAI) and scored macroscopically and microscopically. Biochemical assessment of tissue myeloperoxidase (MPO), catalase (CAT) and superoxide dismutase (SOD) was done in colonic tissue homogenate and malondialdehyde (MDA) was estimated in serum. Results: P. foetida showed significant (P < 0.05) reduction in DAI, macroscopic and microscopic lesion score as well as significant (P < 0.05) improvement in MPO, MDA, CAT, and SOD level as compared to Group B. Conclusions: The ethanolic extract of leaves of P. foetida showed significant amelioration of experimentally induced colitis, which may be attributed to its anti-inflammatory and antioxidant property. PMID:24130378

  4. Protective effect of Bauhinia tomentosa on acetic acid induced ulcerative colitis by regulating antioxidant and inflammatory mediators.

    PubMed

    Kannan, Narayanan; Guruvayoorappan, Chandrasekharan

    2013-05-01

    Inflammatory bowel diseases (IBD), including Crohn's disease and Ulcerative colitis (UC), are life-long and recurrent disorders of the gastrointestinal tract with unknown etiology. The present study is designed to evaluate the ameliorative effect of Bauhinia tomentosa during ulcerative colitis (UC). Three groups of animals (n=6) were treated with B. tomentosa (5, 10, 20 mg/kg B.wt respectively) for 5 consecutive days before induction of UC. UC was induced by intracolonic injection of 3% acetic acid. The colonic mucosal injury was assessed by macroscopic scoring and histological examination. Furthermore, the mucosal content of lipid peroxidation (LPO), reduced glutathione (GSH), nitric oxide (NO), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity confirms that B. tomentosa could significantly inhibit colitis in a dose dependent manner. The myeloperoxidase (MPO), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS) expression studies and lactate dehydrogenase (LDH) assay also supported that B. tomentosa could significantly inhibit experimental colitis. The effect was comparable to the standard drug sulfasalazine. Colonic mucosal injury parallels with the result of histological and biochemical evaluations. The extracts obtained from B. tomentosa possess active substances, which exert marked protective effects in acute experimental colitis, possibly by regulating the antioxidant and inflammatory mediators. PMID:23538025

  5. Evaluation of anti-colitic effect of fluvoxamine against acetic acid-induced colitis in normal and reserpinized depressed rats.

    PubMed

    Minaiyan, Mohsen; Hajhashemi, Valiollah; Rabbani, Mohammad; Fattahian, Ehsan; Mahzouni, Parvin

    2015-01-01

    High prevalence of psychological comorbidities such as depression and anxiety in patients with inflammatory bowel disease (IBD) supports the premise that adding an anti-depressant drug with known anti-inflammatory effect to the medical treatment have beneficial effect in the course of the underlying disease. Colitis was induced by intracolonic instillation of 2 ml of 4% v/v acetic acid solution in rats. Anti-colitic effect of fluvoxamine was evaluated in two categories: A: normal rats, B: reserpinized (6 mg/kg, i.p.) depressed rats. In group A, fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after induction of colitis and in group B: reserpine (6 mg/kg, i.p.) was administered 1 h prior to colitis induction and then fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after colitis induction. Dexamethasone (1 mg/kg) was used as reference drug. All the treatments continued daily for five days. The effect was assessed on the basis of macroscopic score, biochemical (myeloperoxidase) changes and histopathological studies. Results showed that fluvoxamine (2.5 and 5 mg/kg) and dexamethasone treatment markedly reduced disease severity in both reserpinized and non-reserpinized rats as indicated by reduction in macroscopic and microscopic colonic damages while reserpine adversely exacerbated the colitis damage. Myeloperoxidase activity which was increased following colitis induction was also decreased. The findings of this study elucidate the anti-colitic and anti-inflammatory properties of fluvoxamine and so introduced it as a good candidate to treat depressive symptoms in people comorbid to IBD. PMID:25460023

  6. Protective effect of marine mangrove Rhizophora apiculata on acetic acid induced experimental colitis by regulating anti-oxidant enzymes, inflammatory mediators and nuclear factor-kappa B subunits.

    PubMed

    V, Vinod Prabhu; C, Guruvayoorappan

    2014-01-01

    Ulcerative colitis is a disease that causes inflammation and ulcer in the lining of the large intestine. In this study we investigate the effect of Rhizophora apiculata (R. apiculata) on acetic acid induced colitis in mouse model. Experimental animals were randomized into four groups: normal untreated, colitis control, R. apiculata treated group and sulfasalazine treated group. R. apiculata significantly (p<0.01) decreased macroscopic score and wet weight of damaged colon compared to colitis control. This effect was confirmed biochemically by significant (p<0.01) reduction of colitis associated increase in myeloperoxidase activity. R. apiculata significantly (p<0.05) increased anti-oxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH) levels compared to colitis control. R. apiculata significantly (p<0.01) reduced lipid peroxides (LPO), nitric oxide (NO) and inflammatory mediators such as myeloperoxidase (MPO), lactate dehydrogenase (LDH), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expressions compared to colitis control. R. apiculata treatment significantly (p<0.01) inhibits the translocation of NF-kB p65 and p50 subunits. Taken together these findings suggest that R. apiculata prevents acetic acid induced colitis in experimental mouse model and may serve as an excellent anti-oxidant and anti-inflammatory agent that could potentially be useful as a (natural) therapy for inflammatory bowel disease (IBD). PMID:24269623

  7. Anti-inflammatory effect of Helichrysum oligocephalum DC extract on acetic acidInduced acute colitis in rats

    PubMed Central

    Minaiyan, Mohsen; Ghassemi-Dehkordi, Nasrollah; Mahzouni, Parvin; Ahmadi, Najme-Sadat

    2014-01-01

    Background: Helichrysum oligocephalum DC. from Asteraceae family is an endemic plant growing wild in Iran. This study was carried out to investigate the effect of H. oligocephalum hydroalcoholic extract (HOHE) on ulcerative colitis (UC) induced by acetic acid (AA) in rats. Materials and Methods: Rats were grouped (n = 6) and fasted for 24 h before colitis induction. Treatments were started 2 h before the induction of colitis and continued for two consecutive days with different doses of HOHE (100, 200, and 400 mg/kg) orally (p.o.) and intraperitoneally (i.p.). The colon tissue was removed and tissue damages were scored after macroscopic and histopathologic assessments. Results: Among the examined doses of HOHE, 100 mg/kg was the most effective dose that reduced the extent of UC lesions and resulted in significant alleviation. Weight/length ratio as an index of tissue inflammation and extravasation was also diminished in the treatment group administered HOHE at a dose of 100 mg/kg, and the results showed correlation with macroscopic and histopathologic evaluations. These data suggest that HOHE (100 mg/kg) administered either p.o. or i.p. was effective in diminishing inflammation and ulcer indices in this murine model of acute colitis in a non–dose-related manner. Conclusions: H. oligocephalum could be considered as a suitable anticolitis alternative; however, further studies are needed to support this hypothesis for clinical setting. PMID:24761395

  8. Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid- induced acute colitis in rats

    PubMed Central

    Heidari, Bahareh; Sajjadi, Seyed Ebrahim; Minaiyan, Mohsen

    2016-01-01

    Objective: The aim of this study was to determine the protective effects of Coriandrum sativum on acetic acid-inducedcolitis in rats. C. sativum (Coriander) has long been used in Iranian traditional medicine and its use as an anti-inflammatory agent is still common in some herbal formulations. Materials and Methods: Colitis was induced by intra-rectal administration of 2ml acetic acid 4% in fasted male Wistar rats. Treatment was carried out using three increasing doses of extract (250, 500, 1000 mg/kg) and essential oil (0.25, 0.5, 1 ml/kg) of coriander started 2 h before colitis induction and continued for a five-day period. Colon biopsies were taken for weighting, macroscopic scoring of injured tissue, histopathological examination and measuring myeloperoxidase (MPO) activity. Results: Colon weight was decreased in the groups treated with extract (500 and 1000 mg/kg) and essential oil (0.5 ml/kg) compared to the control group. Regarding MPO levels, ulcer severity and area as well as the total colitis index, same results indicating meaningful alleviation of colitis was achieved after treatment with oral extract and essential oil. Conclusion: Since the present experiment was made by oral fractions of coriander thus the resulting effects could be due to both the absorption of the active ingredients and/or the effect of non-absorbable materials on colitis after reaching the colon. In this regard, we propose more toxicological and clinical experiments to warranty its beneficial application in human inflammatory bowel diseases. PMID:27222834

  9. Anti-inflammatory effect of Moringa oleifera Lam. seeds on acetic acid-induced acute colitis in rats

    PubMed Central

    Minaiyan, Mohsen; Asghari, Gholamreza; Taheri, Diana; Saeidi, Mozhgan; Nasr-Esfahani, Salar

    2014-01-01

    Objective: Anti-inflammatory, immuno-modulatory, and antioxidant properties of Moringa oleifera Lam. suggest that it might have beneficial effects on colitis. The present study was performed to investigate the anticolitis effect of Moringa oleifera seeds hydro-alcoholic extract (MSHE) and its chloroform fraction (MCF) on acetic acid-induced colitis in rats. Materials and Methods: Both MSHE and MCF with three increasing doses (50, 100, and 200 mg/kg) were administered orally to separate groups of male Wistar rats, 2 h before ulcer induction (using acetic acid 4%) and continued for 5 days. Prednisolone (4 mg/kg) and normal saline (1 ml/kg) were used in reference and control groups, respectively. All rats were sacrificed 24 h after the last dose (at day 6) and tissue injuries were assessed macroscopically and pathologically. Results: Extracts with three doses mentioned before were effective to reduce weight of distal colon (8 cm) as a marker for inflammation and tissue edema. Three doses of MSHE and two greater doses of MCF (100 and 200 mg/kg) were effective to reduce ulcer severity, area, and index as well as mucosal inflammation severity and extent, crypt damage, invasion involvement, total colitis index, and MPO activity compared with controls. MCF (50 mg/kg) was not significantly effective in reducing evaluated parameters of colitis compared with controls. Conclusion: It is concluded that MSHE and MCF were both effective to treat experimental colitis and this might be attributed to their similar major components, biophenols and flavonoids. Since the efficacy was evident even in low doses of MSHE, presence of active constituents with high potency in seeds is persuasive. PMID:25050310

  10. Healing Acceleration of Acetic Acid-induced Colitis by Marigold (Calendula officinalis) in Male Rats

    PubMed Central

    Tanideh, Nader; Jamshidzadeh, Akram; Sepehrimanesh, Masood; Hosseinzadeh, Masood; Koohi-Hosseinabadi, Omid; Najibi, Asma; Raam, Mozhdeh; Daneshi, Sajad; Asadi-Yousefabad, Seyedeh-Leili

    2016-01-01

    Background/Aim: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Materials and Methods: Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. Results: A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Conclusion: Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats. PMID:26831607

  11. Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: studies on inflammation, oxidative stress, DNA damage and fibrosis.

    PubMed

    Trivedi, P P; Jena, G B

    2013-09-01

    Ulcerative colitis affects many people worldwide. Inflammation and oxidative stress play a vital role in its pathogenesis. Previously, we reported that ulcerative colitis leads to systemic genotoxicity in mice. The present study was aimed at elucidating the role of α-lipoic acid in ulcerative colitis-associated local and systemic damage in mice. Experimental colitis was induced using 3%w/v dextran sulfate sodium in drinking water for 2 cycles. α-Lipoic acid was administered in a co-treatment (20, 40, 80 mg/kg bw) and post-treatment (80 mg/kg bw) schedule. Various biochemical parameters, histological evaluation, comet and micronucleus assays, immunohistochemistry and western blot analysis were employed to evaluate the effect of α-lipoic acid in mice with ulcerative colitis. The protective effect of α-lipoic acid was mediated through the modulation of nuclear factor kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, NADPH: quinone oxidoreductase-1, matrix metalloproteinase-9 and connective tissue growth factor. Further, ulcerative colitis led to an increased gut permeability, plasma lipopolysaccharide level, systemic inflammation and genotoxicity in mice, which was reduced with α-lipoic acid treatment. The present study identifies the underlying mechanisms involved in α-lipoic acid-mediated protection against ulcerative colitis and the associated systemic damage in mice. PMID:23793040

  12. Beneficial effect of trimebutine and N-monodesmethyl trimebutine on trinitrobenzene sulfonic acid-induced colitis in rats.

    PubMed

    Chevalier, Eric; Pétoux, Francine; Chovet, Maria; Langlois, Annik

    2004-12-01

    The use of local anesthetics, such as lidocaine, has been proposed in the treatment of distal ulcerative colitis. Trimebutine maleate (TMB) displays a local anesthetic activity higher than that of lidocaine in rabbit corneal reflex. TMB and nor-TMB its main metabolite in human show similar affinity to that of bupivacaine toward sodium channel labeled by [3H]batrachotoxin and block sodium currents in sensory neurons from rat dorsal root ganglia. The aim of this study was to evaluate the effects of TMB and nor-TMB in comparison to lidocaine and bupivacaine in a rat model of acute colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS). A single intracolonic instillation of TNBS (50 mg/kg dissolved in ethanol 30%) led to early plasma extravasation then macroscopic damage (hyperemia and necrosis), increased colonic weight and tissular MPO, a marker of neutrophilic infiltration. Local administration of TMB at dose of 3 to 60 mg/kg, 30 min before, 24 and 48 h after colitis induction, significantly reduced the severity of colitis. Nor-TMB (1, 3, 10, 30 mg/kg) as well as lidocaine (1, 3, 10 mg/kg) dose-dependently reduced colitis while bupivacaine at 10 mg/kg did not affect it significantly. In contrast systemic administration of TMB, nor-TMB and lidocaine at 10 mg/kg had no significant effect. Furthermore, local administration of TMB (30 mg/kg) and lidocaine (10 mg/kg) significantly reduced plasmatic extravasation. In conclusion, intracolonic treatment with TMB and nor-TMB improved acute experimental TNBS-induced colitis in rat and these effects could be explained by their local anesthetic activity. PMID:15531383

  13. Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester, a polymeric colon-specific prodrug releasing 5-aminosalicylic acid and benzocaine, ameliorates TNBS-induced rat colitis.

    PubMed

    Nam, Joon; Kim, Wooseong; Lee, Sunyoung; Jeong, Seongkeun; Yoo, Jin-Wook; Kim, Min-Soo; Jung, Yunjin

    2016-06-01

    Local anesthetics have beneficial effects on colitis. Dextran-5-(4-ethoxycarbonylphenylazo)salicylic acid ester (Dex-5-ESA), designed as a polymeric colon-specific prodrug liberating 5-ASA and benzocaine in the large intestine, was prepared and its therapeutic activity against colitis was evaluated using a TNBS-induced rat colitis model. Dex-5-ESA liberated 5-ASA and benzocaine in the cecal contents while (bio)chemically stable in the small intestinal contents and mucosa. Oral administration of Dex-5-ESA (equivalent to 10 mg 5-ASA/kg, twice a day) alleviated colonic injury and reduced MPO activity in the inflamed colon. In parallel, pro-inflammatory mediators, COX-2, iNOS and CINC-3, elevated by TNBS-induced colitis, were substantially diminished in the inflamed colon. Dex-5-ESA was much more effective for the treatment of colitis than 5-(4-ethoxycarbonylphenylazo)salicylic acid (5-ESA) that may not deliver benzocaine to the large intestine. Our data suggest that Dex-5-ESA is a polymeric colon-specific prodrug, liberating 5-ASA and benzocaine in the target site (large intestine), probably exerting anti-colitic effects by combined action of 5-ASA and benzocaine. PMID:26377354

  14. Anti-inflammatory effects of nesfatin-1 in rats with acetic acid - induced colitis and underlying mechanisms.

    PubMed

    Ozturk, C C; Oktay, S; Yuksel, M; Akakin, D; Yarat, A; Kasimay Cakir, O

    2015-10-01

    Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and

  15. Ascorbic acid ameliorates oxidative stress and inflammation in dextran sulfate sodium-induced ulcerative colitis in mice.

    PubMed

    Yan, Haiyan; Wang, Hongjuan; Zhang, Xiaoli; Li, Xiaoqin; Yu, Jing

    2015-01-01

    Ascorbic acid (AA) has been shown to exert beneficial effects, including mitigating oxidative stress and inhibiting inflammation. However, the preventative effect of vitamin C in chronic inflammatory diseases such as inflammatory bowel disease (IBD) remains unclear. In our study, we investigated the anti-inflammatory effects of AA and possible mechanism involved in inhibiting dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Male C57BL/6 mice were randomly divided to three groups: control group, DSS group, and DSS plus ascorbic acid treated group. Several clinical and inflammatory parameters as well as oxidative stress were evaluated. The results demonstrated that ascorbic acid significantly reduced clinical signs, inflammatory cytokines, myeloperoxidase (MPO) and malonaldehyde (MDA) activities, whereas the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were increased in DSS-induced mice. In addition, ascorbic acid was capable of inhibiting NF-κB, COX-2 and iNOS expression in the colonic. Taken together, these findings suggest that ascorbic acid contributes to the reduction of oxidative stress and inflammatory response in DSS-induced colitis and exerts the potential to prevent and clinical treatment of inflammatory bowel disease. PMID:26884937

  16. Ascorbic acid ameliorates oxidative stress and inflammation in dextran sulfate sodium-induced ulcerative colitis in mice

    PubMed Central

    Yan, Haiyan; Wang, Hongjuan; Zhang, Xiaoli; Li, Xiaoqin; Yu, Jing

    2015-01-01

    Ascorbic acid (AA) has been shown to exert beneficial effects, including mitigating oxidative stress and inhibiting inflammation. However, the preventative effect of vitamin C in chronic inflammatory diseases such as inflammatory bowel disease (IBD) remains unclear. In our study, we investigated the anti-inflammatory effects of AA and possible mechanism involved in inhibiting dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Male C57BL/6 mice were randomly divided to three groups: control group, DSS group, and DSS plus ascorbic acid treated group. Several clinical and inflammatory parameters as well as oxidative stress were evaluated. The results demonstrated that ascorbic acid significantly reduced clinical signs, inflammatory cytokines, myeloperoxidase (MPO) and malonaldehyde (MDA) activities, whereas the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were increased in DSS-induced mice. In addition, ascorbic acid was capable of inhibiting NF-κB, COX-2 and iNOS expression in the colonic. Taken together, these findings suggest that ascorbic acid contributes to the reduction of oxidative stress and inflammatory response in DSS-induced colitis and exerts the potential to prevent and clinical treatment of inflammatory bowel disease. PMID:26884937

  17. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice.

    PubMed

    Devkota, Suzanne; Wang, Yunwei; Musch, Mark W; Leone, Vanessa; Fehlner-Peach, Hannah; Nadimpalli, Anuradha; Antonopoulos, Dionysios A; Jabri, Bana; Chang, Eugene B

    2012-07-01

    The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(−/−), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(−/−) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts. PMID:22722865

  18. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats

    PubMed Central

    Al-Rejaie, Salim S; Abuohashish, Hatem M; Al-Enazi, Maher M; Al-Assaf, Abdullah H; Parmar, Mihir Y; Ahmed, Mohammed M

    2013-01-01

    AIM: To evaluate the ameliorative effect of naringenin (NG) during ulcerative colitis (UC) in rats. METHODS: Rats were treated with three different doses (25, 50 and 100 mg/kg per day) of NG and a single dose of mesalazine (MES, 300 mg/kg per day) for seven days prior to ulcerative colitis induction by 4% acetic acid (AA). Twenty four hours after AA rectal administration, animals were scarified and the colonic tissues were dissected. Colonic mucus content was estimated using Alcian blue dye binding technique. In colon tissues, levels of total glutathione sulphadryls (T-GSH), non-protein sulphadryls (NP-SH) and thiobarbituric acid reactive substances (TBARS) were evaluated. The activities of the antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD) were measured. Concentrations of nucleic acids (DNA and RNA) and total protein were also estimated in colon tissues. Colonic levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated. In cross section of colitis tissue the histopathological changes were observed. RESULTS: Colonic mucus content was decreased in AA compared to controls (587.09 ± 65.59 mg/kg vs 941.78 ± 68.41 mg/kg, P < 0.001). AA administration markedly reduced T-GSH (5.25 ± 0.37 nmol/L vs 3.04 ± 0.24 nmol/L, P < 0.01), NP-SH (3.16 ± 0.04 nmol/L vs 2.16 ± 0.30 nmol/L, P < 0.01), CAT (6.77 ± 0.40 U/mg vs 3.04 ± 0.2 U/mg, P < 0.01) and SOD (3.10 ± 0.11 U/mg vs 1.77 ± 0.18 U/mg, P < 0.01) while TBARS, TNF-α, IL-1β, IL-6, PGE2 and NO levels (15.09 ± 3.84 nmol/L vs 59.90 ± 16.34 nmol/L, P < 0.01; 113.56 ± 1.91 pg/mg vs 134.24 ± 4.77 pg/mg, P < 0.01; 209.20 ± 36.38 pg/mg vs 422.19 ± 31.47 pg/mg, P < 0.01; 250.83 ± 25.09 pg/mg vs 638.58 ± 115.9 pg/mg, P < 0.01; 248.19 ± 36.98 pg/mg vs 541.74 ± 58.34 pg/mg, P < 0.01 and 81.26 ± 2.98 mmol/g vs 101.90 ± 10.73 mmol/g, P < 0.001) were increased in colon of rats with UC compared controls

  19. Lubiprostone induced ischemic colitis.

    PubMed

    Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

    2013-01-14

    Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding. PMID:23345954

  20. Acyclovir-induced colitis.

    PubMed

    Wardle, T D; Finnerty, J P; Swale, V; Beer, T

    1997-04-01

    Three patients developed acute colitis, either de novo, or as an exacerbation of pre-existing colitis, following the use of oral acyclovir, prescribed for Herpes zoster or Herpes simplex infection. Rechallenge with oral acyclovir was performed in one patient, and resulted in a recurrence of colitic symptoms. It is speculated that acyclovir can have a direct irritant effect on large bowel mucosa. PMID:9146784

  1. 4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor {gamma} agonist alleviates the symptoms of DSS-induced colitis

    SciTech Connect

    Yamamoto, Keiko; Ninomiya, Yuichi; Iseki, Mioko; Nakachi, Yutaka; Kanesaki-Yatsuka, Yukiko; Yamanoue, Yu; Itoh, Toshimasa; Nishii, Yasuho; Petrovsky, Nikolai; Okazaki, Yasushi

    2008-03-14

    (5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.

  2. Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Warzecha, Zygmunt; Ceranowicz, Piotr; Dembiński, Marcin; Cieszkowski, Jakub; Bulanda, Małgorzata; Kuśnierz-Cabala, Beata; Gałązka, Krystyna; Konturek, Peter Christopher

    2016-01-01

    Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (109 CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats. PMID:27433160

  3. Milk whey culture with Propionibacterium freudenreichii ET-3 is effective on the colitis induced by 2,4,6-trinitrobenzene sulfonic acid in rats.

    PubMed

    Uchida, Masayuki; Mogami, Orie

    2005-12-01

    This study aimed to evaluate whether milk whey culture with Propinibacterium freudenreichii ET-3 (milk whey culture), which has been reported to have Bifidogenic activity, is effective on the colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rats. For the induction of colitis, the colon was clamped and 0.1 M TNBS in 35% ethanol was injected into the luminal side of the clamped portion under pentobarbital anesthesia. From the next day of colitis induction, milk whey culture was administered orally at doses of 1 and 3 g/kg, twice a day for 9 days. On the 10th day, rats were sacrificed and ulcer size was measured. Milk whey culture significantly accelerated the healing of the colitis in a dose-dependent manner, but culture medium did not. To clarify the active substance, the effects of propionic acid and acetic acid contained in milk whey culture was tested. Sodium propionate significantly accelerated the healing of TNBS-induced colitis, but sodium acetate did not. The above results show that milk whey culture may become a useful prebiotic for the therapy of inflammatory bowel disease and that propionic acid may be one of the active substances contained in milk whey culture. PMID:16314691

  4. Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

    PubMed Central

    Sałaga, M; Mokrowiecka, A; Zakrzewski, P K; Cygankiewicz, A; Leishman, E; Sobczak, M; Zatorski, H; Małecka-Panas, E; Kordek, R; Storr, M; Krajewska, W M; Bradshaw, H B; Fichna, J

    2014-01-01

    Background and aims Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. Methods We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. Results We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). Conclusions We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation. PMID:24530133

  5. Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats

    PubMed Central

    Akcan, Alper; Muhtaroglu, Sebahattin; Akgun, Hulya; Akyildiz, Hizir; Kucuk, Can; Sozuer, Erdogan; Yurci, Alper; Yilmaz, Namik

    2008-01-01

    AIM: To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. METHODS: In this study, a total of 50 rats were divided equally into 5 groups. In the control group, no colitis induction or drug administration was performed. Colitis was induced in all other groups. Following the induction of colitis, BBS, NTS or both were applied to three groups of rats. The remaining group (colitis group) received no treatment. On the 11th d after induction of colitis and drug treatment, blood samples were collected for TNF-α and IL-6 level studies. Malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO) and caspase-3 activities, as well as histopathological findings, evaluated in colonic tissues. RESULTS: According to the macroscopic and microscopic findings, the study groups treated with BBS, NTS and BBS + NTS showed significantly lower damage and inflammation compared with the colitis group (macroscopic score, 2.1 ± 0.87, 3.7 ± 0.94 and 2.1 ± 0.87 vs 7.3 ± 0.94; microscopic score, 2.0 ± 0.66, 3.3 ± 0.82 and 1.8 ± 0.63 vs 5.2 ± 0.78, P < 0.01). TNF-α and IL-6 levels were increased significantly in all groups compared with the control group. These increases were significantly smaller in the BBS, NTS and BBS + NTS groups compared with the colitis group (TNF-α levels, 169.69 ± 53.56, 245.86 ± 64.85 and 175.54 ± 42.19 vs 556.44 ± 49.82; IL-6 levels, 443.30 ± 53.99, 612.80 ± 70.39 and 396.80 ± 78.43 vs 1505.90 ± 222.23, P < 0.05). The colonic MPO and MDA levels were significantly lower in control, BBS, NTS and BBS + NTS groups than in the colitis group (MPO levels, 24.36 ± 8.10, 40.51 ± 8.67 and 25.83 ± 6.43 vs 161.47 ± 38.24; MDA levels, 4.70 ± 1.41, 6.55 ± 1.12 and 4.51 ± 0.54 vs 15.60 ± 1.88, P < 0.05). Carbonyl content and caspase-3 levels were higher in the colitis and NTS groups than in control, BBS and BBS + NTS groups (carbonyl levels, 553.99 ± 59.58 and 336.26 ± 35.72 vs 209.76 ± 30

  6. The Healing Effect of Teucrium polium in Acetic Acid-Induced Ulcerative Colitis in the Dog as an Animal Model

    PubMed Central

    Mehrabani, Davood; Bahrami, Faranak; Hosseini, Seyed Vahid; Ashraf, Mohammad Javad; Tanideh, Nader; Rezaianzadeh, Abbas; Amini, Masoud; Amini, Afshin

    2012-01-01

    BACKGROUND Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn’s disease (CD), are debilitating and chronic disorders with unpredictable courses and complicated treatment measures. Therefore, an efficient treatment protocol seems necessary as therapeutic prophylaxis for these disorders. This study aims to determine the healing effect of Teucrium polium (T. polium) in acetic acid-induced UC in an experimental dog model. METHODS From September to December 2010, eight male (20-25 kg) crossbred dogs were used for induction of UC by 6% acetic acid, transrectally. After one week, three biopsies (10, 20 and 30 cm proximal to the anal verge) were taken from the colon of each animal for histological studies. In the presence of UC, 400 mg/kg/day of T. polium extract was administered orally and transrectally (via enema) for 30 days in six of the dogs. The remaining two dogs were used as controls and did not receive T. polium. Multiple biopsies were taken 7, 14, and 30 days after discontinuation of T. polium in the same manner as before treatment. RESULTS After administration of acetic acid, we noted the presence of multiple ulcers, diffuse inflammation, PMN infiltration in the lamina propria, glandular destruction and goblet cell depletion. Treatment with T. polium restored the colonic architecture with an increased number of healthy cells and a reduction in inflammatory cells. Damage of the surface epithelial cells and mucosal layer of the lumen were reversed, which lead to faster ulcer healing. CONCLUSION T. polium may be a treatment choice for UC and can broaden the current therapy options for UC. PMID:24829634

  7. Anti-inflammatory effect of volatile oil and hydroalcoholic extract of Rosa damascena Mill. on acetic acid-induced colitis in rats.

    PubMed

    Latifi, Ghazal; Ghannadi, Alireza; Minaiyan, Mohsen

    2015-01-01

    Rosa damascena is a small plant belonging to Rosaceae family which has been used for the treatment of some inflammatory diseases and digestive disorders in the Iranian folk medicine. This study was performed to investigate the effect of R. damascena hydroalcoholic extract (RDHE) and R. damascena volatile oil (RDVO) on ulcerative colitis induced by acetic acid in rats. Different doses of RDHE (250, 500, 1000 mg/kg) and RDVO (100, 200, 400 µl/kg) were given orally (p.o.) and doses of RDHE (125, 250, 500 mg/kg) were administrated intraperitoneally (i.p.) to the male Wistar rats (n=6) 2 h before induction of colitis which continued daily for 4 successive days. Prednisolone (4 mg/kg p.o.) and dexamethasone (1 mg/kg i.p.) were used in the reference groups. Weight/length ratios of wet colon were measured and the tissues were assessed macroscopically, histopathologically, and biochemically via measuring the myeloperoxidase (MPO) activity. Oral RDHE at all doses examined, and the lowest dose of RDVO given p.o. or RDHE administered i.p. reduced all indices of colitis measured in different assays as well as the MPO activity. These results provide encouraging support for the use of hydroalcoholic extract of R. damascena in relieving alimentary inflammatory conditions and reinforce the use of this plant to develop new agents for treating ulcerative colitis. PMID:26779271

  8. Anti-inflammatory effect of volatile oil and hydroalcoholic extract of Rosa damascena Mill. on acetic acid-induced colitis in rats

    PubMed Central

    Latifi, Ghazal; Ghannadi, Alireza; Minaiyan, Mohsen

    2015-01-01

    Rosa damascena is a small plant belonging to Rosaceae family which has been used for the treatment of some inflammatory diseases and digestive disorders in the Iranian folk medicine. This study was performed to investigate the effect of R. damascena hydroalcoholic extract (RDHE) and R. damascena volatile oil (RDVO) on ulcerative colitis induced by acetic acid in rats. Different doses of RDHE (250, 500, 1000 mg/kg) and RDVO (100, 200, 400 µl/kg) were given orally (p.o.) and doses of RDHE (125, 250, 500 mg/kg) were administrated intraperitoneally (i.p.) to the male Wistar rats (n=6) 2 h before induction of colitis which continued daily for 4 successive days. Prednisolone (4 mg/kg p.o.) and dexamethasone (1 mg/kg i.p.) were used in the reference groups. Weight/length ratios of wet colon were measured and the tissues were assessed macroscopically, histopathologically, and biochemically via measuring the myeloperoxidase (MPO) activity. Oral RDHE at all doses examined, and the lowest dose of RDVO given p.o. or RDHE administered i.p. reduced all indices of colitis measured in different assays as well as the MPO activity. These results provide encouraging support for the use of hydroalcoholic extract of R. damascena in relieving alimentary inflammatory conditions and reinforce the use of this plant to develop new agents for treating ulcerative colitis. PMID:26779271

  9. Addition of Berberine to 5-Aminosalicylic Acid for Treatment of Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice.

    PubMed

    Li, Yan-hong; Zhang, Man; Xiao, Hai-tao; Fu, Hai-bo; Ho, Alan; Lin, Cheng-yuan; Huang, Yu; Lin, Ge; Bian, Zhao-xiang

    2015-01-01

    Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5-aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-α as well as NFκB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-α secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy. PMID:26642326

  10. Addition of Berberine to 5-Aminosalicylic Acid for Treatment of Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice

    PubMed Central

    Li, Yan-hong; Zhang, Man; Xiao, Hai-tao; Fu, Hai-bo; Ho, Alan; Lin, Cheng-yuan; Huang, Yu; Lin, Ge; Bian, Zhao-xiang

    2015-01-01

    Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5-aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-α as well as NFκB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-α secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy. PMID:26642326

  11. Naringin ameliorates acetic acid induced colitis through modulation of endogenous oxido-nitrosative balance and DNA damage in rats

    PubMed Central

    Kumar, Venkatashivam Shiva; Rajmane, Anuchandra Ramchandra; Adil, Mohammad; Kandhare, Amit Dattatraya; Ghosh, Pinaki; Bodhankar, Subhash Laxman

    2014-01-01

    The aim of this study was to evaluate the effect of naringin on experimentally induced inflammatory bowel disease in rats. Naringin (20, 40 and 80 mg/kg) was given orally for 7 days to Wistar rats before induction of colitis by intrarectal instillation of 2 mL of 4% (v/v) acetic acid solution. The degree of colonic mucosal damage was analyzed by examining mucosal damage, ulcer area, ulcer index and stool consistency. Intrarectal administration of 4% acetic acid resulted in significant modulation of serum alkaline phosphatase, lactate dehydrogenase, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) content along with colonic nitric oxide (NO), xanthine oxidase (XO) level and protein carbonyl content in the colonic tissue as well as in blood. Naringin (40 and 80 mg/kg) exerted a dose dependent (P < 0.05) ameliorative effect, as it significantly increased hematological parameter as well as colonic SOD and GSH. There was a significant (P < 0.05) and dose dependant inhibition of macroscopical score, ulcer area along with colonic MDA, MPO activity by the 7 days of pretreatment of naringin (40 and 80 mg/kg). Biochemical studies revealed a significant (P < 0.05) dose dependant inhibition in serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels by pretreatment of naringin. Increased levels of colonic NO, XO, protein carbonyl content and DNA damage were also significantly decreased by naringin pretreatment. The findings of the present investigation propose that naringin has an anti-inflammatory, anti-oxidant and anti-apoptotic potential effect at colorectal sites as it modulates the production and expression of oxidative mediators such as MDA, MPO, NO and XO, thus reducing DNA damage. PMID:24683411

  12. Flaxseed extract exhibits mucosal protective effect in acetic acid induced colitis in mice by modulating cytokines, antioxidant and antiinflammatory mechanisms.

    PubMed

    Palla, Amber Hanif; Iqbal, Najeeha Talat; Minhas, Khurram; Gilani, Anwarul-Hassan

    2016-09-01

    New treatments for inflammatory bowel disease are of interest due to high rate of remission failure. Natural products have been effective in IBD therapeutics as they have multiple constituents. The aim of the present study was to evaluate the effect of Flaxseed extract (Fs.Cr) on ulcerative colitis and identify the possible mechanisms involved. Colitis was induced by intrarectal administration of 6% AA in BALB/c mice. Colonic mucosal damage was assessed after 24h by calculating disease activity index (DAI), macroscopic and histological damage scores, biochemical measurement of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total glutathione activities. Since cytokines are involved in exacerbating inflammatory cascade with emerging role of innate immune cytokines in IBD therapeutics, we hence assessed the effect on the levels of TNF-α, IFN-γ and IL-17, at 6, 12 and 24h by ELISA. Fs.Cr ameliorated the severity of AA colitis as evident by improved DAI, macroscopic damage and the histopathological scores along with restoration of goblet cells. Fs.Cr decreased MDA and MPO activities and enhanced antioxidant activity compared to the AA group. Finally, Fs.Cr in doses (300 and 500mg/kg) decreased TNF-α and IFN-γ levels at all time points with simultaneous increase in IL-17 levels at 24h as compared to the AA group. These results suggest that Fs.Cr ameliorates the severity of AA colitis by reducing goblet cell depletion, scavenging oxygen-derived free radicals, reduce neutrophil infiltration that may be attributed due to decreasing IFN-γ and TNF-α and increasing IL-17 levels. PMID:27280586

  13. Dietary fat-induced taurocholic acid production promotes pathobiont and colitis in IL-10−/− mice

    PubMed Central

    Devkota, Suzanne; Wang, Yunwei; Musch, Mark; Leone, Vanessa; Fehlner-Peach, Hannah; Nadimpalli, Anuradha; Antonopoulos, Dionysios A.; Jabri, Bana; Chang, Eugene B.

    2012-01-01

    The composite human microbiome of Western populations has likely changed over the past century, brought on by new environmental triggers that often have a negative impact on human health1. Here we show that consumption of a diet high in saturated (milk derived)-fat (MF), but not polyunsaturated (safflower oil)-fat (PUFA), changes the conditions for microbial assemblage and promotes expansion of a low abundance, sulfite-reducing pathobiont, Bilophila wadsworthia2. This was associated with a pro-inflammatory TH1 immune response and increased incidence of colitis in genetically susceptible IL-10−/−, but not wild type mice. These effects are mediated by MF-promoted taurine-conjugation of hepatic bile acids, which increases the availability of organic sulfur used by sulfite-reducing microbes like B. wadsworthia. When mice were fed a low-fat (LF) diet supplemented with taurocholic, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in IL10−/− mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can dramatically alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel diseases in genetically susceptible hosts. PMID:22722865

  14. Inflammation-Induced Acid Tolerance Genes gadAB in Luminal Commensal Escherichia coli Attenuate Experimental Colitis

    PubMed Central

    Tchaptchet, Sandrine; Fan, Ting-Jia; Goeser, Laura; Schoenborn, Alexi; Gulati, Ajay S.; Sartor, R. Balfour

    2013-01-01

    Dysregulated immune responses to commensal intestinal bacteria, including Escherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally, E. coli responds to chronic intestinal inflammation by upregulating expression of stress response genes, including gadA and gadB. GadAB encode glutamate decarboxylase and protect E. coli from the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized that E. coli upregulates gadAB during inflammation to enhance its survival and virulence. Using real-time PCR, we determined gadAB expression in luminal E. coli from ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10−/−) mice selectively colonized with a commensal E. coli isolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains. E. coli survival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking the gadAB genes (NC101ΔgadAB). The susceptibility of NC101 and NC101ΔgadAB to killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression of gadAB in luminal E. coli increases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensal E. coli isolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the

  15. Dextran Sodium Sulfate (DSS) Induces Colitis in Mice by Forming Nano-Lipocomplexes with Medium-Chain-Length Fatty Acids in the Colon

    PubMed Central

    Laroui, Hamed; Ingersoll, Sarah A.; Liu, Hong Chun; Baker, Mark T.; Ayyadurai, Saravanan; Charania, Moiz A.; Laroui, Famina; Yan, Yutao; Sitaraman, Shanthi V.; Merlin, Didier

    2012-01-01

    Inflammatory bowel diseases (IBDs), primarily ulcerative colitis and Crohn's disease, are inflammatory disorders caused by multiple factors. Research on IBD has often used the dextran sodium sulfate (DSS)-induced colitis mouse model. DSS induces in vivo but not in vitro intestinal inflammation. In addition, no DSS-associated molecule (free glucose, sodium sulfate solution, free dextran) induces in vitro or in vivo intestinal inflammation. We find that DSS but not dextran associated molecules established linkages with medium-chain-length fatty acids (MCFAs), such as dodecanoate, that are present in the colonic lumen. DSS complexed to MCFAs forms nanometer-sized vesicles ∼200 nm in diameter that can fuse with colonocyte membranes. The arrival of nanometer-sized DSS/MCFA vesicles in the cytoplasm may activate intestinal inflammatory signaling pathways. We also show that the inflammatory activity of DSS is mediated by the dextran moieties. The deleterious effect of DSS is localized principally in the distal colon, therefore it will be important to chemically modify DSS to develop materials beneficial to the colon without affecting colon-targeting specificity. PMID:22427817

  16. Colitis possibly induced by quetiapine.

    PubMed

    de Beaurepaire, Renaud; Trinh, Isabelle; Guirao, Sophie; Taieb, Muriel

    2015-01-01

    A 39-year-old man with bipolar disorder was hospitalised for depression. He was started on quetiapine (titrated up to 300 mg), lactulose (a laxative) and tropatepine (an anticholinergic). Valpromide (a mood stabiliser) and prazepam were later added and rapidly withdrawn. Seven days after quetiapine initiation, the patient reported abdominal pain and constipation; 2 days later, CT revealed an important distention of the colon including the caecum and a pre-perforation. A subtotal colectomy was performed and histology confirmed necrotising ischaemic colitis. The patient survived. This is the first case reported so far of ischaemic colitis related to quetiapine, in the absence of other antipsychotics simultaneously prescribed. Tropatepine likely acted as a cofactor to determine colitis. Clinicians need to be aware of the potential danger of the co-prescription of quetiapine with tropatepine (and possibly other anticholinergics). PMID:25721830

  17. Protective effects of citicoline on TNBS-induced experimental colitis in rats

    PubMed Central

    Ek, Rauf Onur; Serter, Mukadder; Ergin, Kemal; Cecen, Serpil; Unsal, Cengiz; Yildiz, Yuksel; Bilgin, Mehmet D

    2014-01-01

    The aim of this study was to investigate the effects of citicoline on the development of colitis and antioxidant parameters in rats subjected to tribenzene sulfonic acid (TNBS)-induced colitis. Twenty four Wistar Albino female rats were divided into four subgroups (n=6) (control, colitis control, colitis + 50 mg/kg citicoline, colitis + 250 mg/kg citicoline). Colitis was induced using an enema of TNBS and ethanol; following which citicoline was administrated for 3 days and effects of citicoline was subsequently evaluated. Based on microscopic damage scores, there was no difference between rats of the TNBS-colitis and 50 mg/kg citicoline treated groups, whereas treatment with 250 mg/kg citicoline, caused significant reduction in colon injury compared to that observed in rats of TNBS-colitis group. In terms of the biochemical analyses, myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione (GSH), and IL-6 levels in rats from 250 mg/kg citicoline group were significantly different from that TNBS-colitis group. The levels of MPO, MDA, GSH and IL-6 in control rats were also significantly different those of rats in the TNBS-colitis group. Citicoline may have a positive protective effect on the inflammatory bowel disease treatment process and could, therefore, be used as an adjunct therapy in colitis. These effects of citicoline may exist through anti-inflammatory and antioxidant mechanism. PMID:24955172

  18. Protective effects of citicoline on TNBS-induced experimental colitis in rats.

    PubMed

    Ek, Rauf Onur; Serter, Mukadder; Ergin, Kemal; Cecen, Serpil; Unsal, Cengiz; Yildiz, Yuksel; Bilgin, Mehmet D

    2014-01-01

    The aim of this study was to investigate the effects of citicoline on the development of colitis and antioxidant parameters in rats subjected to tribenzene sulfonic acid (TNBS)-induced colitis. Twenty four Wistar Albino female rats were divided into four subgroups (n=6) (control, colitis control, colitis + 50 mg/kg citicoline, colitis + 250 mg/kg citicoline). Colitis was induced using an enema of TNBS and ethanol; following which citicoline was administrated for 3 days and effects of citicoline was subsequently evaluated. Based on microscopic damage scores, there was no difference between rats of the TNBS-colitis and 50 mg/kg citicoline treated groups, whereas treatment with 250 mg/kg citicoline, caused significant reduction in colon injury compared to that observed in rats of TNBS-colitis group. In terms of the biochemical analyses, myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione (GSH), and IL-6 levels in rats from 250 mg/kg citicoline group were significantly different from that TNBS-colitis group. The levels of MPO, MDA, GSH and IL-6 in control rats were also significantly different those of rats in the TNBS-colitis group. Citicoline may have a positive protective effect on the inflammatory bowel disease treatment process and could, therefore, be used as an adjunct therapy in colitis. These effects of citicoline may exist through anti-inflammatory and antioxidant mechanism. PMID:24955172

  19. Ocotillol, a Majonoside R2 Metabolite, Ameliorates 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis in Mice by Restoring the Balance of Th17/Treg Cells.

    PubMed

    Lee, Sang-Yun; Jeong, Jin-Ju; Le, Thi Hong Van; Eun, Su-Hyeon; Nguyen, Minh Duc; Park, Jeong Hill; Kim, Dong-Hyun

    2015-08-12

    In a preliminary experiment, majonoside R2 (MR2), isolated from Vietnamese ginseng (Panax vietnamensis Ha et Grushv.), inhibited differentiation to Th17 cells and was metabolized to ocotillol via pseudoginsenoside RT4 (PRT4) by gut microbiota. Therefore, we examined the inhibitory effects of MR2 and its metabolites PRT4 and ocotillol against Th17 cell differentiation. These ginsenosides significantly suppressed interleukin (IL)-6/tumor growth factor beta-induced differentiation of splenic CD4(+) T cells into Th17 cells and expression of IL-17 in vitro. Among these ginsenosides, ocotillol showed the highest inhibitory effect. We also examined the anti-inflammatory effect of ocotillol in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Oral administration of ocotillol significantly suppressed TNBS-induced colon shortening, macroscopic score, myeloperoxidase activity, and production of nitric oxide and prostaglandin E2. Ocotillol treatment increased TNBS-suppressed expression of tight junction proteins ZO-1, occludin, and claudin-1 in the colon. Treatment with ocotillol inhibited TNBS-induced expression of tumor necrosis factor (TNF)-α and IL-1β, as well as activation of NF-κB and MAPKs. Moreover, treatment with ocotillol inhibited TNBS- induced differentiation to Th17 cells in the lamina propria of colon, as well as expression of T-bet, RORγt, IL-17, and IL-23. Ocotillol treatment also increased Treg cell differentiation and Foxp3 and IL-10 expression. These findings suggest that orally administered MR2 may be metabolized to ocotillol in the intestine by gut microbiota and the transformed ocotillol may ameliorate inflammatory diseases such as colitis by restoring the balance of Th17/Treg cells. PMID:26194345

  20. Sonographic and Endoscopic Findings in Cocaine-Induced Ischemic Colitis

    PubMed Central

    Leth, Thomas; Wilkens, Rune; Bonderup, Ole K.

    2015-01-01

    Cocaine-induced ischemic colitis is a recognized entity. The diagnosis is based on clinical and endoscopic findings. However, diagnostic imaging is helpful in the evaluation of abdominal symptoms and prior studies have suggested specific sonographic findings in ischemic colitis. We report sonographic and endoscopic images along with abdominal computed tomography in a case of cocaine-induced ischemic colitis. PMID:26798523

  1. IL-17/IFN-γ interactions regulate intestinal inflammation in TNBS-induced acute colitis.

    PubMed

    Jin, Yu; Lin, Yan; Lin, Lianjie; Zheng, Changqing

    2012-11-01

    Colonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced acute colitis in mice and elicited a Th1 immune response. Th17 cells are believed to play a major role in TNBS-induced colitis. The aim of this study is to investigate the roles of interleukin (IL)-17 and interferon (IFN)-γ in the pathogenesis of TNBS-induced acute colitis. We assessed the inflammation scores of TNBS-induced acute colitis in wild-type (WT), IL-17 knockout (KO), and IFN-γ KO mice and measured the levels of inflammatory cytokines using real-time PCR and ELISAs. Histology data showed that IL-17 KO mice with TNBS-induced colitis had significantly lower neutrophil infiltration and inflammatory macroscopic scores compared to the IFN-γ KO mice and WT mice. Intraperitoneal injection of anti-IL-17 monoclonal antibody confirmed a specific role for IL-17 in TNBS-induced acute colitis in the 3 strains of mice. The severity of colitis was higher in IFN-γ KO mice and lower in IL-17 KO mice compared to WT mice. Our data suggested that IL-17 signaling plays a critical role in the local inflammation of TNBS-induced colitis, while IFN-γ was not an important mediator of the local inflammation response. IL-17 may represent a target for therapeutic intervention in inflammatory bowel disease patients. PMID:23030668

  2. Acetylsalicylic Acid Reduces the Severity of Dextran Sodium Sulfate-Induced Colitis and Increases the Formation of Anti-Inflammatory Lipid Mediators

    PubMed Central

    Köhnke, Thomas; Bilal, Süleyman; Zhou, Xiangzhi; Rothe, Michael; Baumgart, Daniel C.; Weylandt, Karsten H.

    2013-01-01

    The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation. PMID:24083240

  3. Acetylsalicylic Acid reduces the severity of dextran sodium sulfate-induced colitis and increases the formation of anti-inflammatory lipid mediators.

    PubMed

    Köhnke, Thomas; Gomolka, Beate; Bilal, Süleyman; Zhou, Xiangzhi; Sun, Yanping; Rothe, Michael; Baumgart, Daniel C; Weylandt, Karsten H

    2013-01-01

    The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation. PMID:24083240

  4. A study comparing the efficacy of antimicrobial agents versus enzyme (P-gp) inducers in the treatment of 2,4,6 trinitrobenzenesulfonic acid-induced colitis in rats.

    PubMed

    Toklu, H Z; Kabasakal, L; Imeryuz, N; Kan, B; Celikel, C; Cetinel, S; Orun, O; Yuksel, M; Dulger, G A

    2013-08-01

    The intestinal microflora is an important cofactor in the pathogenesis of intestinal inflammation; and the epithelial cell barrier function is critical in providing protection against the stimulation of mucosal immune system by the microflora. In the present study, therapeutic role of the antibacterial drugs rifampicin and ciprofloxacine were investigated in comparison to spironolactone, an enzyme inducer, in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis of the rats. Drugs were administered for 14 days following induction of colitis. All drug treatments ameliorated the clinical hallmarks of colitis as determined by body weight loss and assessment of diarrhea, colon length, and histology. Oxidative damage and neutrophil infiltration as well as nuclear factor κB (NF-κB) and tumor necrosis factor α (TNF-α) expressions that were increased during colitis, were decreased significantly. Rifampicin and ciprofloxacin were probably effective due to their antibacterial and immunomodulating properties. The multidrug resistence gene (MDR1) and its product p-glycoprotein (P-gp) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). In the present study, findings of the P-gp expression were inconclusive but regarding previous studies, it can be suggested that the beneficial effects of rifampicin and spironolactone may be partly due to their action as a P-gp ligand. Spironolactone has been reported to supress the transcription of proinflamatory cytokines that are considered to be of importance in immunoinflammatory diseases. It is also a powerful pregnane X receptor (PXR) inducer; thus, inhibition of the expression of NF-κB and TNF-α, and amelioration of inflammation by spironolactone suggest that this may have been through the activation of PXR. However, our findings regarding PXR expression were inconclusive. Activation of PXR by spironolactone probably also contributed to the induction of P-gp, resulting in extrusion of noxious substances

  5. The Attenuation of Scutellariae radix Extract on Oxidative Stress for Colon Injury in Lipopolysaccharide-induced RAW264.7 Cell and 2,4,6-trinitrobenzene Sulfonic Acid-induced Ulcerative Colitis Rats

    PubMed Central

    Jin, Yu; Yang, Jun; Lin, Lianjie; Lin, Yan; Zheng, Changqing

    2016-01-01

    Background: Oxidative stress (OS) has been regarded as one of the major pathogeneses of ulcerative colitis (UC) through damaging colon. It has been shown that Scutellariae radix (SR) extract has a beneficial effect for the prevention and treatment of UC. Objective: The aim of this study was to investigate whether SR had a potential capacity on oxidant damage for colon injury both in vivo and in vitro. Materials and Methods: The 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce UC rats model while 1 μg/ml lipopolysaccharide (LPS) was for RAW264.7 cell damage. Disease activity index (DAI) was determined to response the severity of colitis. The myeloperoxidase (MPO) activity in rat colon was also estimated. The 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid assay was performed to evaluate the total antioxidant capacity of SR. Furthermore, the activity of glutathione peroxidase (GSH-PX), catalase (CAT), superoxide dismutase (SOD), and lipid peroxidation malondialdehyde (MDA) in cell supernatant and rat serum were detected by appropriate kits. In addition, an immunohistochemical assay was applied to examine transforming growth factor beta 1 (TGF-β1) protein expression in colon tissue. Results: The treatment with SR could significantly increase the activity of GSH-PX, CAT, and SOD associated with OS in LPS-induced RAW264.7 cell damage and TNBS-induced UC rats. However, the level of MDA was markedly reduced both in vitro and in vivo. Furthermore, SR significantly decreased DAI and reversed the increased MPO activity. Thus, SR could decrease the severity of acute TNBS-induced colitis in rats. Immunohistochemical assay showed that SR significantly downregulated TGF-β1 protein expression in colon tissue. Conclusion: Our data provided evidence to support this fact that SR attenuated OS in LPS-induced RAW264.7 cell and also in TNBS-induced UC rats. Thus, SR may be an interesting candidate drug for the management of UC. SUMMARY Scutellariae radix (SR

  6. Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

    PubMed Central

    Matsuo, Shingo; Yang, Weng-Lang; Aziz, Monowar; Kameoka, Shingo; Wang, Ping

    2014-01-01

    Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD. PMID:24306512

  7. Light-emitting diodes at 940nm attenuate colitis-induced inflammatory process in mice.

    PubMed

    Belém, Mônica O; de Andrade, Giovana M M; Carlos, Thalita M; Guazelli, Carla F S; Fattori, Victor; Toginho Filho, Dari O; Dias, Ivan F L; Verri, Waldiceu A; Araújo, Eduardo J A

    2016-09-01

    Inflammatory bowel disease (IBD) presents intense inflammatory infiltrate, crypt abscesses, ulceration and even loss of function. Despite the clinical relevance of IBD, its current therapy remains poorly effective. Infrared wavelength phototherapy shows therapeutic potential on inflammation. Our goal was to evaluate whether light-emitting diodes (LED) at 940nm are capable of mitigating the colitis-induced inflammatory process in mice. Forty male Swiss mice were assigned into five groups: control; control treated with LED therapy; colitis without treatment; colitis treated with LED therapy; colitis treated with Prednisolone. Experimental colitis was induced by acetic acid 7.5% (pH2.5) rectal administration. LED therapy was performed with light characterized by wavelength of 940nm, 45nm bandwidth, intensity of 4.05J/cm(2), total power of 270mW and total dose of 64.8J for 4min in a single application. Colitis-induced intestinal transit delay was inhibited by LED therapy. Colitis caused an increase of colon dimensions (length, diameter, total area) and colon weight (edema), which were inhibited by LED therapy. LED therapy also decreased colitis-induced tissue gross lesion, myeloperoxidase activity, microscopic tissue damage score and the presence of inflammatory infiltrate in all intestinal layers. Furthermore, LED therapy inhibited colitis-induced IL-1β, TNF-α, and IL-6 production. We conclude LED therapy at 940nm inhibited experimental colitis-induced colon inflammation in mice, therefore, rendering it a promising therapeutic approach that deserves further investigation. PMID:27424097

  8. Effects of arachidonic acid intake on inflammatory reactions in dextran sodium sulphate-induced colitis in rats.

    PubMed

    Naito, Yukiko; Ji, Xu; Tachibana, Shigehiro; Aoki, Satoko; Furuya, Mami; Tazura, Yoshiyuki; Miyazawa, Daisuke; Harauma, Akiko; Moriguchi, Toru; Nagata, Tomoko; Iwai, Naoharu; Ohara, Naoki

    2015-09-14

    The aim of this study was to investigate the effects of the administration of oral arachidonic acid (AA) in rats with or without dextran sulphate sodium (DSS)-induced inflammatory bowel disease. Male Wistar rats were administered AA at 0, 5, 35 or 240 mg/kg daily by gavage for 8 weeks. Inflammatory bowel disease was induced by replacing drinking water with 3 % DSS solution during the last 7 d of the AA dosing period. These animals passed loose stools, diarrhoea and red-stained faeces. Cyclo-oxygenase-2 concentration and myeloperoxidase activity in the colonic tissue were significantly increased in the animals given AA at 240 mg/kg compared with the animals given AA at 0 mg/kg. Thromboxane B2 concentration in the medium of cultured colonic mucosae isolated from these groups was found to be dose-dependently increased by AA, and the increase was significant at 35 and 240 mg/kg. Leukotriene B4 concentration was also significantly increased and saturated at 5 mg/kg. In addition, AA at 240 mg/kg promoted DSS-induced colonic mucosal oedema with macrophage infiltration. In contrast, administration of AA for 8 weeks, even at 240 mg/kg, showed no effects on the normal rats. These results suggest that in rats with bowel disease AA metabolism is affected by oral AA, even at 5 mg/kg per d, and that excessive AA may aggravate inflammation, whereas AA shows no effects in rats without inflammatory bowel disease. PMID:26234346

  9. Grim19 Attenuates DSS Induced Colitis in an Animal Model

    PubMed Central

    Kim, Jae-kyung; Lee, Seung Hoon; Lee, Seon-Young; Kim, Eun-Kyung; Kwon, Jeong-Eun; Seo, Hyeon-Beom; Lee, Han Hee; Lee, Bo-In; Park, Sung-Hwan; Cho, Mi-La

    2016-01-01

    DSS induced colitis is a chronic inflammatory disease characterized by inflammation in the gastrointestinal tract, which destabilizes the gut and induces an uncontrolled immune response. Although DSS induced colitis is generally thought to develop as a result of an abnormally active intestinal immune system, its pathogenesis remains unclear. Gene associated with retinoid interferon induced mortality (Grim) 19 is an endogenous specific inhibitor of STAT3, which regulates the expression of proinflammatory cytokines. In this study, we investigated the influence of GRIM19 in a DSS induced colitis mouse model. We hypothesized that Grim19 would ameliorate DSS induced colitis by altering STAT3 activity and intestinal inflammation. Grim19 ameliorated DSS induced colitis severity and protected intestinal tissue. The expression of STAT3 and proinflammatory cytokines such as IL-1β and TNF-α in colon and lymph nodes was decreased significantly by Grim19. Moreover, DSS induced colitis progression in a Grim19 transgenic mouse line was inhibited in association with a reduction in STAT3 and IL-17 expression. These results suggest that Grim19 attenuates DSS induced colitis by suppressing the excessive inflammatory response mediated by STAT3 activation. PMID:27258062

  10. Prednisolone-appended alpha-cyclodextrin: alleviation of systemic adverse effect of prednisolone after intracolonic administration in 2,4,6-trinitrobenzenesulfonic acid-induced colitis rats.

    PubMed

    Yano, H; Hirayama, F; Arima, H; Uekama, K

    2001-12-01

    The titled compound is a cyclodextrin derivative in which prednisolone 21-succinate (PDsuc) is covalently bound to one of the secondary hydroxyl groups of alpha-cyclodextrin (alpha-CyD) via an ester linkage. In this study, the PDsuc-appended alpha-CyD ester conjugate (PDsuc/alpha-CyD conjugate) was intracolonically administered to rats with 2,4,6-trinitrobenzensulfonic acid-induced colitis, and its antiinflammatory and systemic adverse effects were compared with those of prednisolone (PD) alone and the PD/2-hydroxypropyl-beta-CyD complex (PD/HP-beta-CyD complex), which is a noncovalent inclusion complex. Colonic damage score, ratio of distal colon wet weight to body weight, and myeloperoxidase activity were evaluated as measures of the therapeutic effect of PD, whereas the ratio of thymus wet weight to body weight was evaluated as a measure of the side effect of PD. The local antiinflammatory activity increased in the order of PD alone approximately PDsuc/alpha-CyD conjugate < PD/HP-beta-CyD complex. As to systemic adverse effect, the PD/HP-beta-CyD complex and PD alone caused thymolysis at doses of 5-10 mg/kg. In contrast, the PDsuc/alpha-CyD conjugate showed no clear systemic adverse effect at the same doses. The low adverse effect of the conjugate may be ascribed to the slow release of PD in the colon, which keeps the local concentration in the colon at a low but constant level. The results suggest that the PDsuc/alpha-CyD conjugate can alleviate the systemic adverse effect of PD while maintaining the therapeutic activity of PD. This kind of knowledge will be useful in the rational design of steroid prodrugs for the colon-specific drug delivery system. PMID:11745769

  11. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

    SciTech Connect

    Huang, T.-Y.; Chu, H.-C.; Lin, Y.-L.; Lin, C.-K.; Hsieh, T.-Y.; Chang, W.-K.; Chao, Y.-C.; Liao, C.-L.

    2009-05-15

    In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.

  12. NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice

    PubMed Central

    Fiorucci, Stefano; Antonelli, Elisabetta; Distrutti, Eleonora; Del Soldato, Piero; Flower, Roderick J.; Clark, Mark J. Paul; Morelli, Antonio; Perretti, Mauro; Ignarro, Louis J.

    2002-01-01

    NCX-1015 is a nitric oxide (NO)-releasing derivative of prednisolone. In this study we show NCX-1015 protects mice against the S. A. development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The beneficial effect of NCX-1015 was reflected in increased survival rates, improvement of macroscopic and histologic scores, a decrease in the mucosal content of T helper cell type 1 cytokines (protein and mRNA), and diminished myeloperoxidase activity in the colon. In contrast to its NO derivative, only very high doses of prednisolone were effective in reproducing these beneficial effects. NCX-1015 was 10- to 20-fold more potent than the parent compound in inhibiting IFN-γ secretion by lamina propria mononuclear cells. Protection against developing colitis correlated with inhibition of nuclear translocation of p65/Rel A in these cells. In vivo treatment with NCX-1015 potently stimulated IL-10 production, suggesting that the NO steroid induces a regulatory subset of T cells that negatively modulates intestinal inflammation. PMID:12427966

  13. Intestinal anti-inflammatory activity of apigenin K in two rat colitis models induced by trinitrobenzenesulfonic acid and dextran sulphate sodium.

    PubMed

    Mascaraque, Cristina; González, Raquel; Suárez, María Dolores; Zarzuelo, Antonio; Sánchez de Medina, Fermín; Martínez-Augustin, Olga

    2015-02-28

    Flavonoids are polyphenolic compounds that are widespread in nature, and consumed as part of the human diet in significant amounts. The aim of the present study was to test the intestinal anti-inflammatory activity of apigenin K, a soluble form of apigenin, in two models of rat colitis, namely the trinitrobenzenesulfonic acid (TNBS) model and the dextran sulphate sodium (DSS) model. Apigenin K (1, 3 and 10 mg/kg; by the oral route; n 4-6 per group) was administered as a pre-treatment to rats with TNBS and DSS colitis, and colonic status was checked by macroscopic and biochemical examination. Apigenin K pre-treatment resulted in the amelioration of morphological signs and biochemical markers in the TNBS model. The results demonstrated a reduction in the inflamed area, as well as lower values of score and colonic weight:length ratio compared with the TNBS group. Myeloperoxidase (MPO) activity was reduced by 30 % (P< 0·05). Moreover, apigenin K pre-treatment ameliorated morphological signs and biochemical markers in the DSS model. Thus, macroscopic damage was significantly reduced and the colonic weight:length ratio was lowered by approximately 10 %, while colonic MPO and alkaline phosphatase activities were decreased by 35 and 21 %, respectively (P< 0·05). Apigenin K pre-treatment also tended to normalise the expression of a number of colonic inflammatory markers (e.g. TNF-α, transforming growth factor-β, IL-6, intercellular adhesion molecule 1 or chemokine (C-C motif) ligand 2). In conclusion, apigenin K is found to have anti-inflammatory effects in two preclinical models of inflammatory bowel disease. PMID:25654996

  14. Comparative Protective Effect of Hawthorn Berry Hydroalcoholic Extract, Atorvastatin, and Mesalamine on Experimentally Induced Colitis in Rats

    PubMed Central

    Shafie-Irannejad, Vahid; Hobbenaghi, Rahim; Tabatabaie, Seyed Hamed; Moshtaghion, Seyed-Mehdi

    2013-01-01

    Abstract The protective effect of hydroalcoholic extract of hawthorn berries (HBE) on acetic acid (AA)–induced colitis in rats was investigated. Forty-two Wistar rats were divided into seven groups, including control and test groups (n=6). The control animals received saline, and the test animals were treated with saline (sham group), mesalamine (50 mg/kg; M group), atorvastatin (20 mg/kg; A group), HBE (100 mg/kg; H group), mesalamine and HBE (HM group), or atorvastatin plus HBE (HA group), 3 days before and a week after colitis induction. Colitis was induced by administration of 1 mL AA (4%) via a polyethylene catheter intrarectally. High-performance liquid chromatography analyses showed that HBE contained 0.13% and 0.5% oleanolic acid and ursolic acid, respectively. Elevated myeloperoxidase activity and lipid peroxidation were attenuated in the HA group. The H and HM groups showed marked reductions in colitis-induced decreases in total thiol molecules and body weight. The histopathological studies revealed that HBE decreased colitis-induced edema and infiltration of neutrophils. Our data suggest the anti-inflammatory and antioxidant effects of HBE and atorvastatin protect against AA-induced colitis. The anti-inflammatory effect of HBE may be attributable to its ability to decrease myeloperoxidase activity as a biomarker of neutrophil infiltration. PMID:23875899

  15. Angelica acutiloba Kitagawa Extract Attenuates DSS-Induced Murine Colitis

    PubMed Central

    Jang, Jong-Chan; Lee, Kang Min

    2016-01-01

    We examined the protective effects of Angelica acutiloba Kitagawa (AAK) extract on a murine model of acute experimental colitis. Colitis was induced by 4% dextran sulfate sodium (DSS) in the drinking water of male C57BL/6 mice, for 7 consecutive days. Oral administration of AAK extract (500 mg/kg/day) significantly alleviated DSS-induced symptoms such as anorexia, weight loss, events of diarrhea or bloody stools, and colon shortening. Histological damage was also ameliorated, as evidenced by the architectural preservation and suppression of inflammatory cell infiltration in colonic samples. Treatment improved the colonic mRNA expression of different inflammatory markers: cytokines, inducible enzymes, matrix metalloproteinases, and tight junction-related proteins. In the isolated serum, IgE levels were downregulated. Collectively, these findings indicate the therapeutic potentials of AAK as an effective complementary or alternative modality for the treatment of ulcerative colitis. PMID:27293323

  16. Propionibacterium freudenreichii component 1.4‐dihydroxy‐2‐naphthoic acid (DHNA) attenuates dextran sodium sulphate induced colitis by modulation of bacterial flora and lymphocyte homing

    PubMed Central

    Okada, Y; Tsuzuki, Y; Miyazaki, J; Matsuzaki, K; Hokari, R; Komoto, S; Kato, S; Kawaguchi, A; Nagao, S; Itoh, K; Watanabe, T; Miura, S

    2006-01-01

    Background and aim 1.4‐Dihydroxy‐2‐naphthoic acid (DHNA), a bifidogenic growth stimulator from Propionibacterium freudenreichii, is thought to have a beneficial effect as a prebiotic; however, its in vivo effect on intestinal inflammation remains unknown. The aim of this study was to determine whether oral administration of DHNA can ameliorate dextran sodium sulphate (DSS) induced colitis and to determine the possible underlying mechanisms. Method Colitis was induced in mice by treatment with 2.0% DSS for seven days. DHNA (0.6 or 2.0 mg/kg) was given in drinking water prior to (preventive study) or after (therapeutic study) DSS administration. Colonic damage was histologically scored, and mucosal addressin cell adhesion molecule 1 (MAdCAM‐1) expression and β7 positive cell infiltration were determined by immunohistochemistry. mRNA levels of proinflammatory cytokines (interleukin (IL)‐1β, IL‐6 and tumour necrosis factor α (TNF‐α)) were determined by quantitative real time polymerase chain reaction. In addition, bacterial flora in the caecum, concentrations of short chain acids, and luminal pH were examined. Results DHNA improved survival rate and histological damage score in mice administered DSS in both the preventive and therapeutic studies. DHNA significantly attenuated the enhanced expression of MAdCAM‐1, the increased β7 positive cell number, and the increased mRNA levels of IL‐1β, IL‐6, and TNF‐α in DSS treated colon. In addition, the decreased number of Lactobacillus and Enterobacteriaceae induced by DSS was recovered by DHNA. Preventive effects on decrease in butyrate concentration and decrease in pH level in mice administered DSS were also observed in the DHNA preventive study. Conclusion DHNA, a novel type of prebiotic, attenuates colonic inflammation not only by balancing intestinal bacterial flora but also by suppressing lymphocyte infiltration through reduction of MAdCAM‐1. PMID:16299037

  17. Alleviation of Antioxidant Defense System by Ozonized Olive Oil in DNBS-Induced Colitis in Rats

    PubMed Central

    Bayoumi, Fatehia A.; Ahmed, Naglaa G.

    2014-01-01

    The aim of the study was to evaluate the potential protective effect of ozonized olive oil (OZO) in 2,4-dinitrobenzene sulphuric acid (DNBS) induced colitis in rats and to elucidate the role of some antioxidant defense system (superoxide dismutase “SOD,” glutathione peroxidase “GSH-Px,” and catalase “CAT”) in these effects. The physicochemical parameters including viscosity, peroxide, and acid values of olive oil and OZO were evaluated. The animals were divided into several groups and the colitis was induced in the rats by intracolonic instillation of DNBS at dose of 15 mg/rat. Olive oil (OO) at dose of 6 mg/kg and OZO at doses of 3 and 6 mg/kg was administered orally for 7 days, starting the day before induction of colitis. Our results showed that macroscopic and microscopic damage scores were significantly reduced in a dose response manner in rats pretreated with OZO only. In contrast, CAT, GSH-Px, and SOD activities were significantly increased in the distal colon of inflamed animals pretreated with OZO with respect to control group dose dependently. Results demonstrate that OZO pretreatment exerts protective effects in DNBS induced colitis in rats and provide evidence that the protective effects of OZO are mediated by stimulation of some antioxidant enzymes. PMID:25276059

  18. Alleviation of antioxidant defense system by ozonized olive oil in DNBS-induced colitis in rats.

    PubMed

    Abu-Gharbieh, Eman; Bayoumi, Fatehia A; Ahmed, Naglaa G

    2014-01-01

    The aim of the study was to evaluate the potential protective effect of ozonized olive oil (OZO) in 2,4-dinitrobenzene sulphuric acid (DNBS) induced colitis in rats and to elucidate the role of some antioxidant defense system (superoxide dismutase "SOD," glutathione peroxidase "GSH-Px," and catalase "CAT") in these effects. The physicochemical parameters including viscosity, peroxide, and acid values of olive oil and OZO were evaluated. The animals were divided into several groups and the colitis was induced in the rats by intracolonic instillation of DNBS at dose of 15 mg/rat. Olive oil (OO) at dose of 6 mg/kg and OZO at doses of 3 and 6 mg/kg was administered orally for 7 days, starting the day before induction of colitis. Our results showed that macroscopic and microscopic damage scores were significantly reduced in a dose response manner in rats pretreated with OZO only. In contrast, CAT, GSH-Px, and SOD activities were significantly increased in the distal colon of inflamed animals pretreated with OZO with respect to control group dose dependently. Results demonstrate that OZO pretreatment exerts protective effects in DNBS induced colitis in rats and provide evidence that the protective effects of OZO are mediated by stimulation of some antioxidant enzymes. PMID:25276059

  19. The Role of CXCR3 in DSS-Induced Colitis

    PubMed Central

    Chami, Belal; Yeung, Amanda W. S.; van Vreden, Caryn; King, Nicholas J. C.; Bao, Shisan

    2014-01-01

    Inflammatory bowel disease (IBD) is a group of disorders that are characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the aetiopathogenesis is poorly understood, it is widely believed that IBD stems from a dysregulated immune response towards otherwise harmless commensal bacteria. Chemokines induce and enhance inflammation through their involvement in cellular trafficking. Reducing or limiting the influx of these proinflammatory cells has previously been demonstrated to attenuate inflammation. CXCR3, a chemokine receptor in the CXC family that binds to CXCL9, CXCL10 and CXCL11, is strongly overexpressed in the intestinal mucosa of IBD patients. We hypothesised that CXCR3 KO mice would have impaired cellular trafficking, thereby reducing the inflammatory insult by proinflammatory cell and attenuating the course of colitis. To investigate the role of CXCR3 in the progression of colitis, the development of dextran sulfate sodium (DSS)-induced colitis was investigated in CXCR3−/− mice over 9 days. This study demonstrated attenuated DSS-induced colitis in CXCR3−/− mice at both the macroscopic and microscopic level. Reduced colitis correlated with lower recruitment of neutrophils (p = 0.0018), as well as decreased production of IL-6 (p<0.0001), TNF (p = 0.0038), and IFN-γ (p = 0.0478). Overall, our results suggest that CXCR3 plays an important role in recruiting proinflammatory cells to the colon during colitis and that CXCR3 may be a therapeutic target to reduce the influx of proinflammatory cells in the inflamed colon. PMID:24992040

  20. Kefir treatment ameliorates dextran sulfate sodium-induced colitis in rats

    PubMed Central

    Senol, Altug; Isler, Mehmet; Sutcu, Recep; Akin, Mete; Cakir, Ebru; Ceyhan, Betul M; Kockar, M Cem

    2015-01-01

    AIM: To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium (DSS) in rats. METHODS: Twenty-four male Wistar-albino rats were randomized into four groups: normal control, kefir-control, colitis, and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 mL kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo (skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index (DAI), based on daily weight loss, stool consistency, and presence of bleeding in feces. Rats were sacrificed on the 15th day, blood specimens were collected, and colon tissues were rapidly removed. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-10, malondialdehyde, and inducible nitric oxide synthase (iNOS) were measured in colon tissue. RESULTS: The DAI was lower in the kefir-colitis group than in the colitis group (on the 3rd and 5th days of colitis induction; P < 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6th day in the kefir-colitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores (P < 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group (P < 0

  1. Validation and optimization of experimental colitis induction in rats using 2, 4, 6-trinitrobenzene sulfonic acid

    PubMed Central

    Motavallian-Naeini, A.; Andalib, S.; Rabbani, M.; Mahzouni, P.; Afsharipour, M.; Minaiyan, M.

    2012-01-01

    Trinitrobenzene sulfonic acid (TNBS)-induced colitis is one of the most common methods for studying inflammatory bowel disease in animal models. Several factors may, however, affect its reproducibility, rate of animal mortality, and macroscopic and histopathological outcomes. Our aim was to validate the main contributing factors to this method and compare the effects of different reference drugs upon remission of resultant colon injuries. TNBS was dissolved in 0.25 ml of ethanol (50% v/v) and instilled (25, 50, 100 and 150 mg/kg) intracolonically to the male Wistar rats. After determination of optimum dose of TNBS in male rats and assessment of this dose in female rats, they were treated with reference drugs including dexamethasone [1 mg/kg, intraperitoneally (i.p.) and 2 mg/kg, orally (p.o.)], Asacol (mesalazine, 100 mg/kg, p.o.; 150 mg/kg, enema) and hydrocortisone acetate (20 mg/kg, i.p.; 20 mg/kg, enema) which started 2 h after colitis induction and continued daily for 6 consecutive days. Thereafter, macroscopic and microscopic parameters and clinical features were assessed and compared in different groups. We found that the optimum dose of TNBS for the reproducibility of colonic damage with the least mortality rate was 50 mg/kg. Amongst studied reference drugs, hydrocortisone acetate (i.p.), dexamethasone (i.p. and p.o.) and Asacol (p.o.) significantly diminished the severity of macroscopic and microscopic injuries and could be considered effective for experimental colitis studies in rats . Our findings suggest that optimization of TNBS dose is essential for induction of colitis under the laboratory conditions; and gender exerts no impact upon macroscopic and histological characteristics of TNBS-induced colitis in rats. Furthermore, the enema forms of hydrocortisone and Asacol are not appropriate reference drugs. PMID:23181094

  2. Validation and optimization of experimental colitis induction in rats using 2, 4, 6-trinitrobenzene sulfonic acid.

    PubMed

    Motavallian-Naeini, A; Andalib, S; Rabbani, M; Mahzouni, P; Afsharipour, M; Minaiyan, M

    2012-07-01

    Trinitrobenzene sulfonic acid (TNBS)-induced colitis is one of the most common methods for studying inflammatory bowel disease in animal models. Several factors may, however, affect its reproducibility, rate of animal mortality, and macroscopic and histopathological outcomes. Our aim was to validate the main contributing factors to this method and compare the effects of different reference drugs upon remission of resultant colon injuries. TNBS was dissolved in 0.25 ml of ethanol (50% v/v) and instilled (25, 50, 100 and 150 mg/kg) intracolonically to the male Wistar rats. After determination of optimum dose of TNBS in male rats and assessment of this dose in female rats, they were treated with reference drugs including dexamethasone [1 mg/kg, intraperitoneally (i.p.) and 2 mg/kg, orally (p.o.)], Asacol (mesalazine, 100 mg/kg, p.o.; 150 mg/kg, enema) and hydrocortisone acetate (20 mg/kg, i.p.; 20 mg/kg, enema) which started 2 h after colitis induction and continued daily for 6 consecutive days. Thereafter, macroscopic and microscopic parameters and clinical features were assessed and compared in different groups. We found that the optimum dose of TNBS for the reproducibility of colonic damage with the least mortality rate was 50 mg/kg. Amongst studied reference drugs, hydrocortisone acetate (i.p.), dexamethasone (i.p. and p.o.) and Asacol (p.o.) significantly diminished the severity of macroscopic and microscopic injuries and could be considered effective for experimental colitis studies in rats . Our findings suggest that optimization of TNBS dose is essential for induction of colitis under the laboratory conditions; and gender exerts no impact upon macroscopic and histological characteristics of TNBS-induced colitis in rats. Furthermore, the enema forms of hydrocortisone and Asacol are not appropriate reference drugs. PMID:23181094

  3. BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats.

    PubMed

    Yukitake, Hiroshi; Kimura, Haruhide; Suzuki, Hirobumi; Tajima, Yasukazu; Sato, Yoshimi; Imaeda, Toshihiro; Kajino, Masahiro; Takizawa, Masayuki

    2011-01-01

    Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that are primarily represented by ulcerative colitis and Crohn's disease. The etiology of IBD is not well understood; however, oxidative stress is considered a potential etiological and/or triggering factor for IBD. We have recently reported the identification of BTZO-1, an activator of antioxidant response element (ARE)-mediated gene expression, which protects cardiomyocytes from oxidative stress-induced insults. Here we describe the potential of BTZO-15, an active BTZO-1 derivative for ARE-activation with a favorable ADME-Tox profile, for the treatment of IBD. BTZO-15 induced expression of heme oxygenase-1 (HO-1), an ARE-regulated cytoprotective protein, and inhibited NO-induced cell death in IEC-18 cells. Large intestine shortening, rectum weight gain, diarrhea, intestinal bleeding, and an increase in rectal myeloperoxidase (MPO) activity were observed in a dextran sulfate sodium (DSS)-induced colitis rat model. Oral administration of BTZO-15 induced HO-1 expression in the rectum and attenuated DSS-induced changes. Furthermore BTZO-15 reduced the ulcerated area and rectal MPO activity in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats without affecting rectal TNF-α levels. These results suggest that BTZO-15 is a promising compound for a novel IBD therapeutic drug with ARE activation properties. PMID:21853095

  4. Systemic responses of mice to dextran sulfate sodium-induced acute ulcerative colitis using 1H NMR spectroscopy.

    PubMed

    Dong, Fangcong; Zhang, Lulu; Hao, Fuhua; Tang, Huiru; Wang, Yulan

    2013-06-01

    The interplay between genetic mutation and environmental factors is believed to contribute to the etiology of inflammatory bowel disease (IBD). While focused attention has been paid to the aforementioned research, time-specific and organ-specific metabolic changes associated with IBD are still lacking. Here, we induced acute ulcerative colitis in mice by providing water containing 3% dextran sulfate sodium (DSS) for 7 days and investigated the metabolic changes of plasma, urine, and a range of biological tissues by employing a (1)H nuclear magnetic resonance (NMR)-based metabonomics approach with complementary information on serum clinical chemistry and histopathology. We found that DSS-induced acute ulcerative colitis leads to significant elevations in the levels of amino acids in plasma and decreased levels in the membrane-related metabolites and a range of nucleotides, nucleobases, and nucleosides in the colon. In addition, acute-colitis-induced elevations in the levels of nucleotides in the liver were observed, accompanied by reduced levels of glucose. DSS-induced acute colitis also resulted in increased levels of oxidized glutathione and attenuated levels of taurine in the spleen. Furthermore, acute colitis resulted in depletion in the levels of gut microbial cometabolites in urine along with an increase in citric acid cycle intermediates. These findings suggest that DSS-induced acute colitis causes a disturbance of lipid and energy metabolism, damage to the colon and liver, a promoted antioxidative and anti-inflammatory response, and perturbed gut microbiotal communities. The information obtained here provided details of the time-dependent and holistic metabolic changes in the development of the DSS-induced acute ulcerative colitis, which could be useful in discovery of novel therapeutic targets for management of IBD. PMID:23651354

  5. Anti-inflammatory effect of taurocholate on TNBS-induced ulcerative colitis in mice.

    PubMed

    Yang, Yang; He, Jiao; Suo, Yuan; Lv, Le; Wang, Jingjing; Huo, Chuanchuan; Zheng, Zongwei; Wang, Ziye; Li, Jing; Sun, Wenji; Zhang, Yongmin

    2016-07-01

    Taurocholate is a natural conjugated bile acid. The aim of this study was to evaluate the anti-inflammatory effect of taurocholate in TNBS-induced ulcerative colitis in mice. The colitis were induced by rectal administration of TNBS. After 24h, the experimental animals were treated with sulfasalazine (SASP, 500mg/kg/day) and taurocholate (20, 40 and 60mg/kg) for 7 consecutive days. The anti-inflammatory effects of taurocholate for colitis were assessed by body weight, colonic weight and length, macroscopic scores, and histopathological examinations. In addition, the colonic tissue levels of myeloperoxidase (MPO) activity, interleukin (IL)-1β, interferon (IFN-γ) and tumour necrosis factor-α (TNF-α) were also determined to assess the effect of taurocholate. Compared with the model group, treatment with taurocholate (20, 40 and 60mg/kg) significantly inhibited the body weight loss, improved colonic weight and length, and decreased macroscopic and histopathological scores. Furthermore, the activity accumulation of MPO and the colonic tissue levels of IL-1β, IFN-γ and TNF-α were also decreased by administration of taurocholate. All the findings of this study suggested that taurocholate has the anti-inflammatory effect in ulcerative colitis in mice and indicated it as a good candidate to treat inflammatory bowel disease. PMID:27261622

  6. The effect of chemically induced colitis, psychological stress and their combination on visceral pain in female Wistar rats.

    PubMed

    Deiteren, Annemie; Vermeulen, Wim; Moreels, Tom G; Pelckmans, Paul A; De Man, Joris G; De Winter, Benedicte Y

    2014-09-01

    Visceral sensitivity is of pathophysiological importance in abdominal pain disorders and can be modulated by inflammation and stress. However, it is unclear whether inflammation and stress alter visceral perception independently of each other or in conjunction through neuroendocrine interactions. Therefore, we compared the short- and long-term effects of experimental colitis and water avoidance stress (WAS), alone or in combination, on visceral sensitivity in female Wistar rats. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colonoscopically confirmed. During WAS, rats were placed on a platform surrounded by water for 1 h. Visceral sensitivity was assessed by quantifying the visceromotor responses (VMRs) to colorectal distension. Activation of the hypothalamic-pituitary-adrenal axis was determined by measuring serum corticosterone in a separate protocol. TNBS instillation resulted in overt colitis, associated with significant visceral hypersensitivity during the acute inflammatory phase (3 days post-TNBS; n = 8/group); after colitis had subsided (28 days post-TNBS), hypersensitivity was resolved (n = 4-8/group). Single WAS was associated with increased VMRs of a magnitude comparable to acute TNBS-induced hypersensitivity (n = 8/group). However, after repetitive WAS no significant hypersensitivity was present (n = 8/group). No additive effect of colitis and stress was seen on visceral pain perception (n = 6-8/group). Corticosterone levels were only increased in acute TNBS-colitis, acute WAS and their combination. To conclude, both colitis and stress successfully induced short-term visceral hypersensitivity and activated the hypothalamic-pituitary-adrenal axis, but long-term effects were absent. In addition, our current findings do not support an additive effect of colitis and stress on visceral sensitivity in female Wistar rats. PMID:25089934

  7. Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice.

    PubMed

    Liu, Baohai; Piao, Xuehua; Guo, Lianyi; Liu, Shanshan; Chai, Fang; Gao, Leming

    2016-06-01

    Ursolic acid (UA) has been reported to have a protective effect in colitis. However, the underlying mechanisms remain to be elucidated. In the present study, experimental ulcerative colitis was induced in male BALB/c mice by the administration of 5% dextran sulfate sodium (DSS) for 7 days, followed by treatment with UA for another 7 days. Hematoxylin & eosin staining was performed to evaluate colon tissue damage, and enzyme assays were used to measure malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon homogenate. In addition, serum levels of interleukin (IL)‑1β and tumor necrosis factor (TNF)‑α were measured using an ELISA, and the level of nuclear factor (NF)‑κB p65 in the colonic tissues was assessed by western blotting. The 7‑day DSS administration induced marked colon damage, increased the serum levels of IL‑1β and TNF‑α, increased MDA content and decreased SOD activity in the colon homogenate. These changes were significantly improved by treatment with UA. UA also reduced the DSS‑stimulated high nuclear level of NF‑κB p65 in the colon tissues. These results demonstrate a protective role of UA in ulcerative colitis, and suggest that anti-inflammatory and antioxidant activities are involved in the underlying mechanisms. PMID:27082984

  8. Baicalin attenuates TNBS-induced colitis in rats by modulating the Th17/Treg paradigm.

    PubMed

    Zou, Ying; Dai, Shi-Xue; Chi, Hong-Gang; Li, Tao; He, Zhi-Wei; Wang, Jian; Ye, Cai-Guo; Huang, Guo-Liang; Zhao, Bing; Li, Wen-Yang; Wan, Zheng; Feng, Jin-Shan; Zheng, Xue-Bao

    2015-10-01

    Baicalin, a flavonoid, has a wide range of pharmacological properties, including immunomodulation. The objective of this study was to investigate the effect of baicalin on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in a colitis model. The rat colitis model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baicalin (10 ml/kg, each) or mesalazine (positive control) was then administered orally for 7 days. Inflammatory and immunological responses were evaluated by pathology, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, western blot analysis, and flow cytometry. Our study showed that baicalin not only significantly attenuated TNBS-induced colitis by reducing the disease activity index as well as macroscopic and microscopic scores, but it also improved the weight loss and shortening of the colon. Baicalin treatment also induced a significant decrease in the levels of inflammatory mediators, including the myeloperoxidase activity, the levels of tumor necrosis factor α, IL-1β, and Th1-related cytokines IL-12 and IFN-γ. Furthermore, the beneficial effects of baicalin seem to be associated with regulation of the Th17 and Treg paradigm. We found that administration of baicalin significantly downregulated the number of Th17 cells and the levels of Th17-related cytokines (IL-17 and IL-6) and retinoic acid receptor-related orphan receptor γt. In contrast, there was an increase in Treg cells numbers, Treg-related cytokines transforming growth factor-β and IL-10, and forkhead box P3. Our results suggest that the anti-inflammatory effect of baicalin may be linked to modulation of the balance between Th17 and Treg cells in TNBS-induced ulcerative colitis. PMID:25269538

  9. On the benefit of galls of Quercus brantii Lindl. in murine colitis: the role of free gallic acid

    PubMed Central

    Khanavi, Mahnaz; Sabbagh-Bani-Azad, Mansoureh; Abdolghaffari, Amir Hossein; Vazirian, Mahdi; Isazadeh, Isa; Rezvanfar, Mohammad Amin; Baeeri, Maryam; Mohammadirad, Azadeh; Rahimi, Roja; Shams-Ardekani, Mohammad Reza

    2014-01-01

    Introduction In this study we investigated the effect of gall of Quercus brantii Lindl., a traditional Iranian medicine, in a murine model of experimental colitis induced in male rats by rectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Material and methods Quantification of the main active components was done for estimation of total phenolic content and free gallic acid. Gall of Quercus brantii Lindl. in two forms (gall powder and gall hydro alcoholic extract) was gavaged for 10 days (500 mg/kg). Ten days after induction of colitis, colonic status was examined by macroscopic, microscopic and biochemical analyses. Colonic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were analyzed as biomarkers of inflammatory condition. To determine the role of oxidative stress (OS) in colitis, the levels of cellular lipid peroxidation (LPO), total antioxidant power (TAP) and myeloperoxidase (MPO) were measured in colon tissues. Results TNBS-induced colitis exhibited a significant increase in colon MPO activity and concentrations of cellular LPO, TNF-α and IL-1β, while TAP was significantly reduced. Microscopic evaluations of the colonic damage in the colitis group revealed multifocal degenerative changes in the epithelial lining and areas of necrosis, extensive mucosal and sub-mucosal damage with congested blood vessels, edema and hemorrhages along with extensive infiltration of inflammatory cells. Parameters including macroscopic and microscopic scores, TNF-α, IL-1β, LPO, TAP and MPO improved by both gall extract and gall powder of Quercus brantii Lindl. and reached close to normal levels. The level of total phenols (GAE/100 g of sample) and free gallic acid were estimated to be 88.43 ±7.23 (mean ± SD) and 3.74% of dry weight, respectively. Conclusions The present study indicates that the gall of Quercus brantii Lindl. is able to exert antioxidative and anti-inflammatory effects on the biochemical and pathological parameters of colitis

  10. Very long O-antigen chains enhance fitness during Salmonella-induced colitis by increasing bile resistance.

    PubMed

    Crawford, Robert W; Keestra, A Marijke; Winter, Sebastian E; Xavier, Mariana N; Tsolis, Renée M; Tolstikov, Vladimir; Bäumler, Andreas J

    2012-09-01

    Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine. PMID:23028318

  11. Very Long O-antigen Chains Enhance Fitness during Salmonella-induced Colitis by Increasing Bile Resistance

    PubMed Central

    Crawford, Robert W.; Keestra, A. Marijke; Winter, Sebastian E.; Xavier, Mariana N.; Tsolis, Renée M.; Tolstikov, Vladimir; Bäumler, Andreas J.

    2012-01-01

    Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine. PMID:23028318

  12. Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, attenuates colonic inflammation in rats with DSS-induced colitis.

    PubMed

    Camuesco, Desirée; Gálvez, Julio; Nieto, Ana; Comalada, Mònica; Rodríguez-Cabezas, M Elena; Concha, Angel; Xaus, Jordi; Zarzuelo, Antonio

    2005-04-01

    Previous studies proposed a protective role of the dietary intake of (n-3) PUFA in human inflammatory bowel disease (IBD), but almost no studies have been performed using olive oil. The aims of the present study were to test the beneficial effects of an olive oil-based diet with or without fish oil, rich in (n-3) PUFA, in the dextran sodium sulfate (DSS) model of rat colitis and to elucidate the mechanisms involved in their potential beneficial effects, with special attention to the production of some of the mediators involved in the intestinal inflammatory response, such as leukotriene B(4) (LTB(4)), tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). Rats were fed the different diets for 2 wk before colitis induction and thereafter until colonic evaluation 15 d later. Colitic rats fed the olive oil-based diet had a lower colonic inflammatory response than those fed the soybean oil diet, and this beneficial effect was increased by the dietary incorporation of (n-3) PUFA. A restoration of colonic glutathione levels and lower colonic NO synthase expression occurred in all colitic rats fed an olive oil diet compared with the control colitic group that consumed the soybean oil diet. However, (n-3) PUFA incorporation into an olive oil diet significantly decreased colonic TNFalpha and LTB(4) levels compared with colitic rats that were not supplemented with fish oil. These results affirm the benefits of an olive oil diet in the management of IBD, which are further enhanced by the addition of (n-3) PUFA. PMID:15795419

  13. Effect of Nanometric Lactobacillus plantarum in Kimchi on Dextran Sulfate Sodium-Induced Colitis in Mice.

    PubMed

    Lee, Hyun Ah; Bong, Yeon-Ju; Kim, Hyunung; Jeong, Ji-Kang; Kim, Hee-Young; Lee, Kwang-Won; Park, Kun-Young

    2015-10-01

    Nanometric Lactobacillus plantarum (nLp) is a processed form of Lab. plantarum derived from kimchi and is 0.5-1.0 μm in size. This study was undertaken to determine the effect of nLp and kimchi plus nLp (K-nLp) on a dextran sulfate sodium (DSS)-induced mouse model of colitis. Animals fed nLp or K-nLp had longer colons, but lower colon weights per unit length than DSS controls. In addition, nLp- or K-nLp-fed animals showed lower levels of proinflammatory cytokines and inflammatory genes in serum and in colon tissues, lower populations of total bacteria, but higher populations of lactic acid bacteria in feces, and lower activities of fecal β-glucosidase and β-glucuronidase. Furthermore, these suppressive activities of nLp on colitis were equivalent to or higher than those of naive Lab. plantarum. Consequently, nLp was found to exhibit anticolitic effects, and the addition of nLp to kimchi was found to enhance the protective activity of kimchi against DSS-induced colitis. These results suggest that nLp might be an effective substitute for live probiotics and be useful as a functional ingredient with the anticolitic activity by the probiotic and food processing industries. PMID:26305853

  14. Soluble epoxide hydrolase deficiency inhibits dextran sulfate sodium-induced colitis and carcinogenesis in mice.

    PubMed

    Zhang, Wanying; Li, Haonan; Dong, Hua; Liao, Jie; Hammock, Bruce D; Yang, Guang-Yu

    2013-12-01

    Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH(-/-) mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62±20.91 mm(3) vs. 22.42±11.22 mm(3)), and a significant number of pre-cancerous dysplasia (3±1.18 vs. 2±0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH(-/-) mice (44.7%±24.9% vs. 20.2%±16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1β and TNF-α expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/ dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis

  15. Selecting lactic acid bacteria for their safety and functionality by use of a mouse colitis model.

    PubMed

    Daniel, Catherine; Poiret, Sabine; Goudercourt, Denise; Dennin, Veronique; Leyer, Gregory; Pot, Bruno

    2006-09-01

    Studies showed that specific probiotics might provide therapeutic benefits in inflammatory bowel disease. However, a rigorous screening of new probiotics is needed to study possible adverse interactions with the host, particularly when intended for administration to individuals with certain health risks. In this context, the objective of this study was to investigate the role of three lactobacilli (LAB) on intestinal inflammation and bacterial translocation using variations of the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis. We first compared the in vitro ability of LAB to survive gastrointestinal tract (GIT) conditions and their ability to persist in the GIT of mice following daily oral administration. As a control, we included a nonprobiotic Lactobacillus paracasei strain, previously isolated from an endocarditis patient. Feeding high doses of LAB strains to healthy and to TNBS-treated mice did not induce any detrimental effect or abnormal translocation of the bacteria. Oral administration of Lactobacillus salivarius Ls-33 had a significant preventive effect on colitis in mice, while Lactobacillus plantarum Lp-115 and Lactobacillus acidophilus NCFM did not. None of the three selected LAB strains translocated to extraintestinal organs of TNBS-treated mice. In contrast, L. paracasei exacerbated colitis under severe inflammatory conditions and translocated to extraintestinal organs. This study showed that evaluations of the safety and functionality of new probiotics are recommended. We conclude that not all lactobacilli have similar effects on intestinal inflammation and that selected probiotics such as L. salivarius Ls-33 may be considered in the prevention or treatment of intestinal inflammation. PMID:16957197

  16. Oleic acid, hydroxytyrosol and n-3 fatty acids collectively modulate colitis through reduction of oxidative stress and IL-8 synthesis; in vitro and in vivo studies.

    PubMed

    Reddy, K Vijay Kumar; Naidu, K Akhilender

    2016-06-01

    Our recent study has demonstrated that medium chain triglycerides (MCT) and monounsaturated fatty acids potentiate the beneficial effects of fish oil on risk factors of cardiovascular disease. In the present study, we have investigated the influence of MCT or olive oil on the protective and mucosal healing ability of fish oil in ulcerative colitis using cell simulation and animal models. Caco-2 cells grown in medium chain fatty acids enriched medium has exaggerated t-butyl hydroperoxide induced cell damage, GSH depletion, and IL-1β induced IL-8 synthesis, compared to the cells grown in oleic acid & hydroxytyrosol (OT) enriched medium. Further, combined treatment of cells with eicosapentaenoic acid, docosahexaenoic acid, and OT has remarkably attenuated the cell damage, and IL-8 synthesis, compared to individual treatments. To evaluate the effect of these lipid formulations in vivo, adult Wistar rats were fed diet enriched with high amount of medium chain triglycerides (MCT), virgin olive oil, or their combination with fish oil. Colitis was induced in rats using dextran sulfate sodium (DSS) for 7days followed by 10-days of recovery period. Rats of MCT group exhibit severe disease activity, higher levels of inflammatory cytokines in the colon compared to the olive oil group. Furthermore, there was persistent body weight loss, loose stools, higher levels of inflammatory cytokines in the rats of MCT group, even after DSS was withdrawn from drinking water. Conversely, fish oil has remarkably attenuated the DSS induced alterations in both MCT and olive oil diet groups with significantly greater effect in the olive oil group. Thus, MCT increase the susceptibility to colitis through oxidative damage and IL-8 synthesis in intestinal epithelial cells. The beneficial effects of virgin olive oil could be partially attributed to hydroxytyrosol. Combined treatment of hydroxytyrosol, oleic acid and n-3 fatty acids exhibit huge therapeutic benefits in colitis. PMID:27016717

  17. IDO1 plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice.

    PubMed

    Takamatsu, Manabu; Hirata, Akihiro; Ohtaki, Hirofumi; Hoshi, Masato; Hatano, Yuichiro; Tomita, Hiroyuki; Kuno, Toshiya; Saito, Kuniaki; Hara, Akira

    2013-09-15

    IDO, an enzyme that degrades the essential amino acid L-tryptophan to N-formylkynurenine, is known to exert immunomodulatory effects in a number of diseases and disorders. IDO expression is increased in tumors, where it is thought to be involved in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for relapsed or refractory solid tumors; however, there remains a concern that attenuation of the immunosuppressive function of IDO might exacerbate inflammatory responses. In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in Ido1 gene-deficient (Ido1⁻/⁻) mice than in Ido1 wild-type (Ido1⁺/⁺) mice, indicating a role for IDO1 in suppression of acute colitis. Consistent with this, the expression of Ido1 was increased in the colonic interstitial tissues of TNBS-treated Ido1⁺/⁺ mice. Furthermore, transplantation of Ido1⁺/⁺ bone marrow cells into Ido1⁻/⁻ mice reduced the pathological damage associated with colitis, altered the expression of cytokines, including IFN-γ, TNF-α, and IL-10, and increased the number of CD4⁺ Foxp3⁺ regulatory T cells in the colon. Pharmacological inhibition of IDO enzymatic activity by oral administration of 1-methyltryptophan (1-methyl-L-tryptophan or 1-methyl-D-tryptophan) significantly increased the severity of TNBS-induced colitis in mice, demonstrating that both stereoisomers can promote colitis. Collectively, our data indicate that IDO1 plays an important immunoregulatory role in the colon. PMID:23956437

  18. Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice

    PubMed Central

    Agollah, Germaine D; Wu, Grace; Peng, Ho-Lan; Kwon, Sunkuk

    2015-01-01

    AIM: To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium (DSS)-induced acute colitis. METHODS: Balb/c mice were administered 4% DSS in lieu of drinking water ad libitum for 7 d and monitored to assess disease activity including body weight, diarrhea severity, and fecal bleeding. Control mice received standard drinking water with no DSS. Changes in mesenteric lymphatics were assessed following oral administration of a fluorescently-labelled fatty acid analogue, while dermal lymphatic function and architecture was longitudinally characterized using dynamic near-infrared fluorescence (NIRF) imaging following intradermal injection of indocyanine green (ICG) at the base of the tail or to the dorsal aspect of the left paw prior to, 4, and 7 d after DSS administration. We also measured dye clearance rate after injection of Alexa680-bovine serum albumin (BSA). NIRF imaging data was analyzed to reveal lymphatic contractile activity after selecting fixed regions of interest (ROIs) of the same size in fluorescent lymphatic vessels on fluorescence images. The averaged fluorescence intensity within the ROI of each fluorescence image was plotted as a function of imaging time and the lymphatic contraction frequency was computed by assessing the number of fluorescent pulses arriving at a ROI. RESULTS: Mice treated with DSS developed acute inflammation with clinical symptoms of loss of body weight, loose feces/watery diarrhea, and fecal blood, all of which were aggravated as disease progressed to 7 d. Histological examination of colons of DSS-treated mice confirmed acute inflammation, characterized by segmental to complete loss of colonic mucosa with an associated chronic inflammatory cell infiltrate that extended into the deeper layers of the wall of the colon, compared to control mice. In situ intravital imaging revealed that mice with acute colitis showed significantly fewer fluorescent mesenteric lymphatic vessels

  19. Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

    PubMed Central

    Ino, Satoshi; Kohda, Chikara; Takeshima, Kosuke; Ishikawa, Hiroki; Norose, Tomoko; Yamochi, Toshiko; Takimoto, Masafumi; Takahashi, Hiroshi; Tanaka, Kazuo

    2016-01-01

    AIM: To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis. METHODS: Colitis was induced in 6- to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-)] were intragastrically (i.g.) administered ovalbumin (OVA) as a tolerogen before systemic challenge with OVA. Following this, serum levels of OVA-specific IgE antibodies were measured. In mice with active colitis, CD4+CD25+Foxp3+ cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction. RESULTS: Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS [DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4+CD25+Foxp3+ cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change. CONCLUSION: Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correlate with these results. PMID:27158540

  20. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress

    PubMed Central

    Tong, Ling-chang; Wang, Yue; Wang, Zhi-bin; Liu, Wei-ye; Sun, Sheng; Li, Ling; Su, Ding-feng; Zhang, Li-chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7–14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  1. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress.

    PubMed

    Tong, Ling-Chang; Wang, Yue; Wang, Zhi-Bin; Liu, Wei-Ye; Sun, Sheng; Li, Ling; Su, Ding-Feng; Zhang, Li-Chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7-14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  2. Experimental colitis in mice is attenuated by topical administration of chlorogenic acid.

    PubMed

    Zatorski, Hubert; Sałaga, Maciej; Zielińska, Marta; Piechota-Polańczyk, Aleksandra; Owczarek, Katarzyna; Kordek, Radzisław; Lewandowska, Urszula; Chen, Chunqiu; Fichna, Jakub

    2015-06-01

    Epidemiological data suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease, and inflammation. Chlorogenic acid (CGA), an ester of caffeic and quinic acids, is one of the most abundant polyphenol compounds in human diet with proven biological effectiveness both in vitro and in vivo. The aim of the study is to investigate the possible anti-inflammatory effect of CGA in the gastrointestinal (GI) tract and its mechanism of action. We used a well-established model of colitis, induced by intracolonic (i.c.) administration of trinitrobenzenesulfonic acid (TNBS) in mice. The anti-inflammatory effect of CGA in the colon was evaluated based on the clinical and macroscopic and microscopic parameters. To investigate the mechanism of protective action of CGA, myeloperoxidase (MPO), H2O2, and NF-κB levels were assessed in the colon tissue. CGA administered i.c. at the dose of 20 mg/kg (two times daily) protected against TNBS-induced colitis more effectively than the same dose administered orally (p.o.), as evidenced by significantly lower macroscopic and ulcer scores. Furthermore, CGA (20 mg/kg, i.c.) reduced neutrophil infiltration, as demonstrated by decreased MPO activity. Moreover, CGA suppressed activation of NF-κB, as evidenced by lower levels of phospho-NF-κB/NF-κB ratio in the tissue. CGA did not affect the oxidative stress pathways. CGA exhibits anti-inflammatory properties through reduction of neutrophil infiltration and inhibition of NF-κB-dependent pathways. Our results suggest that CGA may have the potential to become a valuable supplement in the treatment of GI diseases. PMID:25743575

  3. Halofuginone reduces the inflammatory responses of DSS-induced colitis through metabolic reprogramming.

    PubMed

    Liu, Jing; Xiao, Hai-Tao; Wang, Hong-Sheng; Mu, Huai-Xue; Zhao, Ling; Du, Jun; Yang, Depo; Wang, Dongmei; Bian, Zhao-Xiang; Lin, Shu-Hai

    2016-06-21

    Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease. PMID:27197570

  4. The Influence of Ghrelin on the Development of Dextran Sodium Sulfate-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Dagmara; Warzecha, Zygmunt; Ceranowicz, Piotr; Fyderek, Krzysztof; Gałązka, Krystyna; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Pihut, Małgorzata; Dembiński, Artur

    2015-01-01

    Ghrelin has protective and therapeutic effects in the gut. The aim of present studies was to investigate the effect of treatment with ghrelin on the development of colitis evoked by dextran sodium sulfate (DSS). Methods. Studies have been performed on rats. Colitis was induced by adding 5% DSS to the drinking water for 5 days. During this period animals were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 8 nmol/kg/dose. On the sixth day, animals were anesthetized and the severity of colitis was assessed. Results. Treatment with ghrelin during administration of DSS reduced the development of colitis. Morphological features of colonic mucosa exhibited a reduction in the area and deep of mucosal damage. Ghrelin reversed the colitis-induced decrease in blood flow, DNA synthesis, and superoxide dismutase activity in colonic mucosa. These effects were accompanied by a decrease in the colitis-evoked increase in mucosal concentration of interleukin-1β and malondialdehyde. Treatment with ghrelin reversed the DSS-induced reduction in body weight gain. Conclusions. Administration of ghrelin exhibits the preventive effect against the development of DSS-induced colitis. This effect seems to be related to ghrelin's anti-inflammatory and antioxidative properties. PMID:26713317

  5. Serum Amino Acids Profile and the Beneficial Effects of L-Arginine or L-Glutamine Supplementation in Dextran Sulfate Sodium Colitis

    PubMed Central

    Wu, Miaomiao; Liu, Gang; Yang, Guan; Xion, Yan; Su, Dingding; Wu, Li; Li, Tiejun; Chen, Shuai; Duan, Jielin; Yin, Yulong; Wu, Guoyao

    2014-01-01

    This study was conducted to investigate serum amino acids profile in dextran sulfate sodium (DSS)-induced colitis, and impacts of graded dose of arginine or glutamine supplementation on the colitis. Using DSS-induced colitis model, which is similar to human ulcerative colitis, we determined serum profile of amino acids at day 3, 7, 10 and 12 (5 days post DSS treatment). Meanwhile, effects of graded dose of arginine (0.4%, 0.8%, and 1.5%) or glutamine (0.5%, 1.0% and 2.0%) supplementation on clinical parameters, serum amino acids, colonic tight junction proteins, colonic anti-oxidative indicators [catalase, total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px)], colonic pro-inflammatory cytokines [interleukin-1 beta (IL-1β), IL-6, IL-17 and tumor necrosis factor alpha (TNF-α)] in DSS-induced colitis were fully analyzed at day 7 and 12. Additionally, the activation of signal transduction pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), phosphoinositide-3-kinases (PI3K)/PI3K-protein kinase B (Akt), and myosin light chain kinase (MLCK)- myosin light chain (MLC20), were analyzed using immunoblotting. Serum amino acids analysis showed that DSS treatment changed the serum contents of amino acids, such as Trp, Glu, and Gln (P<0.05). Dietary arginine or glutamine supplementation had significant (P<0.05) influence on the clinical and biochemical parameters (T-SOD, IL-17 and TNF-α) in colitis model. These results were associated with colonic NF-κB, PI3K-Akt and MLCK signaling pathways. In conclusion, arginine or glutamine could be a potential therapy for intestinal inflammatory diseases. PMID:24505477

  6. Vitamin E has a dual effect of anti-inflammatory and antioxidant activities in acetic acid–induced ulcerative colitis in rats

    PubMed Central

    Tahan, Gulgun; Aytac, Erman; Aytekin, Huseyin; Gunduz, Feyza; Dogusoy, Gulen; Aydin, Seval; Tahan, Veysel; Uzun, Hafize

    2011-01-01

    Background Increased free radical production, decreased antioxidant capacity and excessive inflammation are well-known features in the pathogenesis of inflammatory bowel disease. Vitamin E is a powerful antioxidant and a scavenger of hydroxyl radicals, and it has been shown to have anti-inflammatory activities in tissues. We investigated the effects of vitamin E on inflammatory activities using an acetic acid (AA)–induced ulcerative colitis model in rats. Methods Wistar rats were divided into 4 groups. Acetic acid was given to 2 groups of animals to induce colitis while the other 2 groups received saline intrarectally. One AA-induced colitis group and 1 control group received vitamin E (30 U/kg/d) intraperitoneally and the pair groups received saline. After 4 days, we evaluated colonic changes biochemically by measuring proinflammatory cytokine levels in tissue homogenates and by histopathologic examination. Results Acetic acid caused colonic mucosal injury, whereas vitamin E administration suppressed these changes in the AA-induced colitis group (p < 0.001). Administration of AA resulted in increased levels of tumour necrosis factor-α, interleukin-1β, interleukin-6, myeloperoxidase and malondialdehyde, and decreased levels of glutathione and superoxide dismutase; vitamin E reversed these effects (all p < 0.001). Conclusion Our study proposes that vitamin E is an effective anti-inflammatory and antioxidant and may be a promising therapeutic option for ulcerative colitis. PMID:21933527

  7. Effect of acute and chronic DSS induced colitis on plasma eicosanoid and oxylipin levels in the rat.

    PubMed

    Willenberg, Ina; Ostermann, Annika I; Giovannini, Samoa; Kershaw, Olivia; von Keutz, Anne; Steinberg, Pablo; Schebb, Nils Helge

    2015-07-01

    Eicosanoids and oxylipins are potent lipid mediators involved in the regulation of inflammation. In order to evaluate their role and suitability as biomarkers in colitis, we analyzed their systemic levels in the acute and chronic phase of dextran sulfate sodium (DSS) induced colitis. Male Fischer 344 rats were treated in three cycles with 4% DSS in the drinking water (4 days followed by 10 days recovery) and blood was drawn 3 days prior to the first DSS treatment and on days 4, 11, 32 and 39. Histopathological evaluation of the colon tissue after 42 days showed that the animals developed a mild to severe chronic colitis. Consistently, prostaglandin levels were massively (twofold) elevated in the colonic tissue. LC-MS based targeted metabolomics was used to determine plasma oxylipin levels at the different time points. In the acute phase of inflammation directly after DSS treatment, epoxy-fatty acid (FA), dihydroxy-FA and hydroxy-FA plasma concentrations were uniformly elevated. With each treatment cycle the increase in these oxylipin levels was more pronounced. Our data suggest that in the acute phase of colitis release of polyunsaturated FAs from membranes in the inflamed tissue is reflected by a uniform increase of oylipins formed in different branches of the arachidonic acid cascade. However, during the recovery phases the systemic oxylipin pattern is not or only moderately altered and does not allow to evaluate the onset of chronic inflammation in the colon. PMID:25908302

  8. Astragalus polysaccharide attenuates rat experimental colitis by inducing regulatory T cells in intestinal Peyer’s patches

    PubMed Central

    Zhao, Hai-Mei; Wang, Yan; Huang, Xiao-Ying; Huang, Min-Fang; Xu, Rong; Yue, Hai-Yang; Zhou, Bu-Gao; Huang, Hong-Yan; Sun, Qi-Meng; Liu, Duan-Yong

    2016-01-01

    AIM: To explore probable mechanism underlying the therapeutic effect of Astragalus polysaccharide (APS) against experimental colitis. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into four groups. Colitis was induced with 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The rats with colitis were treated with 400 mg/kg of APS for 7 d. The therapeutic effect was evaluated by colonic weight, weight index of the colon, colonic length, and macroscopic and histological scores. The levels of regulatory T (Treg) cells in Peyer’s patches were measured by flow cytometry, and cytokines in colonic tissue homogenates were analyzed using enzyme-linked immunosorbent assay. The expression of related orphan receptor-γt (ROR-γt), IL-23 and STAT-5a was measured by Western blot. RESULTS: After 7-d treatment with APS, the weight index of the colon, colonic weight, macroscopical and histological scores were decreased, while the colonic length was increased compared with the model group. The expression of interleukin (IL)-2, IL-6, IL-17, IL-23 and ROR-γt in the colonic tissues was down-regulated, but Treg cells in Peyer’s patches, TGF-β and STAT5a in the colonic tissues were up-regulated. CONCLUSION: APS effectively ameliorates TNBS-induced experimental colitis in rats, probably through restoring the number of Treg cells, and inhibiting IL-17 levels in Peyer’s patches. PMID:27003994

  9. Gadolinium chloride improves the course of TNBS and DSS-induced colitis through protecting against colonic mucosal inflammation

    PubMed Central

    Du, Chao; Wang, Peng; Yu, Yanbo; Chen, Feixue; Liu, Jun; Li, Yanqing

    2014-01-01

    Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFα, IL-1β and IL-6 secretions. Also, Western blotting analysis indicated that NF-κB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS-stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-κB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD. PMID:25146101

  10. Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility.

    PubMed

    Murase, Remi; Sato, Hiroyasu; Yamamoto, Kei; Ushida, Ayako; Nishito, Yasumasa; Ikeda, Kazutaka; Kobayashi, Tetsuyuki; Yamamoto, Toshinori; Taketomi, Yoshitaka; Murakami, Makoto

    2016-03-25

    Within the secreted phospholipase A2(sPLA2) family, group X sPLA2(sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies usingPla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2(cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2 Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizerin vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization. PMID:26828067

  11. Perilla frutescens extract ameliorates DSS-induced colitis by suppressing proinflammatory cytokines and inducing anti-inflammatory cytokines.

    PubMed

    Urushima, Hayato; Nishimura, Junichi; Mizushima, Tsunekazu; Hayashi, Noriyuki; Maeda, Kazuhisa; Ito, Toshinori

    2015-01-01

    Anti-inflammatory effects have been reported in Perilla frutescens leaf extract (PE), which is a plant of the genus belonging to the Lamiaceae family. We examined the effect of PE on dextran sulfate sodium (DSS)-induced colitis. Preliminarily, PE was safely administered for 7 wk without any adverse effects. In the preventive protocol, mice were fed 1.5% DSS solution dissolved in distilled water (control group) or 0.54% PE solution (PE group) ad libitum for 7 days. In the therapeutic protocol, distilled water or 0.54% PE solution was given for 10 days just after administration of 1.5% DSS for 5 days. PE intake significantly improved body weight loss. The serum cytokine profile demonstrated that TNF-α, IL-17A, and IL-10 were significantly lower in the PE group than in the control group. In the therapeutic protocol, mice in the PE group showed significantly higher body weight and lower histological colitis scores compared with mice in the control group on day 15. The serum cytokine profile demonstrated that TGF-β was significantly higher in the PE group than in the control group. In distal colon mRNA expression, TNF-α, and IL-17A were significantly downregulated. In vitro analyses of biologically active ingredients, such as luteolin, apigenin, and rosmarinic acid, in PE were performed. Luteolin suppressed production of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-17A. Apigenin also suppressed secretion of IL-17A and increased the anti-inflammatory cytokine IL-10. Rosmarinic acid increased the regulatory T cell population. We conclude that PE might be useful in treatment and prevention of DSS-induced colitis. PMID:25359539

  12. Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats.

    PubMed

    Minaiyan, M; Ghannadi, A; Asadi, M; Etemad, M; Mahzouni, P

    2014-01-01

    Prunus armeniaca L. (Apricot) is a tree cultivated in different parts of the world. Apricot kernel as a good dietary supplement has shown antioxidant, anti-inflammatory and other pharmacologic properties which suggest that it may be functional as an anticolitis agent. In this study we evaluated the effects of apricot kernel extract and oil on ulcerative colitis in rats. Rats were fasted for 36 h before the experiment. Colitis was induced by intra-rectal instillation of 50 mg/kg trinitrobenzene sulfonic acid in male Wistar rats. Treatments were started 6 h after colitis induction and continued every 24 h for 5 days. Apricot kernel extract (100, 200, 400 mg/kg p.o. and 100, 400 mg/kg i.p.) and apricot kernel extract/oil (100, 200, 400 mg/kg p.o.) were used as experimental treatments and prednisolone (4 mg/kg p.o. or i.p.) was used as reference drug. On the day 6, colon tissue was removed and macroscopic and pathologic parameters were evaluated. Ulcer index and total colitis index as representative of macroscopic and histologic parameters respectively showed ameliorating effects in experimental groups especially those treated by intraperitoneal administration route. Results also demonstrated that oil fraction was not able to potentiate the effects of extract. These data suggest that apricot kernel extracts (with or without oil) can be introduced for further mechanistic and clinical studies as a complementary medicine for inflammatory bowel disorders. PMID:25657793

  13. Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats

    PubMed Central

    Minaiyan, M.; Ghannadi, A.; Asadi, M.; Etemad, M.; Mahzouni, P.

    2014-01-01

    Prunus armeniaca L. (Apricot) is a tree cultivated in different parts of the world. Apricot kernel as a good dietary supplement has shown antioxidant, anti-inflammatory and other pharmacologic properties which suggest that it may be functional as an anticolitis agent. In this study we evaluated the effects of apricot kernel extract and oil on ulcerative colitis in rats. Rats were fasted for 36 h before the experiment. Colitis was induced by intra-rectal instillation of 50 mg/kg trinitrobenzene sulfonic acid in male Wistar rats. Treatments were started 6 h after colitis induction and continued every 24 h for 5 days. Apricot kernel extract (100, 200, 400 mg/kg p.o. and 100, 400 mg/kg i.p.) and apricot kernel extract/oil (100, 200, 400 mg/kg p.o.) were used as experimental treatments and prednisolone (4 mg/kg p.o. or i.p.) was used as reference drug. On the day 6, colon tissue was removed and macroscopic and pathologic parameters were evaluated. Ulcer index and total colitis index as representative of macroscopic and histologic parameters respectively showed ameliorating effects in experimental groups especially those treated by intraperitoneal administration route. Results also demonstrated that oil fraction was not able to potentiate the effects of extract. These data suggest that apricot kernel extracts (with or without oil) can be introduced for further mechanistic and clinical studies as a complementary medicine for inflammatory bowel disorders. PMID:25657793

  14. Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis.

    PubMed

    Crespo, Irene; San-Miguel, Beatriz; Prause, Carolina; Marroni, Norma; Cuevas, María J; González-Gallego, Javier; Tuñón, María J

    2012-01-01

    Endoplasmic reticulum (ER) stress and apoptotic cell death play an important role in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). We aimed to explore the potential of glutamine to reduce ER stress and apoptosis in a rat model of experimental IBD. Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/dL) was given by rectal route daily for 2 d or 7 d. Both oxidative stress (TBARS concentration and oxidised/reduced glutathione ratio) and ER stress markers (CHOP, BiP, calpain-1 and caspase-12 expression) increased significantly within 48 h of TNBS instillation, and glutamine attenuated the extent of the changes. Glutamine also inhibited the significant increases of ATF6, ATF4 and spliced XBP-1 mRNA levels induced by TNBS instillation. TNBS-colitis resulted in a significant increase in p53 and cytochrome c expression, and a reduced Bcl-xL expression and Bax/Bcl-2 ratio. These effects were significantly inhibited by glutamine. Treatment with the amino acid also resulted in significant decreases of caspase-9, caspase-8 and caspase-3 activities. Double immunofluorescence staining showed co-localization of CHOP and cleaved caspase-3 in colon sections. Phospho-JNK and PARP-1 expression was also significantly higher in TNBS-treated rats, and treatment with glutamine significantly decreased JNK phosphorylation and PARP-1 proteolysis. To directly address the effect of glutamine on ER stress and apoptosis in epithelial cells, the ER stress inducers brefeldin A and tunicamycin were added to Caco-2 cells that were treated with glutamine (5 mM and 10 mM). The significant enhancement in PERK, ATF6 phosphorylated IRE1, BiP and cleaved caspase-3 expression induced by brefeldin A and tunicamycin was partly prevented by glutamine. Data obtained indicated that modulation of ER stress signalling and anti-apoptotic effects contribute to protection by glutamine against damage

  15. Phospholipase C gamma mediates endogenous brain-derived neurotrophic factor-regulated calcitonin gene-related peptide expression in colitis-induced visceral pain

    PubMed Central

    Hashmi, Fiza; Liu, Miao; Shen, Shanwei

    2016-01-01

    Background Visceral hypersensitivity is a complex pathophysiological paradigm with unclear mechanisms. Primary afferent neuronal plasticity marked by alterations in neuroactive compounds such as calcitonin gene-related peptide is suggested to underlie the heightened sensory responses. Signal transduction that leads to calcitonin gene-related peptide expression thereby sensory neuroplasticity during colitis remains to be elucidated. Results In a rat model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid, we found that endogenously elevated brain-derived neurotrophic factor elicited an up-regulation of calcitonin gene-related peptide in the lumbar L1 dorsal root ganglia. At seven days of colitis, neutralization of brain-derived neurotrophic factor with a specific brain-derived neurotrophic factor antibody reversed calcitonin gene-related peptide up-regulation in the dorsal root ganglia. Colitis-induced calcitonin gene-related peptide transcription was also inhibited by brain-derived neurotrophic factor antibody treatment. Signal transduction studies with dorsal root ganglia explants showed that brain-derived neurotrophic factor-induced calcitonin gene-related peptide expression was mediated by the phospholipase C gamma, but not the phosphatidylinositol 3-kinase/Akt or the mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. Application of PLC inhibitor U73122 in vivo confirmed that colitis-induced and brain-derived neurotrophic factor-mediated calcitonin gene-related peptide up-regulation in the dorsal root ganglia was regulated by the phospholipase C gamma pathway. In contrast, suppression of the phosphatidylinositol 3-kinase activity in vivo had no effect on colitis-induced calcitonin gene-related peptide expression. During colitis, calcitonin gene-related peptide also co-expressed with phospholipase C gamma but not with p-Akt. Calcitonin gene-related peptide up-regulation during colitis correlated to the activation

  16. Faecalibacterium prausnitzii supernatant ameliorates dextran sulfate sodium induced colitis by regulating Th17 cell differentiation

    PubMed Central

    Huang, Xiao-Li; Zhang, Xin; Fei, Xian-Yan; Chen, Zhao-Gui; Hao, Yan-Ping; Zhang, Shu; Zhang, Ming-Ming; Yu, Yan-Qiu; Yu, Cheng-Gong

    2016-01-01

    AIM: To explore the preventive and therapeutic effects of Faecalibacterium prausnitzii (F. prausnitzii) supernatant on dextran sulfate sodium (DSS) induced colitis in mice. METHODS: Forty C57BL/6J male mice were randomly divided into four groups: control group, model group, treatment group, and prevention group. Mice were weighed daily. On day 10, the colon length was measured, the colorectal histopathologic damage score (HDS) was assessed, and plasma interleukin (IL)-17A, IL-6, and IL-4 levels were detected by enzyme-linked immunosorbent assay. The expression of transcription factor retinoic acid-related orphan receptor-γt (RORγt) and IL-17A in colon inflammatory mucosa tissue were determined by immunohistochemical assay, and the expression levels of RORγt mRNA, IL-17A mRNA, and IL-6 mRNA were detected by real-time quantitative polymerase chain reaction (PCR). The proportion of Th17 in mononuclear cells in spleen was assayed by fluorescence activated cell sorter. RESULTS: When compared with the model group, the colon length (P < 0.05) and body weight (P < 0.01) in the treatment and prevention groups were significantly increased, and the colon HDS was decreased (P < 0.05 and P < 0.01). There was no statistical difference between the treatment group and prevention group. After treatment with F. prausnitzii supernatant, the plasma levels of IL-17A and IL-6 (P < 0.05), the protein and mRNA expression of IL-17A and RORγt, and the Th17 cell ratio of spleen cells (P < 0.01) were significantly decreased compared to the model group. Plasma IL-4 level in the prevention group was significantly higher than that in the model group (P < 0.05), but there was no significant difference between these two groups in the expression of IL-6 in both the plasma and colon mucosa tissues. CONCLUSION: F. prausnitzii supernatant exerts protective and therapeutic effects on DSS-induced colitis in mice, probably via inhibition of Th17 differentiation and IL-17A secretion in the plasma and

  17. A study of the effects of Cydonia oblonga Miller (Quince) on TNBS-induced ulcerative colitis in rats.

    PubMed

    Minaiyan, M; Ghannadi, A; Etemad, M; Mahzouni, P

    2012-04-01

    Cydonia oblonga Miller (Quince) from Rosaceae family is a fruit tree cultivated in many countries mainly in Iran. This study was carried out to investigate the effect of quince juice (QJ) and quince hydroalcoholic extract (QHE) on ulcerative colitis (UC) induced by TNBS (trinitrobenzene sulfonic acid) in rats. Rats were grouped (n=6) and fasted for 36 h before colitis induction. TNBS was instilled into the colon with a hydroalcoholic carrier and then treatments were made for 5 days starting 6 h after colitis induction with different doses of QJ (200, 400, 800 mg/kg), QHE (200, 500 & 800 mg/kg) orally, QJ (400 mg/kg) and QHE (200 and 500 mg/kg) intraperitoneally. The colon tissue was removed and tissue damages were scored after macroscopic and histopathologic assessments. Albeit the examined doses of QJ and QHE were apparently effective to reduce the extent of UC lesions, only the greatest doses (500 and 800 mg/kg) resulted in significant alleviation. Weight/Length ratio as an illustrative of tissue inflammation and extravasation was also diminished with quince treatments while the results correlated with macroscopic and histopathologic evaluations. These data suggest that QJ and QHE were effective to diminish inflammation and ulcer indices in this murine model of acute colitis. Although QHE with different doses was effective in induced colitis, the dose and/or route of administration dependency was not confirmed. So quince fractions could be considered as a suitable anticolitic alternative, however further studies are needed to support this hypothesis for clinical setting. PMID:23181087

  18. A study of the effects of Cydonia oblonga Miller (Quince) on TNBS-induced ulcerative colitis in rats

    PubMed Central

    Minaiyan, M.; Ghannadi, A.; Etemad, M.; Mahzouni, P.

    2012-01-01

    Cydonia oblonga Miller (Quince) from Rosaceae family is a fruit tree cultivated in many countries mainly in Iran. This study was carried out to investigate the effect of quince juice (QJ) and quince hydroalcoholic extract (QHE) on ulcerative colitis (UC) induced by TNBS (trinitrobenzene sulfonic acid) in rats. Rats were grouped (n=6) and fasted for 36 h before colitis induction. TNBS was instilled into the colon with a hydroalcoholic carrier and then treatments were made for 5 days starting 6 h after colitis induction with different doses of QJ (200, 400, 800 mg/kg), QHE (200, 500 & 800 mg/kg) orally, QJ (400 mg/kg) and QHE (200 and 500 mg/kg) intraperitoneally. The colon tissue was removed and tissue damages were scored after macroscopic and histopathologic assessments. Albeit the examined doses of QJ and QHE were apparently effective to reduce the extent of UC lesions, only the greatest doses (500 and 800 mg/kg) resulted in significant alleviation. Weight/Length ratio as an illustrative of tissue inflammation and extravasation was also diminished with quince treatments while the results correlated with macroscopic and histopathologic evaluations. These data suggest that QJ and QHE were effective to diminish inflammation and ulcer indices in this murine model of acute colitis. Although QHE with different doses was effective in induced colitis, the dose and/or route of administration dependency was not confirmed. So quince fractions could be considered as a suitable anticolitic alternative, however further studies are needed to support this hypothesis for clinical setting. PMID:23181087

  19. Successfully Treated Acute Fulminant Myocarditis Induced by Ulcerative Colitis with Extracorporeal Life Support and Infliximab

    PubMed Central

    Kim, Han-Kyul; Kim, Kun Il; Jung, Sung Won; Mun, Hee-Sun; Cho, Jung Rae; Lee, Namho

    2016-01-01

    We report a case of successfully treated acute fulminant myocarditis induced by ulcerative colitis with extracorporeal life support and infliximab. Myocarditis is a rare but crucial complication during an exacerbation of inflammatory bowel disease. In our case, we applied extracorporeal membrane oxygenation (ECMO) for cardiac rest under impression of acute myocarditis associated with ulcerative colitis, and added infliximab for uncontrolled inflammation by corticosteroid. As a result, our patient was completely recovered with successful weaning of ECMO. PMID:27358710

  20. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

    PubMed

    Dubin, Krista; Callahan, Margaret K; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G; Wolchok, Jedd D

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  1. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis

    PubMed Central

    Dubin, Krista; Callahan, Margaret K.; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G.; Wolchok, Jedd D.

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  2. Exosomes released by granulocytic myeloid-derived suppressor cells attenuate DSS-induced colitis in mice

    PubMed Central

    Rui, Ke; Tian, Xinyu; Ma, Jie; Ma, Bin; Xu, Huaxi; Lu, Liwei; Wang, Shengjun

    2016-01-01

    Myeloid-derived suppressor cells (MDSC) have been described in inflammatory bowel disease (IBD), but their role in the disease remains controversial. We sought to define the effect of granulocytic MDSC-derived exosomes (G-MDSC exo) in dextran sulphate sodium (DSS)-induced murine colitis. G-MDSC exo-treated mice showed greater resistance to colitis, as reflected by lower disease activity index, decreased inflammatory cell infiltration damage. There was a decrease in the proportion of Th1 cells and an increase in the proportion of regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) from G-MDSC exo-treated colitis mice. Moreover, lower serum levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α were detected in G-MDSC exo-treated colitis mice. Interestingly, inhibition of arginase (Arg)-1 activity in G-MDSC exo partially abrogated the spontaneous improvement of colitis. In addition, G-MDSC exo could suppress CD4+ T cell proliferation and IFN-γ secretion in vitro and inhibit the delayed-type hypersensitivity (DTH) response, and these abilities were associated with Arg-1 activity. Moreover, G-MDSC exo promoted the expansion of Tregs in vitro. Taken together, these results suggest that G-MDSC exo attenuate DSS-induced colitis through inhibiting Th1 cells proliferation and promoting Tregs expansion. PMID:26885611

  3. Does Cisapride, as a 5HT(4) Receptor Agonist, Aggravate the Severity of TNBS-Induced Colitis in Rat?

    PubMed

    Motavallian, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Mahzouni, Parvin; Andalib, Sasan; Abed, Alireza; Babavalian, Mohammad Reza

    2012-01-01

    There is a pressing need for research that will lead to the reveal of targets designed to analyse the possible pathways for the treatment of IBD. Because of the probable involvement of serotonin in inflammatory conditions of intestine and the important role of 5HT(4) receptors in GI function, the investigation of the role of 5HT(4) receptors in the pathogenesis of IBD will be interesting. The aim of this study was to investigate the effects of cisapride, a 5HT(4) receptor agonist, in trinitrobenzenesulfonic-acid-(TNBS) induced rat colitis. Two hours subsequent to induction of colitis using TNBS in rats, cisapride (2 mg/kg, intraperitoneally (i.p); 4 mg/kg, orally (p.o)) and dexamethasone (1 mg/kg, i.p; 2 mg/kg, p.o) were administrated for 6 days. Animals were thereafter euthanized; macroscopic, histological, and biochemical assessments and ELISA test were carried out on distal colon samples. Our data showed that dexamethasone treatment (i.p, p.o) significantly decreased macroscopic and microscopic damage and also biochemical markers, but there were no significant differences in aforementioned parameters between cisapride (i.p or p.o) and TNBS-treated rats. It can be deduced that because the severity of colitis produced by TNBS is massive (through various pathways), cisapride could not bring about more colitis damages through 5HT(4) receptors. Based on the present study further researches are required for investigating the exact roles of 5HT(4) receptors in the pathogenesis of ulcerative colitis. PMID:22888336

  4. Rhenium-coated glass beads for intracolonic administration attenuate TNBS-induced colitis in mice: Proof-of-Concept Study.

    PubMed

    Siczek, Krzysztof; Zatorski, Hubert; Pawlak, Wojciech; Fichna, Jakub

    2015-01-01

    In search for novel effective treatments in inflammatory bowel diseases, a new strategy employing glass beads coated with rhenium nanolayer has been developed and validated in the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Briefly, mice were randomly divided into 5 experimental groups: control (vehicle alone, Group 1); control treated with rhenium-coated glass beads (Group 2); TNBS (Group 3); TNBS treated with rhenium-coated glass beads (Group 4); and TNBS treated with uncoated glass beads (Group 5). Mice from Group 2, 4 and 5 were treated with respective beads (once daily, 5 beads / animal, i.c.) between D3-D6 post-TNBS/vehicle and evaluation of colonic damage was performed on D7, based on macroscopic scoring and clinical parameters. Severe colonic inflammation developed in post-TNBS mice (Group 3) [P <0.001 vs. control (Group 1) for macroscopic score], which was significantly attenuated by treatment with rhenium-coated glass beads (Group 4) [P <0.01 vs. TNBS (Group 3), for macroscopic score]. Neither rhenium-coated glass beads had any effect in control animals (Group 2), nor uncoated glass beads influenced TNBS-induced colitis (Group 5). In conclusion, a novel and attractive strategy for the treatment of colonic inflammation has been proposed; therapy with rhenium-coated glass beads already proved effective in the mouse model of TNBS-induced colitis, now requires further characterization in clinical conditions. PMID:26867119

  5. [Meloxicam-induced colitis revealed by acute abdominal pain].

    PubMed

    Seddik, H; Rabhi, M

    2013-03-01

    Whether intestinal toxicity of preferential or selective COX-2 inhibitors is reduced compared with that of standard NSAIDs is controversial. A 26-year-old woman presented with acute abdominal pain and bloody diarrhoea a few days after beginning meloxicam treatment. Endoscopic examination of the colon showed erythematous and ulcerative lesions involving 15 cm of the left colon. No aetiology has been found for colitis. Diarrhea disappeared 1 week after meloxicam was stopped. Total colonoscopy 3 months and 2 years later was normal. The role of meloxicam in the etiology of colitis was considered plausible. This report and a few other cases in the literature suggest that cyclooxygenase-2 selective non-steroidal anti-inflammatory drug inhibitor toxicity should be investigated in case of unexplained acute colitis. PMID:23537413

  6. Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis

    PubMed Central

    Zhang, Wei; Xu, Li; Cho, Si-Young; Min, Kyung-Jin; Oda, Tatsuya; Zhang, LiJun; Yu, Qing; Jin, Jun-O

    2016-01-01

    This study investigates the in vivo functions of ginseng berry extract (GB) as a therapy for dextran sodium sulfate (DSS)-induced colitis. C57BL/6 mice were given drinking water containing DSS (3%) for eight days to induce acute colitis. At the same time, the mice received an oral dose of GB (50 mg/kg) once daily. The GB-treated mice were less susceptible to the development of acute colitis than were control mice treated with saline, as determined by weight loss, disease activity, and colon histology. The administration of GB to DSS-treated mice also reduced the numbers and inhibited the activation of colon-infiltrating T cells, neutrophils, intestinal CD103−CD11c+ dendritic cells (cDCs), and macrophages. In addition, GB treatment promoted the migration of CD103+CD11c+ cDCs and expansion of Foxp3+ regulatory T cells in the colons of DSS-treated mice. Similarly, in the DSS-induced chronic colitis model, GB treatment improved the macroscopic and histological appearance of the colon wall when compared to untreated control mice, as indicated by longer colon length and lower histological scores. This is the first report to show that oral administration of GB suppresses immune activation and protects against experimentally induced colitis. PMID:27058552

  7. Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis.

    PubMed

    Zhang, Wei; Xu, Li; Cho, Si-Young; Min, Kyung-Jin; Oda, Tatsuya; Zhang, LiJun; Yu, Qing; Jin, Jun-O

    2016-01-01

    This study investigates the in vivo functions of ginseng berry extract (GB) as a therapy for dextran sodium sulfate (DSS)-induced colitis. C57BL/6 mice were given drinking water containing DSS (3%) for eight days to induce acute colitis. At the same time, the mice received an oral dose of GB (50 mg/kg) once daily. The GB-treated mice were less susceptible to the development of acute colitis than were control mice treated with saline, as determined by weight loss, disease activity, and colon histology. The administration of GB to DSS-treated mice also reduced the numbers and inhibited the activation of colon-infiltrating T cells, neutrophils, intestinal CD103(-)CD11c⁺ dendritic cells (cDCs), and macrophages. In addition, GB treatment promoted the migration of CD103⁺CD11c⁺ cDCs and expansion of Foxp3⁺ regulatory T cells in the colons of DSS-treated mice. Similarly, in the DSS-induced chronic colitis model, GB treatment improved the macroscopic and histological appearance of the colon wall when compared to untreated control mice, as indicated by longer colon length and lower histological scores. This is the first report to show that oral administration of GB suppresses immune activation and protects against experimentally induced colitis. PMID:27058552

  8. Ipilimumab-induced colitis: experience from a tertiary referral center

    PubMed Central

    O’Connor, Anthony; Marples, Maria; Mulatero, Clive; Hamlin, John; Ford, Alexander C.

    2016-01-01

    Background: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. Methods: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. Results: A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. Conclusions: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea. PMID:27366214

  9. Heme Oxygenase-1 Ameliorates Dextran Sulfate Sodium-induced Acute Murine Colitis by Regulating Th17/Treg Cell Balance*

    PubMed Central

    Zhang, Liya; Zhang, Yanjie; Zhong, Wenwei; Di, Caixia; Lin, Xiaoliang; Xia, Zhenwei

    2014-01-01

    Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of autoimmune diseases characterized by nonspecific inflammation in the gastrointestinal tract. Recent investigations suggest that activation of Th17 cells and/or deficiency of regulatory T cells (Treg) is involved in the pathogenesis of IBD. Heme oxygenase (HO)-1 is a protein with a wide range of anti-inflammatory and immune regulatory function, which exerts significantly protective roles in various T cell-mediated diseases. In this study, we aim to explore the immunological regulation of HO-1 in the dextran sulfate sodium-induced model of experimental murine colitis. BALB/c mice were administered 4% dextran sulfate sodium orally; some mice were intraperitoneally pretreated with HO-1 inducer hemin or HO-1 inhibitor stannum protoporphyrin IX. The results show that hemin enhances the colonic expression of HO-1 and significantly ameliorates the symptoms of colitis with improved histological changes, accompanied by a decreased proportion of Th17 cells and increased number of Tregs in mesenteric lymph node and spleen. Moreover, induction of HO-1 down-regulates retinoic acid-related orphan receptor γt expression and IL-17A levels, while promoting Treg-related forkhead box p3 (Foxp3) expression and IL-10 levels in colon. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. Therefore, HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, thus providing a possible novel therapeutic target in IBD. PMID:25112868

  10. Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats

    PubMed Central

    Malago, Joshua J.; Sangu, Catherine L.

    2015-01-01

    Intrarectal infusion of butyrate improves colorectal disorders including ulcerative colitis (UC). However, it is not established whether systemically administered butyrate benefits such patients. The current study aimed at exploring and comparing the potential of intraperitoneally, intrarectally, and orally administered butyrate against acetic acid (AA)-induced UC in rats. Intrarectal administration of 2 ml of 50% AA was done after or without prior treatment of rats for 7 consecutive days with 100 mg/kg sodium butyrate (SB) intraperitoneally, intrarectally, or orally. Rats were sacrificed after 48 h of AA-treatment. Subsequently, colon sections were processed routinely for histopathological examination. We clinically observed diarrhea, loose stools, and hemoccult-positive stools, and histologically, epithelial loss and ulceration, crypt damage, goblet cell depletion, hemorrhage, and mucosal infiltration of inflammatory cells. The changes were significantly reduced by intraperitoneal, intrarectal, or oral butyrate, with intraperitoneal butyrate exhibiting the highest potency. It is concluded that intraperitoneal administration of butyrate abrogates the lesions of AA-induced UC and its potency surpasses that of intrarectal or oral butyrate. PMID:25743124

  11. Phosphorylation of NMDA NR1 subunits in the myenteric plexus during TNBS induced colitis.

    PubMed

    Zhou, QiQi; Caudle, Robert M; Moshiree, Baharak; Price, Donald D; Verne, G Nicholas

    2006-10-01

    N-Methyl-d-aspartic acid (NMDA) receptors are known to function in the mediation of pain and have a significant role in the development of hyperalgesia following inflammation. Serine phosphorylation regulation of NMDA receptor function occurs in a variety of conditions. No studies have demonstrated a change in phosphorylation of enteric NMDA receptors following colonic inflammation. We examined the levels of NMDA NR1 phosphorylation in trinitrobenzene sulfonic acid (TNBS) induced colitis in rats and compared it to protein translation and the development of visceral hypersensitivity. We have previously, demonstrated an increase in the C1 cassette of NR1 mRNA expression at 14, 21, and 28 days following TNBS administration. In this study, we examined the NR1 serine phosphorylation at 14 days following TNBS injection. Male Sprague-Dawley rats (200-250 g) were treated with TNBS (20mg per rat) diluted in 50% ethanol (n=3) and vehicle controls of 50% ethanol (n=3). TNBS and vehicle controls were administered with a 24 gauge catheter inserted into the lumen of the rat colon. The animals were sacrificed at 14 days after induction of the colitis and their distal colon was retrieved for two-dimensional (2D) western blot analysis. Serine phosphorylation of the NR1 subunit with C1 cassette appears at 14 days after TNBS injection. In contrast, there was no NR1-C1 expression in the vehicle controls and untreated normal controls. These results suggest a role for colonic-NMDA receptor phosphorylation in the development of neuronal plasticity following colonic inflammation. Phosphorylation of NR1 may partially explain visceral hypersensitivity present during colonic inflammation. PMID:16942839

  12. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.

    PubMed

    Lee, Hae-Youn; Kim, Jinyoung; Quan, Wenying; Lee, June-Chul; Kim, Min-Soo; Kim, Seok-Hyung; Bae, Jin-Woo; Hur, Kyu Yeon; Lee, Myung-Shik

    2016-08-01

    Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mφs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 β release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD(+):NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mφs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mφs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mφs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mφs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis. PMID:27337687

  13. Myristica fragrans seed extract protects against dextran sulfate sodium-induced colitis in mice.

    PubMed

    Kim, Hyojung; Bu, Youngmin; Lee, Beom-Joon; Bae, Jinhyun; Park, Sujin; Kim, Jinsung; Lee, Kyungjin; Cha, Jae-Myung; Ryu, Bongha; Ko, Seok-Jae; Han, Gajin; Min, Byungil; Park, Jae-Woo

    2013-10-01

    Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed. PMID:24063406

  14. The correlation between NF-κB inhibition and disease activity by coadministration of silibinin and ursodeoxycholic acid in experimental colitis.

    PubMed

    Esmaily, Hadi; Vaziri-Bami, Amanollah; Miroliaee, Amir Ebrahim; Baeeri, Maryam; Abdollahi, Mohammad

    2011-12-01

    NF-κB is one of the most important nuclear factors responsible for overexpression of proinflammatory cytokines. This is demonstrated by increased NF-κB activity and other dependent immune factors in inflammatory bowel disease (IBD). Anti-inflammatory effects of silibinin and ursodeoxycholic acid (UDCA) along with their NF-κB inhibitory property are thought to be beneficial in colitis. Trinitrobenzene sulfonic acid was used to induce colitis rat models. After instillation, 48 rats were treated with oral silibinin, UDCA alone or a combination of both. Intraperitoneal dexamethasone was used in the control group. After 12 days of treatment, colonic samples were tested for the severity of mucosal damage macroscopically and microscopically. The levels of activated NF-κB, IL-1β, TNF-α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), protein carbonyl, and the antioxidant power of the bowel homogenates were determined. The results indicated a significant reduction in NF-κB activity as well as the levels of IL-1β, TNF-α, TBARS, protein carbonyl, myeloperoxidase activity, and an improvement in antioxidant power of colitis in treated rats. Combination therapy resulted in a more prominent improvement in bowel antioxidant power and myeloperoxidase activity. In conclusion, combination of silibinin and UDCA by inhibition of NF-κB and other relevant inflammatory factors of colitis is a good candidate for management of Crohn's disease. PMID:21077947

  15. Immune/Inflammatory Response and Hypocontractility of Rabbit Colonic Smooth Muscle After TNBS-Induced Colitis

    PubMed Central

    Zhang, Yonggang; Li, Fang; Wang, Hong; Yin, Chaoran; Huang, JieAn; Mahavadi, Sunila; Murthy, Karnam S.

    2016-01-01

    Background The contractility of colonic smooth muscle is dysregulated due to immune/inflammatory responses in inflammatory bowel diseases. Inflammation in vitro induces up-regulation of regulator of G-protein signaling 4 (RGS4) expression in colonic smooth muscle cells. Aims To characterize the immune/inflammatory responses and RGS4 expression pattern in colonic smooth muscle after induction of colitis. Methods Colitis was induced in rabbits by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Innate/adaptive immune response RT-qPCR array was performed using colonic circular muscle strips. At 1–9 weeks after colonic intramuscular microinjection of lentivirus, the distal and proximal colons were collected, and muscle strips and dispersed muscle cells were prepared from circular muscle layer. Expression levels of RGS4 and NFκB signaling components were determined by Western blot analysis. The biological consequences of RGS4 knockdown were assessed by measurement of muscle contraction and phospholipase C (PLC)-β activity in response to acetylcholine (ACh). Results Contraction in response to ACh was significantly inhibited in the inflamed colonic circular smooth muscle cells. RGS4, IL-1, IL-6, IL-8, CCL3, CD1D, and ITGB2 were significantly up-regulated, while IL-18, CXCR4, CD86, and C3 were significantly down-regulated in the inflamed muscle strips. RGS4 protein expression in the inflamed smooth muscles was dramatically increased. RGS4 stable knockdown in vivo augmented ACh-stimulated PLC-β activity and contraction in colonic smooth muscle cells. Conclusion Inflamed smooth muscle exhibits up-regulation of IL-1-related signaling components, Th1 cytokines and RGS4, and inhibition of contraction. Stable knockdown of endogenous RGS4 in colonic smooth muscle increases PLC-β activity and contractile responses. PMID:26879904

  16. B-vitamin deficiency is protective against DSS-induced colitis in mice.

    PubMed

    Benight, Nancy M; Stoll, Barbara; Chacko, Shaji; da Silva, Vanessa R; Marini, Juan C; Gregory, Jesse F; Stabler, Sally P; Burrin, Douglas G

    2011-08-01

    Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met), and its increase in patients with IBD indicates a disruption of Met metabolism; however, the role of Hcys and Met metabolism in IBD is not well understood. We hypothesized that disrupted Met metabolism from a B-vitamin-deficient diet would exacerbate experimental colitis. Mice were fed a B(6)-B(12)-deficient or control diet for 2 wk and then treated with dextran sodium sulfate (DSS) to induce colitis. We monitored disease activity during DSS treatment and collected plasma and tissue for analysis of inflammatory tissue injury and Met metabolites. We also quantified Met cycle activity by measurements of in vivo Met kinetics using [1-(13)C-methyl-(2)H(3)]methionine infusion in similarly treated mice. Unexpectedly, we found that mice given the B-vitamin-deficient diet had improved clinical outcomes, including increased survival, weight maintenance, and reduced disease scores. We also found lower histological disease activity and proinflammatory gene expression (TNF-α and inducible nitric oxide synthase) in the colon in deficient-diet mice. Metabolomic analysis showed evidence that these effects were associated with deficient B(6), as markers of B(12) function were only mildly altered. In vivo methionine kinetics corroborated these results, showing that the deficient diet suppressed transsulfuration but increased remethylation. Our findings suggest that disrupted Met metabolism attributable to B(6) deficiency reduces the inflammatory response and disease activity in DSS-challenged mice. These results warrant further human clinical studies to determine whether B(6) deficiency and elevated Hcys in patients with IBD contribute to disease pathobiology. PMID:21596995

  17. Increased Production of Lysozyme Associated with Bacterial Proliferation in Barrett's Esophagitis, Chronic Gastritis, Gluten-induced Atrophic Duodenitis (Celiac Disease), Lymphocytic Colitis, Collagenous Colitis, Ulcerative Colitis and Crohn's Colitis.

    PubMed

    Rubio, Carlos A

    2015-12-01

    The mucosa of the esophagus, the stomach, the small intestine, the large intestine and rectum are unremittingly challenged by adverse micro-environmental factors, such as ingested pathogenic and non-pathogenic bacteria, and harsh secretions with digestive properties with disparate pH, as well as bacteria and secretions from upstream GI organs. Despite the apparently inauspicious mixture of secretions and bacteria, the normal GI mucosa retains a healthy state of cell renewal. To by-pass the tough microenvironment, the epithelia of the GI react by speeding-up cell exfoliation, by increasing peristalsis, eliminating bacteria through secretion of plasma cell-immunoglobulins and by increasing production of natural antibacterial enzymes (lysozyme) and host defense peptides (defensin-5). Lysozyme was recently found up-regulated in Barrett's esophagitis, in chronic gastritis, in gluten-induced atrophic duodenitis (celiac disease), in collagenous colitis, in lymphocytic colitis and in Crohn's colitis. This up-regulation is a response directed towards the special types of bacteria thriving in the microenvironment in each of the aforementioned clinical inflammatory maladies. The purpose of that up-regulation is to protect the mucosa affected by the ongoing chronic inflammation. Bacterial antibiotic resistance continues to exhaust our supply of effective antibiotics. The future challenge is how to solve the increasing menace of bacterial resistance to anti-bacterial drugs. Further research on natural anti-bacterial enzymes such as lysozyme, appears mandatory. PMID:26637845

  18. Boehmeria nivea Attenuates the Development of Dextran Sulfate Sodium-Induced Experimental Colitis

    PubMed Central

    Shin, Eun Ju; Sung, Mi Jeong; Yang, Hye Jeong; Kim, Myung Sunny; Hwang, Jin-Taek

    2014-01-01

    We examined the therapeutic effect of an ethanol extract derived from Boehmeria nivea (Linn.) Gaudich in a mouse model of experimental colitis. Treatment with 70% ethanol extract derived from B. nivea (EBN) at a dose of 100, 200, or 500 mg/(kg·d) improved colon shortening, body weight, the disease activity index (DAI), and histopathological score of DSS-induced colitis mice. DSS significantly increased the levels of cyclooxygenase-(COX-) 2 in colon tissue relative to that of the untreated control group. EBN administered at 100, 200, or 500 mg/(kg·d) reduced COX-2 levels in the DSS-treated mice. In addition, EBN decreased the DSS-induced secretion of the inflammatory cytokine interleukin-6 (IL-6) and chemokine monocyte chemotactic protein-1 (MCP-1). Taken together, these data suggest that B. nivea extract is effective in preventing colitis. PMID:25045208

  19. Evaluation of the usefulness of colonoscopy with mucosal biopsies in the follow-up of TNBS-induced colitis in rats.

    PubMed

    El-Salhy, Magdy; Wendelbo, Ingvild Haukaas; Gundersen, Doris; Hatlebakk, Jan Gunnar; Hausken, Trygve

    2013-08-01

    Animal models are required for research regarding the pathogenesis and efficacy of anti-inflammatory agents in inflammatory bowel disease (IBD). Trinitrobenzene sulfonic acid (TNBS)-induced colitis closely mimics Crohn's disease. The present study was undertaken in order to determine the reliability of following the inflammatory course of TNBS-induced colitis using colonoscopy together with biopsy samples obtained during the examination. In this study we used 20 adult male Wistar rats, with a mean weight of 201.9 g. The rats were divided into two groups, control and TNBS, with ten rats in each group. Following the induction of TNBS colitis, the rats underwent colonoscopy with mucosal biopsies. At the end of the experiment, the rats were sacrificed and whole-wall colonic samples were obtained. The degree of inflammation was assessed endoscopically, macroscopically and microscopically. There was no significant change in the body weight of the control group but significant weight loss was observed in the TNBS group. Examination of the control group did not reveal any inflammation. Severe colitis was observed in the TNBS-induced colitis rats, as assessed endoscopically, macroscopically and microscopically. The endoscopic inflammation score obtained through colonoscopy examinations correlated with that obtained macroscopically, and those obtained microscopically from the whole-wall colon and biopsy samples collected during the colonoscopy. Moreover, the inflammation scores obtained from the whole-wall colon and biopsy samples collected during colonoscopy correlated markedly. In conclusion, colonoscopy is a reliable method for following up the course of inflammation in experimentally induced colitis. Although biopsy samples collected during colonoscopies may be used to assess the degree of inflammation, whole-wall samples are superior in this regard. PMID:23778962

  20. Vitamin A Inhibits Development of Dextran Sulfate Sodium-Induced Colitis and Colon Cancer in a Mouse Model

    PubMed Central

    Okayasu, Isao; Hana, Kiyomi; Nemoto, Noriko; Yoshida, Tsutomu; Saegusa, Makoto; Yokota-Nakatsuma, Aya; Song, Si-Young; Iwata, Makoto

    2016-01-01

    Vitamin A is essential to mucosal immunity and cell differentiation. The fact that lack of it might involve chronic inflammation and increased risk of cancer has been reported. Little is known about the mechanism of vitamin A deficiency in the development of colitis and its influence on development of colorectal cancer. To determine the influence of vitamin A deficiency on colitis and colorectal cancer development, an experimental study using a colitis mouse model was performed. Dextran sulfate sodium (DSS) colitis was induced in vitamin A-deficient and vitamin A-supplemented mice. Further, colorectal carcinoma was induced by a combination of azoxymethane preinjection and DSS colitis. Results were compared between the two groups mainly by immunohistochemical analysis. Colitis was more severe and recovery from colitis was slower in vitamin A-deficient mice than in vitamin A-supplemented mice. Compared with vitamin A-supplemented mice, vitamin A-deficient mice had decreases in colonic subepithelial myofibroblasts and the ratio of mucosal IgA+/IgG+ cells, increases in CD11c+ dendritic cells, and a higher rate of development of colorectal carcinoma with colitis following azoxymethane. Vitamin A lipid droplets in subepithelial myofibroblasts were decreased in vitamin A-deficient mice, suggesting alterations in colonic crypt niche function. Thus, vitamin A inhibited colitis and the development of colorectal cancer. PMID:27298823

  1. Vitamin A Inhibits Development of Dextran Sulfate Sodium-Induced Colitis and Colon Cancer in a Mouse Model.

    PubMed

    Okayasu, Isao; Hana, Kiyomi; Nemoto, Noriko; Yoshida, Tsutomu; Saegusa, Makoto; Yokota-Nakatsuma, Aya; Song, Si-Young; Iwata, Makoto

    2016-01-01

    Vitamin A is essential to mucosal immunity and cell differentiation. The fact that lack of it might involve chronic inflammation and increased risk of cancer has been reported. Little is known about the mechanism of vitamin A deficiency in the development of colitis and its influence on development of colorectal cancer. To determine the influence of vitamin A deficiency on colitis and colorectal cancer development, an experimental study using a colitis mouse model was performed. Dextran sulfate sodium (DSS) colitis was induced in vitamin A-deficient and vitamin A-supplemented mice. Further, colorectal carcinoma was induced by a combination of azoxymethane preinjection and DSS colitis. Results were compared between the two groups mainly by immunohistochemical analysis. Colitis was more severe and recovery from colitis was slower in vitamin A-deficient mice than in vitamin A-supplemented mice. Compared with vitamin A-supplemented mice, vitamin A-deficient mice had decreases in colonic subepithelial myofibroblasts and the ratio of mucosal IgA(+)/IgG(+) cells, increases in CD11c(+) dendritic cells, and a higher rate of development of colorectal carcinoma with colitis following azoxymethane. Vitamin A lipid droplets in subepithelial myofibroblasts were decreased in vitamin A-deficient mice, suggesting alterations in colonic crypt niche function. Thus, vitamin A inhibited colitis and the development of colorectal cancer. PMID:27298823

  2. Anti-inflammatory effects of Inonotus obliquus in colitis induced by dextran sodium sulfate.

    PubMed

    Choi, Se Young; Hur, Sun Jin; An, Chi Sun; Jeon, Yun Hui; Jeoung, Young Jun; Bak, Jong Phil; Lim, Beong Ou

    2010-01-01

    A total of 28 male BALB/c mice (average weight 20.7 +/- 1.6 g) were divided into 4 treatment groups and fed a commercial diet (A), a commercial diet + induced colitis by dextran sodium sulfate (DSS) (B), Inonotus obliquus (IO) administration (C), and IO administration + induced colitis by DSS (D). IO treatment (C, D) decreased the expression of tumor necrosis factor (TNF)-alpha and signal transducers and activators of transcription (STAT)1 compared to those of the colitis induced group (B). The expressions of IL-4 and STAT6 were decreased in group D compared to the colitis induced group (B). The serum immunoglobulin (Ig)E level decreased in IO treatment groups (C, D) compared to no IO treatment groups (A and B) although there was no significant difference between the IO treatment groups. Extract from IO itself had a weak cytotoxic effect on murine macrophage cell line (RAW264.7 cells). Extract from IO inhibited lipopolysaccharide- (LPS-) induced, TNF-alpha, STAT1, pSTAT1, STAT6, and pSTAT6 production in RAW264.7 cells. PMID:20300439

  3. Anti-Inflammatory Effects of Inonotus obliquus in Colitis Induced by Dextran Sodium Sulfate

    PubMed Central

    Choi, Se Young; Hur, Sun Jin; An, Chi Sun; Jeon, Yun Hui; Jeoung, Young Jun; Bak, Jong Phil; Lim, Beong Ou

    2010-01-01

    A total of 28 male BALB/c mice (average weight 20.7 ± 1.6 g) were divided into 4 treatment groups and fed a commercial diet (A), a commercial diet + induced colitis by dextran sodium sulfate (DSS) (B), Inonotus obliquus (IO) administration (C), and IO administration + induced colitis by DSS (D). IO treatment (C, D) decreased the expression of tumor necrosis factor (TNF)-α and signal transducers and activators of transcription (STAT)1 compared to those of the colitis induced group (B). The expressions of IL-4 and STAT6 were decreased in group D compared to the colitis induced group (B). The serum immunoglobulin (Ig)E level decreased in IO treatment groups (C, D) compared to no IO treatment groups (A and B) although there was no significant difference between the IO treatment groups. Extract from IO itself had a weak cytotoxic effect on murine macrophage cell line (RAW264.7 cells). Extract from IO inhibited lipopolysaccharide- (LPS-) induced, TNF-α, STAT1, pSTAT1, STAT6, and pSTAT6 production in RAW264.7 cells. PMID:20300439

  4. Anti-inflammatory effect of diosmectite in hapten-induced colitis in the rat

    PubMed Central

    González, Raquel; Sánchez de Medina, Fermin; Martínez-Augustin, Olga; Nieto, Ana; Gálvez, Julio; Risco, Severiano; Zarzuelo, Antonio

    2004-01-01

    Diosmectite is a natural silicate effectively used in the treatment of infectious diarrhoea. Its antidiarrhoeal properties involve adsorption of toxins and bacteria and modifications of the rheological characteristics of gastrointestinal mucus. Hence, the aim of this study was to test the intestinal anti-inflammatory activity of diosmectite. Diosmectite (500 mg kg−1 day−1, p.o.) was administered as a post-treatment to rats with chronic trinitrobenzene sulphonic acid colitis. Colonic status was checked 1 and 2 weeks after colitis induction by macroscopic, histological and biochemical examination. Diosmectite post-treatment resulted in amelioration of the morphological signs (intestinal weight, macroscopic damage, necrosed area, histology) and biochemical markers (myeloperoxidase activity, glutathione levels, MUC2 expression, inducible nitric oxide synthase and interleukin-1β (IL-1β) and leukotriene B4 synthesis), as well as in the reduction of the severity of diarrhoea. The effect of the clay was comparable to that of sulphasalazine (50 mg kg−1 day−1). Diosmectite exhibited a dose-dependent capacity to adsorb proteins in vitro as well as a dose-dependent inhibitory effect on the basolateral secretion of IL-8 by lipopolysaccharide (LPS)-stimulated HT29 cells. Diosmectite had a dose-dependent inhibitory effect on IL-1β production by LPS-stimulated THP-1 cells. The effect of diosmectite on MUC2 was post-transcriptional, since mRNA levels were unaffected. However, diosmectite is able to upregulate MUC2 mRNA levels in HT29-MTX cells. Diosmectite has anti-inflammatory activity administered as a post-treatment. Possible mechanisms include adsorption of luminal antigens, increase of colonic mucin levels and possibly a direct modulatory action of cytokine production by mucosal cells. PMID:14993105

  5. Over-Expression of CD200 Protects Mice from Dextran Sodium Sulfate Induced Colitis

    PubMed Central

    Chen, Zhiqi; Yu, Kai; Zhu, Fang; Gorczynski, Reginald

    2016-01-01

    Background and aim CD200:CD200 receptor (CD200R) interactions lead to potent immunosuppression and inhibition of autoimmune inflammation. We investigated the effect of "knockout"of CD200 or CD200R, or over-expression of CD200, on susceptibility to dextran sodium sulfate (DSS)—induced colitis, a mouse model of inflammatory bowel disease (IBD). Methods Acute or chronic colitis was induced by administration of dextran sodium sulfate (DSS) in four groups of age-matched C57BL/6 female mice: (1) CD200-transgenic mice (CD200tg); (2) wild-type (WT) mice; (3) CD200 receptor 1-deficient (CD200R1KO) mice; and (4) CD200-deficient (CD200KO) mice. The extent of colitis was determined using a histological scoring system. Colon tissues were collected for quantitative RT-PCR and Immunohistochemical staining. Supernatants from colonic explant cultures and mononuclear cells isolated from colonic tissue were used for ELISA. Results CD200KO and CD200R1KO mice showed greater sensitivity to acute colitis than WT mice, with accelerated loss of body weight, significantly higher histological scores, more severe infiltration of macrophages, neutrophils and CD3+ cells, and greater expression of macrophage-derived inflammatory cytokines, whose production was inhibited in vitro (in WT/CD200KO mouse cells) by CD200. In contrast, CD200tg mice showed less sensitivity to DSS compared with WT mice, with attenuation of all of the features seen in other groups. In a chronic colitis model, greater infiltration of Foxp3+ regulatory T (Treg) cells was seen in the colon of CD200tg mice compared to WT mice, and anti-CD25 mAb given to these mice attenuated protection. Conclusions The CD200:CD200R axis plays an immunoregulatory role in control of DSS induced colitis in mice. PMID:26841120

  6. Repeated predictable stress causes resilience against colitis-induced behavioral changes in mice

    PubMed Central

    Hassan, Ahmed M.; Jain, Piyush; Reichmann, Florian; Mayerhofer, Raphaela; Farzi, Aitak; Schuligoi, Rufina; Holzer, Peter

    2014-01-01

    Inflammatory bowel disease is associated with an increased risk of mental disorders and can be exacerbated by stress. In this study which was performed with male 10-week old C57Bl/6N mice, we used dextran sulfate sodium (DSS)-induced colitis to evaluate behavioral changes caused by intestinal inflammation, to assess the interaction between repeated psychological stress (water avoidance stress, WAS) and colitis in modifying behavior, and to analyze neurochemical correlates of this interaction. A 7-day treatment with DSS (2% in drinking water) decreased locomotion and enhanced anxiety-like behavior in the open field test and reduced social interaction. Repeated exposure to WAS for 7 days had little influence on behavior but prevented the DSS-induced behavioral disturbances in the open field and SI tests. In contrast, repeated WAS did not modify colon length, colonic myeloperoxidase content and circulating proinflammatory cytokines, parameters used to assess colitis severity. DSS-induced colitis was associated with an increase in circulating neuropeptide Y (NPY), a rise in the hypothalamic expression of cyclooxygenase-2 mRNA and a decrease in the hippocampal expression of NPY mRNA, brain-derived neurotrophic factor mRNA and mineralocorticoid receptor mRNA. Repeated WAS significantly decreased the relative expression of corticotropin-releasing factor mRNA in the hippocampus. The effect of repeated WAS to blunt the DSS-evoked behavioral disturbances was associated with a rise of circulating corticosterone and an increase in the expression of hypothalamic NPY mRNA. These results show that experimental colitis leads to a particular range of behavioral alterations which can be prevented by repeated WAS, a model of predictable chronic stress, while the severity of colitis remains unabated. We conclude that the mechanisms underlying the resilience effect of repeated WAS involves hypothalamic NPY and the hypothalamic-pituitary-adrenal axis. PMID:25414650

  7. Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis

    PubMed Central

    Khounlotham, Manirath; Kim, Wooki; Peatman, Eric; Nava, Porfirio; Medina-Contreras, Oscar; Addis, Caroline; Koch, Stefan; Fournier, Benedicte; Nusrat, Asma; Denning, Timothy L.; Parkos, Charles A.

    2012-01-01

    SUMMARY Mice lacking Junctional Adhesion Molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r-/-Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury induced colitis. These data establish a role for adaptive immune mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise. PMID:22981539

  8. In Vivo Evaluation of 5-ASA Colon-Specific Tablets Using Experimental-Induced Colitis Rat Animal Model.

    PubMed

    Sawarkar, Sujata P; Deshpande, S G; Bajaj, A N; Nikam, V S

    2015-12-01

    Colonic drug delivery is intended not only for local treatment in inflammatory bowel disease (IBD) but also for systemic delivery of therapeutics. Intestinal myeloperoxidase (MPO) determination could be used to estimate the average level of inflammation in colon as well as to determine the efficacy of drugs to be used in the treatment of inflammatory bowel diseases or study the specificity of dosage forms to be used for colonic targeting of anti-inflammatory drugs. Colonic prodrug sulfasalazine (SASP) gets metabolized to give 5-aminosalicylic acid (5-ASA), which is the active portion of SASP. However, when given orally, 5-ASA is absorbed in upper part of gastrointestinal tract (GIT) and not made available in colon. In the present study, colon-targeted delivery of 5-ASA was achieved by formulating tablets with two natural polymers namely guar gum and pectin using compression coating method. Colonic specificity of 5-ASA tablets (prepared using guar gum and pectin as polymers) was evaluated in vitro using simulated fluids mimicking in vivo environment as well as in vivo method using chemically (2,4,6-trinitrobenzenesulfonic acid and acetic acid)-induced colitis rat model. Both colon-specific formulations of 5-ASA (guar gum and pectin) were observed to be more effective in reducing inflammation in chemically induced colitis rat models when compared to colon-specific prodrug sulfasalazine as well as conventional 5-ASA administered orally. PMID:26017284

  9. Effects of Carum carvi L. (Caraway) extract and essential oil on TNBS-induced colitis in rats.

    PubMed

    Keshavarz, A; Minaiyan, M; Ghannadi, A; Mahzouni, P

    2013-01-01

    Carum carvi L. (Apiaceae family) or caraway is a common household plant grown around the world including Iran. Caraway fruits are used as flavoring agent in foods and beverages, and have various traditional uses in ethnomedicine. Anti-inflammatory, spasmolytic, antimicrobial, antioxidant, carminative and immunomodulatory properties of caraway suggest that it might exert beneficial effects on inflammatory bowel disease (IBD). Therefore, this study was carried out to investigate the effects of caraway hydroalcoholic extract (CHE) and its essential oil (CEO) in an immunological model of colitis in rats induced by trinitrobenzene sulfonic acid (TNBS). Different doses of CHE (100, 200, 400 mg/kg) and CEO (100, 200, 400 μl/kg) were administered orally (p.o.) and also doses of CHE (100, 400 mg/kg) and CEO (100, 400 μl/kg) were given intraperitoneally (i.p.) to the separate groups of male Wistar rats (n=6). Administration of the doses started 6 h after induction of colitis and continued daily for 5 consecutive days. Wet colon weight/length ratio was measured and tissue damage scores as well as indices of colitis were evaluated both macroscopically and histopathologically. CHE and CEO at all doses tested were effective in reducing colon tissue lesions and colitis indices and the efficacy was nearly the same when different doses of plant fractions were administered p.o. or i.p. Administration of prednisolone (p.o., 4 mg/kg), Asacol® (mesalazine microgranules, p.o., 100 mg/kg) and hydrocortisone acetate (i.p., 20 mg/kg) as references were effective in reducing colon tissue injures as well. These data suggest that caraway fractions are both effective and possess anti-colitic activity irrespective of the dose and route of administration. PMID:24459470

  10. Effects of Carum carvi L. (Caraway) extract and essential oil on TNBS-induced colitis in rats

    PubMed Central

    Keshavarz, A.; Minaiyan, M.; Ghannadi, A.; Mahzouni, P.

    2013-01-01

    Carum carvi L. (Apiaceae family) or caraway is a common household plant grown around the world including Iran. Caraway fruits are used as flavoring agent in foods and beverages, and have various traditional uses in ethnomedicine. Anti-inflammatory, spasmolytic, antimicrobial, antioxidant, carminative and immunomodulatory properties of caraway suggest that it might exert beneficial effects on inflammatory bowel disease (IBD). Therefore, this study was carried out to investigate the effects of caraway hydroalcoholic extract (CHE) and its essential oil (CEO) in an immunological model of colitis in rats induced by trinitrobenzene sulfonic acid (TNBS). Different doses of CHE (100, 200, 400 mg/kg) and CEO (100, 200, 400 μl/kg) were administered orally (p.o.) and also doses of CHE (100, 400 mg/kg) and CEO (100, 400 μl/kg) were given intraperitoneally (i.p.) to the separate groups of male Wistar rats (n=6). Administration of the doses started 6 h after induction of colitis and continued daily for 5 consecutive days. Wet colon weight/length ratio was measured and tissue damage scores as well as indices of colitis were evaluated both macroscopically and histopathologically. CHE and CEO at all doses tested were effective in reducing colon tissue lesions and colitis indices and the efficacy was nearly the same when different doses of plant fractions were administered p.o. or i.p. Administration of prednisolone (p.o., 4 mg/kg), Asacol® (mesalazine microgranules, p.o., 100 mg/kg) and hydrocortisone acetate (i.p., 20 mg/kg) as references were effective in reducing colon tissue injures as well. These data suggest that caraway fractions are both effective and possess anti-colitic activity irrespective of the dose and route of administration. PMID:24459470

  11. Prior H. pylori infection ameliorates S. typhimurium induced colitis: mucosal crosstalk between stomach and distal intestine

    PubMed Central

    Higgins, Peter D.R.; Johnson, Laura A.; Luther, Jay; Zhang, Min; Kao, John Y.

    2012-01-01

    Background Helicobacter pylori infection is associated with a lower risk of chronic autoimmune diseases including IBD. H. pylori modulates the gastric immune response, decreasing the local inflammatory response to itself. In mice, chronic Salmonella typhimurium infection induces colitis similar to Crohn’s disease characterized by inflammation which progresses towards fibrosis. The aim of this study was to determine whether prior H. pylori infection acts at a distance to modulate the immune response of S. typhimurium-induced colitis. Methods Mice were infected with the mouse-adapted strain of H. pylori (SS1), followed by infection with S. typhimurium. The effect of H. pylori on colitis was determined by gross pathology, histopathology, cytokine response, and development of fibrosis in the cecum. Gastritis and systemic immune response was measured in response to infection. Results H. pylori suppresses the Th17 response to S. typhimurium infection in the mouse cecum, but does not alter the Th2 or Treg response or the development of fibrosis. H. pylori infection induces IL-10 in the mesenteric lymph nodes, suggesting an extra-gastric mechanism for immunomodulation. H. pylori/S. typhimurium co-infection decreases inflammation in both the cecum and the stomach. Conclusions This study demonstrates a potential mechanism for the negative association between H. pylori and IBD in humans. H. pylori represses the lower gastrointestinal tract Th17 response to bacterially induced colitis via extra-gastric immunomodulatory effects, illustrating immunological crosstalk between the upper and lower gastrointestinal tract. PMID:21560200

  12. Catecholamine Mediates Psychological Stress-Induced Colitis Through a2-Adrenoreceptor.

    PubMed

    Bai, Aiping; Chen, Jiang; Liao, Wangdi; Lu, Nonghua; Guo, Yuan

    2015-07-01

    Psychological stress has long been reported to be linked with the disease activity of patients with inflammatory bowel disease (IBD). However, the mechanisms of psychological stress involved in pathogenesis of IBD are still to be elucidated. We have previously shown that catecholamine participates in progression of acute colitis through a2-adrenoreceptors. The study aimed to explore the pivotal role of catecholamine in psychological stress-induced colitis. The expression of dopamine β-hydroxylase (DBH), the rate-limiting enzyme in regulation of catecholamine synthesis, was induced in colon tissues of mice with restraint stress, indicating the association of catecholamine synthesis with psychological stress. Notably, pretreatment with RX821002, an a2-adrenoceptor antagonist, attenuated inflammatory responses of psychological stress-induced colitis. Intriguingly, DBH levels were elevated in colon tissues of patients with active IBD. The study suggests that a2-adrenoreceptors/catecholamine play pivotal role in psychological stress-induced colitis and might contribute to the development of human IBD. PMID:25867043

  13. Nicotine Inhibits Clostridium difficile Toxin A-Induced Colitis but Not Ileitis in Rats

    PubMed Central

    Vigna, Steven R.

    2016-01-01

    Nicotine is protective in ulcerative colitis but not Crohn's disease of the small intestine, but little is known about the effects of nicotine on Clostridium difficile toxin A-induced enteritis. Isolated ileal or colonic segments in anesthetized rats were pretreated with nicotine bitartrate or other pharmacological agents before intraluminal injection of toxin A. After 3 hours, the treated segments were removed and inflammation was assessed. Nicotine biphasically inhibited toxin A colitis but not ileitis. Pretreatment with the nicotinic receptor antagonist, hexamethonium, blocked the effects of nicotine. Pretreating the colonic segments with hexamethonium before toxin A administration resulted in more inflammation than seen with toxin A alone, suggesting that a tonic nicotinic anti-inflammatory condition exists in the colon. Nicotine also inhibited toxin A-induced increased colonic concentrations of the TRPV1 (transient receptor potential vanilloid subtype 1) agonist, leukotriene B4 (LTB4), and release of the proinflammatory neuropeptide, substance P. Pretreatment with nicotine did not protect against direct TRPV1-mediated colitis caused by intraluminal capsaicin. Nicotinic cholinergic receptors tonically protect the colon against inflammation and nicotine inhibits toxin A colitis but not toxin A ileitis in rats in part by inhibition of toxin A-induced activation of TRPV1 by endogenous TRPV1 agonists such as LTB4. PMID:26881175

  14. Brugia malayi abundant larval transcript 2 protein treatment attenuates experimentally-induced colitis in mice.

    PubMed

    Khatri, Vishal; Amdare, Nitin; Yadav, Ravi Shankar; Tarnekar, Aaditya; Goswami, Kalyan; Reddy, Maryada Venkata Rami

    2015-11-01

    Helminths are known to modulate host's immunity by suppressing host protective pro-inflammatory responses. Such immunomodulatory effects have been experimentally shown to have therapeutic implications in immune mediated disorders. In the present study, we have explored a filarial protein i.e. Brugia malayi recombinant abundant larval transcript 2 (rBmALT2) for its therapeutic effect in dextran sodium sulfate (DSS) induced colitis in mouse model. The immunomodulatory activity of rBmALT-2 was initially confirmed by demonstrating that it suppressed the lipopolysaccharide (LPS) induced nitric oxide synthesis and down-regulated the expression of pro-inflammatory cytokines in vitro by peritoneal exudate cells of mice. Treatment with rBmALT2 reduced severity of colitis associated with significant reduction in weight loss, disease activity, colon damage, mucosal edema and histopathological score including myeloperoxidase activity in colon tissues. rBmALT2 was comparatively more effective in attenuation of colitis when used in the preventive mode than when used for curative purpose. The therapeutic effect of rBmALT2 was found to be associated with downregulation of IFN-γ, IL-6, IL-17 and upregulation of IL-10 cytokines. These results provide strong experimental evidence that BmALT2 could be a potential alternative therapeutic agent in colitis. PMID:26669016

  15. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission

    PubMed Central

    Rooks, Michelle G; Veiga, Patrick; Wardwell-Scott, Leslie H; Tickle, Timothy; Segata, Nicola; Michaud, Monia; Gallini, Carey Ann; Beal, Chloé; van Hylckama-Vlieg, Johan ET; Ballal, Sonia A; Morgan, Xochitl C; Glickman, Jonathan N; Gevers, Dirk; Huttenhower, Curtis; Garrett, Wendy S

    2014-01-01

    Dysregulated immune responses to gut microbes are central to inflammatory bowel disease (IBD), and gut microbial activity can fuel chronic inflammation. Examining how IBD-directed therapies influence gut microbiomes may identify microbial community features integral to mitigating disease and maintaining health. However, IBD patients often receive multiple treatments during disease flares, confounding such analyses. Preclinical models of IBD with well-defined disease courses and opportunities for controlled treatment exposures provide a valuable solution. Here, we surveyed the gut microbiome of the T-bet−/− Rag2−/− mouse model of colitis during active disease and treatment-induced remission. Microbial features modified among these conditions included altered potential for carbohydrate and energy metabolism and bacterial pathogenesis, specifically cell motility and signal transduction pathways. We also observed an increased capacity for xenobiotics metabolism, including benzoate degradation, a pathway linking host adrenergic stress with enhanced bacterial virulence, and found decreased levels of fecal dopamine in active colitis. When transferred to gnotobiotic mice, gut microbiomes from mice with active disease versus treatment-induced remission elicited varying degrees of colitis. Thus, our study provides insight into specific microbial clades and pathways associated with health, active disease and treatment interventions in a mouse model of colitis. PMID:24500617

  16. Dietary Uptake of Wedelia chinensis Extract Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice

    PubMed Central

    Chen, Yung-Hsiang; Huang, Wen-Ching; Huang, Li-Ting; Lin, Wen-Ching; Arulselvan, Palanisamy; Liao, Jiunn-Wang; Lin, Shu-Hui; Hsiao, Pei-Wen; Kuo, Sheng-Chu; Yang, Ning-Sun

    2013-01-01

    Scope Traditional medicinal herbs are increasingly used as alternative therapies in patients with inflammatory diseases. Here we evaluated the effect of Wedelia chinensis, a medicinal herb commonly used in Asia, on the prevention of dextran sulfate sodium (DSS)-induced acute colitis in mice. General safety and the effect of different extraction methods on the bioactivity of W. chinensis were also explored. Methods and Results C57BL/6 mice were administrated hot water extract of fresh W. chinensis (WCHF) orally for one week followed by drinking water containing 2% DSS for nine days. WCHF significantly attenuated the symptoms of colitis including diarrhea, rectal bleeding and loss of body weight; it also reduced the shortening of colon length and histopathological damage caused by colonic inflammation. Among four W. chinensis extracts prepared using different extraction techniques, WCHF showed the highest anti-colitis efficacy. Analyses of specific T-cell regulatory cytokines (TNF-α, IL-4, IFN-γ, IL-17, TGF-β, IL-12) revealed that WCHF treatment can suppress the Th1 and Th17, but not Th2, responses in colon tissues and dendritic cells of DSS-induced colitis mice. A 28-day subacute toxicity study showed that daily oral administration of WCHF (100, 500, 1000 mg/kg body weight) was not toxic to mice. Conclusion Together, our findings suggest that specific extracts of W. chinensis have nutritional potential for future development into nutraceuticals or dietary supplements for treatment of inflammatory bowel disease. PMID:23734189

  17. Effect of sophoridine on dextran sulfate sodium-induced colitis in C57BL/6 mice.

    PubMed

    Zhao, Wen-Chang; Song, Li-Jun; Deng, Hong-Zhu

    2010-11-01

    Sophoridine (SRI), one of the quinolizidine alkaloids, is a new anticancer drug with noticeable antitumor action and lower toxicity. To our knowledge, there is no report about its effect on colitis. Repeated colitis was induced by administration of four cycles of 4% DSS. The severity of colitis was assessed on the basis of clinical signs, colon length and histology scores. Moreover, cecum secretory immunoglobulin A (sIgA) and plasma haptoglobin (HP) were analyzed by enzyme-linked immunosorbent assay and ICAM-1, and macrophage migration inhibitory factor (MIF) gene expression was analyzed by quantitative reverse transcriptase real-time polymerase chain reaction using SYBR Green I. SRI administration significantly attenuated the damage and caused substantial reduction of the rise in plasma HP, and maintained the level of cecum sIgA. SRI inhibited the ICAM-1 gene expression and had no effect on MIF gene expression. In conclusion, for the first time, the activity of SRI on DSS-induced colitis mice was investigated, which suggests that SRI could be an attractive therapeutic option in the treatment of inflammatory bowel disease. PMID:21061213

  18. Synthesis, colon-targeted studies and pharmacological evaluation of an anti-ulcerative colitis drug 4-Aminosalicylic acid-β-O-glucoside.

    PubMed

    Li, Feifei; Wu, Guoli; Zheng, Huixia; Wang, Li; Zhao, Zhengbao

    2016-01-27

    A glycoside prodrug of 4-aminosalicylic acid (4-ASA) with d-glucose was synthesized for targeted drug delivery to inflammatory bowel. The in vitro assessment of 4-aminosalicylic acid-β-O-glucoside (4-ASA-Glu) as a colon-specific prodrug was studied using colitis rat with the healthy one as control. The stability studies in aqueous buffers (pH 1.2, 6.8 and 7.4) indicated that 4-ASA-Glu was stable over a period of 12 h. The incubation of 4-ASA-Glu with cecal or colonic contents of healthy rats at 37 °C released 4-ASA in 77 or 80% of the dose in 12 h, respectively. The amount of 4-ASA liberated from the incubation of 4-ASA-Glu in cecal or colonic contents of colitis rats at 37 °C was 69 or 79% in 12 h respectively, while less than 9% 4-ASA was detected from the incubation of 4-ASA-Glu with the homogenates of stomach or small intestine. The curative effect of 4-ASA-Glu was evaluated in 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) induced experimental colitis model in male Sprague-Dawley (SD) rats. It was found that 4-ASA-Glu possess significantly ameliorate effect than sulfasalazine, oral 4- and 5-aminosalicylic acid. PMID:26717200

  19. The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis

    PubMed Central

    Pitcher, M; Beatty, E; Cummings, J

    2000-01-01

    BACKGROUND—Butyrate oxidation within the colonocyte is selectively inhibited by hydrogen sulphide, reproducing the metabolic lesion observed in active ulcerative colitis.
AIMS—To study generation of hydrogen sulphide by sulphate reducing bacteria (SRB) and the effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis in order to identify a role of this noxious agent in pathogenesis.
PATIENTS—Fresh faeces were obtained from 37 patients with ulcerative colitis (23 with active disease) and 16 healthy controls.
METHODS—SRB were enumerated from fresh faecal slurries and measurements made of sulphate reducing activity, and sulphate and hydrogen sulphide concentrations. The effect of 5-ASA on hydrogen sulphide production was studied in vitro.
RESULTS—All controls and patients with active ulcerative colitis carried SRB and total viable counts were significantly related to the clinical severity grade. SRB were of two distinct types: rapidly growing strains (desulfovibrios) which showed high sulphate reduction rates, present in 30% of patients with ulcerative colitis and 44% of controls; and slow growing strains which had little activity. In vitro, 5-ASA inhibited sulphide production in a dose dependent manner; in patients with ulcerative colitis not on these drugs faecal sulphide was significantly higher than in controls (0.55 versus 0.25 mM, p=0.027).
CONCLUSIONS—Counts and carriage rates of SRB in faeces of patients with ulcerative colitis are not significantly different from those in controls. SRB metabolism is not uniform between strains and alternative sources of hydrogen sulphide production exist in the colonic lumen which may be similarly inhibited by 5-ASA. The evidence for hydrogen sulphide as a metabolic toxin in ulcerative colitis remains circumstantial.


Keywords: colitis; sulphate; sulphide; bacteria; fermentation; salicylate PMID:10601057

  20. Treatment of experimental ulcerative colitis.

    PubMed

    Lazebnik, L B; Lychkova, A E; Knyazev, O V

    2012-10-01

    The effects of infliximab, an anticytokine drug, on the course of inflammatory process was studied on the model of ulcerative colitis induced by injection of picrylsulfonic acid. Infliximab prevented the development of toxic dilatation and a drop of bioelectric activity of smooth muscles via maintenance of activity of the intramural nervous system neurons. PMID:23113311

  1. Salvianolic Acid B Restored Impaired Barrier Function via Downregulation of MLCK by microRNA-1 in Rat Colitis Model

    PubMed Central

    Xiong, Yongjian; Wang, Jingyu; Chu, Hongwei; Chen, Dapeng; Guo, Huishu

    2016-01-01

    Salvianolic acid B (Sal B) is isolated from the traditional Chinese medical herb Salvia miltiorrhiza and is reported to have a wide range of therapeutic benefits. The aim of this study was to investigate the effects of Sal B on epithelial barrier dysfunction in rat colitis and to uncover related mechanisms. Rat colitis model was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The intestinal barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in vitro respectively. The protein expression related to intestinal barrier function was studied using western blotting. The effects of Sal B on inflammatory responses, oxidative damage and colitis recurrence were also studied in this study. The intestinal barrier dysfunction in colitis was reversed by Sal B, accompanied with the decrease of tight junction proteins, and the effect could be blocked by microRNA-1(miR-1) inhibition. The inflammatory responses, oxidative damage and colitis recurrence were also decreased by Sal B. The colitis symptoms and recurrences were ameliorated by Sal B, and restoration of impaired barrier function via downregulation of MLCK by miR-1 maybe involved in this effect. This study provides some novel insights into both of the pathological mechanisms and treatment alternatives of inflammatory bowel disease. PMID:27303297

  2. Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice

    PubMed Central

    Santana, Alfredo; Medina, Carlos; Paz-Cabrera, Maria Cristina; Díaz-Gonzalez, Federico; Farré, Esther; Salas, Antonio; Radomski, Marek W; Quintero, Enrique

    2006-01-01

    AIM: To study whether matrix metalloproteinase-9 (MMP-9) is a key factor in epithelial damage in the dextran sodium sulphate (DSS) model of colitis in mice. METHODS: MMP-9-deficient and wild-type (wt) mice were given 5% DSS in drinking water for 5 d followed by recovery up to 7 d. On d 5 and 12 after induction of colitis, gelatinases, MMP-2 and MMP-9, were measured in homogenates of colonic tissue by zymography and Western blot, whereas tissue inhibitor of metalloproteinases (TIMPs) were measured by reverse zymography. The gelatinolytic activity was also determined in supernatants of polymorphonuclear leukocytes (PMN) isolated from mice blood. Moreover, intestinal epithelial cells were stimulated with TNF-α to study whether these cells were able to produce MMPs. Finally, colonic mucosal lesions were measured by microscopic examination. RESULTS: On d 5 of colitis, the activity of MMP-9 was increased in homogenates of colonic tissues (0.24 ± 0.1 vs 21.3 ± 6.4, P < 0.05) and PMN from peripheral blood in wt (0.5 ± 0.1 vs 10.4 ± 0.7, P < 0.05), but not in MMP-9-deficient animals. The MMP-9 activity was also up-regulated by TNF-α in epithelial intestinal cells (2.5 ± 0.5 vs 14.7 ± 3.0, P < 0.05). Although colitis also led to increase of TIMP-1 activity, the MMP-9/TIMP-1 balance remained elevated. Finally, in the MMP-9-deficient colitic mice both the extent and severity of intestinal epithelial injury were significantly attenuated when compared with wt mice. CONCLUSION: We conclude that DSS induced colitis is markedly attenuated in animals lacking MMP-9. This suggests that intestinal injury induced by DSS is modulated by MMP-9 and that inhibition of this gelatinase may reduce inflammation. PMID:17072979

  3. Oat β-glucan ameliorates dextran sulfate sodium (DSS)-induced ulcerative colitis in mice.

    PubMed

    Liu, Bo; Lin, Qinlu; Yang, Tao; Zeng, Linna; Shi, Limin; Chen, Yaya; Luo, Feijun

    2015-11-01

    Ulcerative colitis is a major inflammatory bowel disease (IBD), characterized by inflammation within the gastrointestinal tract through chronic or relapsing immune system activation. The aim of this study is to investigate the potential protective effect of oat β-glucan (βG) against colitis induced by DSS in mice. Eighty mice were randomly divided into the control group (no DSS, no βG), DSS group (DSS only), DSS + L-βG group (DSS plus 500 mg per kg βG), and DSS + H-βG group (DSS plus 1000 mg per kg βG). Compared with the DSS group, administration of βG significantly reduced clinical symptoms with less weight loss, diarrhea and shortening of the colon, the severity of colitis was significantly inhibited as evidenced by the reduced disease activity index (DAI) and degree of histological damage in colon. Moreover, treatment with βG not only decreased myeloperoxidase activity (MPO), and nitric oxide (NO) and malondialdehyde (MDA) levels, but also inhibited mRNA and protein expression of pro-inflammatory factors such as TNF-α, IL-1β, IL-6 and iNOS. This suggests that oat βG in diet might exhibit an anti-inflammatory function against colitis through inhibition of expression of pro-inflammatory factors. PMID:26292622

  4. Anti-inflammatory effect of ondansetron through 5-HT3 receptors on TNBS-induced colitis in rat

    PubMed Central

    Motavallian-Naeini, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Mahzuni, Parvin

    2012-01-01

    Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestinal tract whose etiology has not yet been fully elucidated. Available medicines for treatment of IBD are not universally effective and result in marked deleterious effects. This challenge has thus heightened the need for research in order to adopt new therapeutic approaches for the treatment of IBD. 5-HT3 receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. Our aim was to investigate the effect of ondansetron, 5-HT3 receptor antagonist, in an immune-based animal model of IBD, trinitrobenzene sulfonic acid (TNBS)-induced rat colitis and probable involvement of 5-HT3 receptors. Two hours after induction of colitis (instillation of 50 mg/kg of TNBS dissolved in 0.25 ml of ethanol 50 % v/v) to male Wistar rats, ondansetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT3 receptor agonist, or ondansetron + mCPBG were administrated intraperitoneally (ip) and continued daily for six days. The animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically [myeloperoxidase (MPO), tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta]. Ondansetron and dexamethasone resulted in a decrease in macroscopic and microscopic colonic damage significantly. In addition a dramatic reduction in MPO activity and colonic levels of inflammatory cytokines were seen. The protective effects of ondansetron were antagonized by concurrent administration of mCPBG. Our data suggests that the beneficial effects of ondansetron in TNBS-induced colitis could be mediated by 5-HT3 receptors. PMID:27350767

  5. Effect of Glucans from Caripia montagnei Mushroom on TNBS-Induced Colitis

    PubMed Central

    da Nascimento Santos, Marilia S.; de Magalhães, Joedyson Emmanuel M.; Will Castro, Luiza Sheyla Evenni P.; de Sousa Pinheiro, Thuane; Sabry, Diego Araujo; Nobre, Leonardo Thiago Duarte B.; Lima, João Paulo Matos Santos; Baseia, Iuri Goulart; Leite, Edda Lisboa

    2014-01-01

    In this study, we evaluated the effect of different doses of polysaccharides extracted from Caripia montagnei mushroom at different intervals of treatment on colonic injury in the model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The FT-IR analysis and NMR showed that the polysaccharides from this species of mushroom are composed of α- and β-glucans. The colonic damage was evaluated by macroscopic, histological, biochemical and immunologic analyses. The results showed the reduction of colonic lesions in all groups treated with the glucans. Such glucans significantly reduced the levels of IL-6 (50 and 75 mg/kg, p < 0.05), a major inflammatory cytokine. Biochemical analyses showed that the glucans from C. montagnei acted on reducing levels of alkaline phosphatase (75 mg/kg, p < 0.01) and myeloperoxidase (p < 0.001), a result confirmed by the reduction of cellular infiltration observed microscopically. The increase of catalase activity possibly indicates a protective effect of these glucans on colonic tissue, confirming their anti-inflammatory potential. PMID:24518681

  6. Selective inhibition of fatty acid oxidation in colonocytes by ibuprofen: a cause of colitis?

    PubMed Central

    Roediger, W E; Millard, S

    1995-01-01

    Ibuprofen is associated with initiation or exacerbation of ulcerative colitis. As ibuprofen selectively inhibited fatty acid oxidation in the liver or caused mitochondrial damage in intestinal cells, its effect on substrate oxidation by isolated colonocytes of man and rat was examined. Ibuprofen dose dependently (2.0-7.5 mmol/l) and selectively inhibited 14CO2 production from labelled n-butyrate in colonocytes from the proximal and distal human colon (n = 12, p = < 0.001). Glucose oxidation was either unaltered or increased. Because short chain fatty acid oxidation is the main source of acetyl-CoA for long chain fatty acid synthesis, the inhibition of prostaglandin synthesis by ibuprofen in the colonic mucosa could also occur at this level. Because the concentrations of ibuprofen that can be attained in the human colon are not known, conclusions drawn from current dosages are tentative. The inhibition of fatty acid oxidation by ibuprofen may be biochemically implicated in the initiation and exacerbation of ulcerative colitis, manifestation of which would depend on the ibuprofen concentrations reached in the colon. PMID:7890237

  7. Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response.

    PubMed

    Singh, Kshipra; Coburn, Lori A; Barry, Daniel P; Asim, Mohammad; Scull, Brooks P; Allaman, Margaret M; Lewis, Nuruddeen D; Washington, M Kay; Rosen, Michael J; Williams, Christopher S; Chaturvedi, Rupesh; Wilson, Keith T

    2013-08-01

    L-Arginine (L-Arg) is a semiessential amino acid that has altered availability in human ulcerative colitis (UC), a form of inflammatory bowel disease, and is beneficial in murine colitis induced by dextran sulfate sodium (DSS), a model with similarity to UC. We assessed the role of cationic amino acid transporter 2 (CAT2), the inducible transporter of L-Arg, in DSS colitis. Expression of CAT2 was upregulated in tissues from colitic mice and localized predominantly to colonic macrophages. CAT2-deficient (CAT2-/-) mice exposed to DSS exhibited worsening of survival, body weight loss, colon weight, and histological injury. These effects were associated with increased serum L-Arg and decreased tissue L-Arg uptake and inducible nitric oxide synthase protein expression. Clinical benefits of L-Arg supplementation in wild-type mice were lost in CAT2-/- mice. There was increased infiltration of macrophages, dendritic cells, granulocytes, and T cells in colitic CAT2-/- compared with wild-type mice. Cytokine profiling revealed increases in proinflammatory granulocyte colony-stimulating factor, macrophage inflammatory protein-1α, IL-15, and regulated and normal T cell-expressed and -secreted and a shift from an IFN-γ- to an IL-17-predominant T cell response, as well as an increase in IL-13, in tissues from colitic CAT2-/- mice. However, there were no increases in other T helper cell type 2 cytokines, nor was there a global increase in macrophage-derived proinflammatory cytokines. The increase in IL-17 derived from both CD4 and γδ T cells and was associated with colonic IL-6 expression. Thus CAT2 plays an important role in controlling inflammation and IL-17 activation in an injury model of colitis, and impaired L-Arg availability may contribute to UC pathogenesis. PMID:23703655

  8. Serum Fatty Acids Are Correlated with Inflammatory Cytokines in Ulcerative Colitis

    PubMed Central

    Wiese, Dawn M.; Horst, Sara N.; Brown, Caroline T.; Allaman, Margaret M.; Hodges, Mallary E.; Slaughter, James C.; Druce, Jennifer P.; Beaulieu, Dawn B.; Schwartz, David A.; Wilson, Keith T.; Coburn, Lori A.

    2016-01-01

    Background and Aims Ulcerative colitis (UC) is associated with increased dietary intake of fat and n-6 polyunsaturated fatty acids (PUFA). Modification of fat metabolism may alter inflammation and disease severity. Our aim was to assess differences in dietary and serum fatty acid levels between control and UC subjects and associations with disease activity and inflammatory cytokines. Methods Dietary histories, serum, and colonic tissue samples were prospectively collected from 137 UC subjects and 38 controls. Both histologic injury and the Mayo Disease Activity Index were assessed. Serum and tissue cytokines were measured by Luminex assay. Serum fatty acids were obtained by gas chromatography. Results UC subjects had increased total fat and oleic acid (OA) intake, but decreased arachidonic acid (AA) intake vs controls. In serum, there was less percent saturated fatty acid (SFA) and AA, with higher monounsaturated fatty acids (MUFA), linoleic acid, OA, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) in UC. Tissue cytokine levels were directly correlated with SFA and inversely correlated with PUFA, EPA, and DPA in UC subjects, but not controls. 5-aminosalicylic acid therapy blunted these associations. Conclusions In summary, we found differences in serum fatty acids in UC subjects that correlated with pro-inflammatory tissue cytokines. We propose that fatty acids may affect cytokine production and thus be immunomodulatory in UC. PMID:27227540

  9. MAG-EPA reduces severity of DSS-induced colitis in rats.

    PubMed

    Morin, Caroline; Blier, Pierre U; Fortin, Samuel

    2016-05-15

    Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the intestinal mucosa of the large bowel. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines involved in UC pathogenesis. The aim of this study was to determine the preventive and therapeutic potential of eicosapentaenoic acid monoglyceride (MAG-EPA) in an in vivo rats model of UC induced by dextran sulfate sodium (DSS). DSS rats were untreated or treated per os with MAG-EPA. Morphological, histological, and biochemical analyses were performed following MAG-EPA administrations. Morphological and histological analyses revealed that MAG-EPA pretreatment (12 days pre-DSS) and treatment (6 days post-DSS) exhibited strong activity in reducing severity of disease in DSS rats. Following MAG-EPA administrations, tissue levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly lower compared with rats treated only with DSS. MAG-EPA per os administration decrease neutrophil infiltration in colon tissues, as depicted by myelohyperoxidase activity. Results also revealed a reduced activation of NF-κB pathways correlated with a decreased expression of COX-2 in colon homogenates derived from MAG-EPA-pretreated and treated rats. Tension measurements performed on colon tissues revealed that contractile responses to methacholine and relaxing effect induced by sodium nitroprusside were largely increased following MAG-EPA treatment. The combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in DSS rats. PMID:27012773

  10. Amelioration of dextran sodium sulfate-induced colitis in mice by Rhodobacter sphaeroides extract.

    PubMed

    Liu, Wen-Sheng; Chen, Man-Chin; Chiu, Kuo-Hsun; Wen, Zhi-Hong; Lee, Che-Hsin

    2012-01-01

    Bacteria can produce some compounds in response to their environment. These compounds are widely used in cosmetic and pharmaceutical applications. Some probiotics have immunomodulatory activities and modulate the symptoms of several diseases. Autoimmune diseases represent a complex group of conditions that are thought to be mediated through the development of autoreactive immunoresponses. Inflammatory bowel disease (IBD) is common autoimmune disease that affects many individuals worldwide. Previously, we found that the extracts of Rhodobacter sphaeroides (Lycogen) inhibited nitric oxide production and inducible nitric-oxide synthase expression in activated macrophages. In this study, the effect of Lycogen, a potent anti-inflammatory agent, was evaluated in mice with dextran sodium sulfate (DSS)-induced colitis. Oral administration of Lycogen reduced the expressions of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in female BABL/c mice. In addition, the increased number of bacterial flora in the colon induced by DSS was amelirated by Lycogen. The histological score of intestinal inflammation in 5% DSS-treated mice after oral administration of Lycogen was lower than that of control mice. Meanwhile, Lycogen dramatically prolonged the survival of mice with severe colitis. These findings identified that Lycogen is an anti-inflammatory agent with the capacity to ameliorate DSS-induced colitis. PMID:23159923

  11. Dietary supplementation of arachidonic acid increases arachidonic acid and lipoxin A4 contents in colon, but does not affect severity or prostaglandin E2 content in murine colitis model

    PubMed Central

    2014-01-01

    Background Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4). The effects of dietary ARA on colon maintenance are unclear because PGE2 has both mucosal protective and proinflammatory effects, and LXA4 has an anti-inflammatory role. Our objective is to clarify the effects of dietary ARA on an experimental murine colitis model. Methods C57BL/6 mice were fed three types of ARA diet (0.075%, 0.15% or 0.305% ARA in diet), DHA diet (0.315% DHA) or control diet for 6 weeks, and were then administered dextran sodium sulphate (DSS) for 7 days to induce colitis. We evaluated colitis severity, fatty acid and lipid mediator contents in colonic tissue, and the expression of genes related to lipid mediator formation. Results ARA composition of colon phospholipids was significantly elevated in an ARA dose-dependent manner. ARA, as well as DHA, did not affect colitis severity (body weight loss, colon shortening, diarrhea and hemoccult phenomena) and histological features. PGE2 contents in the colon were unchanged by dietary ARA, while LXA4 contents increased in an ARA dose-dependent manner. Gene expression of cyclooxygenase (COX)-1 and COX-2 was unchanged, while that of 12/15-lipoxgenase (LOX) was significantly increased by dietary ARA. ARA composition did not correlate with neither colon length nor PGE2 contents, but significantly correlated with LXA4 content. Conclusion These results suggest that dietary ARA increases ARA and LXA4 contents in colon, but that it has no effect on severity and PGE2 content in a DSS-induced murine colitis model. PMID:24507383

  12. Use of bacitracin in the prevention and treatment of experimentally-induced idiopathic colitis in horses.

    PubMed Central

    Staempfli, H R; Prescott, J F; Carman, R J; McCutcheon, L J

    1992-01-01

    Ten healthy ponies from a single herd were found by repeated fecal culture to be free of Salmonella species and Clostridium cadaveris. In a preliminary study, four ponies administered a single oral dose of 10 mg/kg lincomycin did not develop idiopathic colitis when the drug was administered alone. Four other ponies were administered 10 mg/kg lincomycin by stomach tube together with 0.45 L of colonic content from a horse with idiopathic colitis induced earlier by lincomycin alone. Two of the four ponies were treated with 25 g oral zinc bacitracin premix (110 g/kg active ingredient) 24 h later. Forty-two hours after inoculation the two untreated ponies had severe signs of idiopathic colitis and were euthanized. Postmortem findings were typical of idiopathic colitis. The two treated ponies had milder illness but the more severely affected was also euthanized; the other was retreated at 42 h with bacitracin pre-mix and again 12 h later. Its illness and diarrhea resolved over the next 24 h. Clostridium cadaveris was isolated in large numbers from the cecum of the euthanized ponies and their cecal content contained mouse lethal and guinea pig dermonecrotic, but not cytotoxic, activity. Enterotoxins of Clostridium perfringens and Clostridium difficile could not be demonstrated. No toxin could be demonstrated in culture supernatants of C. cadaveris or in supernatants of cecal contents treated with ethanol prior to culturing in anaerobically incubated broth. No Salmonella spp. were isolated. A further two ponies were administered 10 mg/kg lincomycin orally with 0.45 L colonic content from a horse with idiopathic colitis, as described.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1423060

  13. Reduced susceptibility of mice overexpressing transforming growth factor α to dextran sodium sulphate induced colitis

    PubMed Central

    Egger, B; Carey, H; Procaccino, F; Chai, N; Sandgren, E; Lakshmanan, J; Buslon, V; French, S; Buchler, M; Eysselein, V

    1998-01-01

    Background—Transforming growth factor α (TGF-α) knockout mice have increased susceptibility to dextran sodium sulphate (DSS) induced colitis. 
Aim—To substantiate the findings that TGF-α is a key mediator of colonic mucosal protection and/or repair mechanisms by evaluating the susceptibility of mice overexpressing TGF-α to DSS induced colitis. 
Methods—TGF-α overexpression was induced in transgenic mice by ZnSO4 administration in drinking water (TG+). Three groups were used as controls: one transgenic group without ZnSO4 administration (TG−), and two non-transgenic littermate groups receiving ZnSO4 (Non-TG+) or only water (Non-TG−). Acute colitis was induced in all groups by administration of DSS (5%, w/v) in drinking water for six days ad libitum. 
Results—About 35-39% of the entire colonic mucosa was destroyed in Non-TG−, Non-TG+, and TG− animals compared with 9% in TG+ mice. The crypt damage score was 18.7 (0.9), 18.2 (1.0), 18.9(0.8), and 6.8 (1.5) (means (SEM)) in Non-TG−, Non-TG+, TG−, and TG+ mice respectively. Mucin and bromodeoxyuridine staining were markedly enhanced in colons of TG+ mice compared with controls, indicating increased mucosal protection and regeneration. 
Conclusions—The significantly reduced susceptibility of mice overexpressing TGF-α to DSS further substantiates that endogenous TGF-α is a pivotal mediator of protection and/or healing mechanisms in the colon. 

 Keywords: transforming growth factor α; epidermal growth factor; dextran sodium sulphate; colitis; inflammatory bowel disease; transgenic mice PMID:9771407

  14. Protective Effect of Amphipterygium adstringens Extract on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice

    PubMed Central

    Rodriguez-Canales, Mario; Jimenez-Rivas, Ruben; Canales-Martinez, Maria Margarita; Garcia-Lopez, Ana Judith; Rivera-Yañez, Nelly; Nieto-Yañez, Oscar; Ledesma-Soto, Yadira; Sanchez-Torres, Luvia Enid; Rodriguez-Sosa, Miriam; Terrazas, Luis Ignacio

    2016-01-01

    Amphipterygium adstringens is an endemic species in Mexico commonly known as “cuachalalate.” Healers to treat gastritis, gastric ulcers, and gastrointestinal cancer have traditionally used the bark. We investigated the effects of alcoholic extract of A. adstringens (AaEE) in DSS-induced colitis in mice. The protective effect of AaEE was determined at 200 mg/kg by oral gavage for 10 days. We determine the effect of AaEE on clinical features (disease activity index), antioxidants, anti-inflammatory, and immunomodulatory activities in relation to the activity of SOD, CAT, and GPx, levels of proinflammatory cytokines, and changes both macroscopic and microscopic of the colonic mucosa. AaEE significantly reduced the inflammation of colon and significantly increased SOD and GPx activities. AaEE also significantly decreased TNF-α, IFN-γ, and IL-1β cytokine levels compared to DSS-treated mice and reduced both infiltration of inflammatory cells and the mucosal damage in colon. The results suggested the protective potential of AaEE in DSS-induced colitis and this might be attributed to its phytochemicals compounds that have been found to induce a wide spectrum of activities such as reduction in oxidative stress, suppression of inflammation, modulating numerous signal transduction pathways, and induction of apoptosis. The findings of this study suggest that AaEE has substantial potential for the treatment of inflammatory colitis.

  15. Chronic administration of galanin attenuates the TNBS-induced colitis in rats.

    PubMed

    Talero, E; Sánchez-Fidalgo, S; Calvo, J R; Motilva, V

    2007-06-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder considered as a consequence of an aberrant response of the immune system to luminal antigens. Numerous groups of agents are being evaluated as novel therapeutic approaches for its treatment; in this way, different peptides have emerged as potential candidates. Galanin is an active neuropeptide distributed in the central and periphery nervous systems although it has been also described having important autocrine and paracrine regulatory capacities with interesting inflammatory and immune properties. In this line, we have observed that galanin treatment has a significant preventive effect in the experimental trinitrobenzensulfonic acid (TNBS) acute model of inflammatory colitis. The aim of the present study was to investigate intensively the role played by the peptide in the evolution of the inflammatory pathology associated to IBD. Galanin (5 and 10 microg/kg/day) was administered i.p., daily, starting 24 h after TNBS instillation, and continuing for 14 and 21 days. The lesions were blindly scored according to macroscopic and histological analyses and quantified as ulcer index. The results demonstrated that chronic administration of galanin improved the colon injury than the TNBS induced. The study by Western-blotting of the expression of nitric oxide inducible enzyme (iNOS), as well as the total nitrite production (NO) assayed by Griess-reaction, showed significant reduction associated with peptide administration. The number of mast cells was also identified in histological preparations stained with toluidine blue and the results showed that samples from galanin treatment, mostly at 21 days, had increased the number of these cells and many of them had a degranulated feature. In conclusion, chronic administration of galanin is able to exert a beneficial effect in the animal model of IBD assayed improving the reparative process. Participation of nitric oxide pathways and mucosal mast cells

  16. Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation.

    PubMed

    Li, Chengzhen; Xi, Yebin; Li, Shan; Zhao, Qing; Cheng, Wenjing; Wang, Zhengting; Zhong, Jie; Niu, Xiaoyin; Chen, Guangjie

    2015-10-01

    Th1 and Th17 cells, and their associated cytokines, have been associated with the pathogenesis of Crohn's disease. Berberine (BBR), a compound long used in traditional Chinese medicines, has been reported to have therapeutic effects in treating experimental colitis. In this study, we show that BBR had a protective effect on mice with TNBS-induced colitis. BBR inhibited levels of IFN-γ, IL-17, IL-6, IL-1β and TNF-α both in the local colon and sera, and transiently increased levels of IL-22. BBR also markedly increased sIgA expression in the colon. BBR had pronounced effects on macrophage populations. Treatment with BBR adjusted the M2/M1 ratio. In addition, BBR exerted effects on adaptive immunity by suppressing numbers of Th1 and Th17 cells, as well as expression levels of their associated cytokines and transcriptional factors. BBR downregulated STAT3 and STAT1 phosphorylation, and inhibited phosphorylation of NF-kB. In vitro experiments showed that BBR inhibited the differentiation of Th17 and, to a lesser degree, Th1 cells, without affecting regulatory T cells. Therefore, we conclude that BBR plays a regulatory role in modulating the balance of immune responses in TNBS-induced colitis. Our study will help us understand the regulatory mechanisms exerted by BBR in the treatment of IBD. PMID:26224047

  17. Preventive effects of cranberry products on experimental colitis induced by dextran sulphate sodium in mice.

    PubMed

    Xiao, Xiao; Kim, Jonggun; Sun, Quancai; Kim, Daeyoung; Park, Cheon-Seok; Lu, Tzong-Shi; Park, Yeonhwa

    2015-01-15

    With the prevalence of inflammatory bowel disease (IBD) and its associated risk for development of colorectal cancer, it is of great importance to prevent and treat IBD. However, due to the complexity of etiology and potentially serious adverse effects, treatment options for IBD are relatively limited. Thus, the purpose of this study was to identify a safe food-based approach for the prevention and treatment of IBD. In this study, we tested the effects of cranberry products on preventing dextran sulphate sodium-induced murine colitis. Our results suggest that both cranberry extract and dried cranberries-fed groups had a significantly reduced disease activity index, where dried cranberries were more effective in preventing colitis than cranberry extract. Shortening of colon length, colonic myeloperoxidase activity and production of pro-inflammatory cytokines were attenuated in animals fed dried cranberries compared to the controls. The current report suggests that cranberries can be applied to prevent and reduce the symptoms of IBD. PMID:25149009

  18. Preventive Effects of Spirogyra neglecta and a Polysaccharide Extract against Dextran Sodium Sulfate Induced Colitis in Mice.

    PubMed

    Taya, Sirinya; Kakehashi, Anna; Wongpoomchai, Rawiwan; Gi, Min; Ishii, Naomi; Wanibuchi, Hideki

    2016-01-01

    Ulcerative colitis (UC) results from colonic epithelial barrier defects and impaired mucosal immune responses. In this study, we aimed to investigate the modifying effects of a Spirogyra neglecta extract (SNE), a polysaccharide extract (PE) and a chloroform fraction (CF) on dextran sodium sulfate (DSS)-induced colitis in mice and to determine the mechanisms. To induce colitis, ICR mice received 3% DSS in their drinking water for 7 days. Seven days preceding the DSS treatment, oral administration of SNE, PE and CF at doses of 50, 25 and 0.25 mg/kg body weight (low dose), 200, 100 and 1 mg/kg body weight (high dose) and vehicle was started and continued for 14 days. Histologic findings showed that DSS-induced damage of colonic epithelial structure and inflammation was attenuated in mice pre-treated with SNE, PE and CF. Furthermore, SNE and PE significantly protected colonic epithelial cells from DSS-induced cell cycle arrest, while SNE, PE and CF significantly diminished apoptosis. Proteome analysis demonstrated that SNE and PE might ameliorate DSS-induced colitis by inducing antioxidant enzymes, restoring impaired mitochondria function, and regulating inflammatory cytokines, proliferation and apoptosis. These results suggest that SNE and PE could prevent DSS-induced colitis in ICR mice by protection against and/or aiding recovery from damage to the colonic epithelium, reducing ROS and maintaining normal mitochondrial function and apoptosis. PMID:27221924

  19. Proinflammatory role of the histamine H4 receptor in dextrane sodium sulfate-induced acute colitis.

    PubMed

    Schirmer, Bastian; Rezniczek, Thomas; Seifert, Roland; Neumann, Detlef

    2015-11-01

    Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed. Out of the four known histamine receptors, the histamine H4 receptor (H4R) has been demonstrated to act proinflammatory in experimental models of several inflammatory diseases. In order to evaluate a potential involvement of H4R in IBD we investigated the effect of genetic or pharmacological blockade of H4R-signaling in the model of dextran sodium sulfate (DSS)-induced colitis in mice. We analysed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colons and systemic or local cytokine concentrations. Both genetic deficiency and pharmacological blockade of H4R with the selective antagonist JNJ7777120 improved clinical and histological signs of colitis and dampened the inflammatory cytokine response. Our results indicate a proinflammatory role of histamine via H4R in IBD, thus extending the current pathophysiological understanding of IBD and demonstrating the therapeutic potential of selective H4R-antagonists for patients suffering from IBD. PMID:26365468

  20. Protective Effect of Dietary Lily Bulb on Dextran Sulfate Sodium-Induced Colitis in Rats Fed a High-Fat Diet.

    PubMed

    Okazaki, Yukako; Chiji, Hideyuki; Kato, Norihisa

    2016-01-01

    Lily bulb is traditionally consumed in East Asia and contains high amounts of glucomannan. This study investigated the effect of dietary lily bulb on dextran sulfate sodium (DSS)-induced colitis in rats fed a high-fat (HF) diet. Male Sprague-Dawley rats were fed a diet containing 30% beef tallow with or without 7% steamed lily bulb powder for 17 d. Experimental colitis was induced by replacing drinking water with DSS during the last 7 d. The disease activity index (DAI) was significantly lower in the lily bulb+DSS group than in the DSS group on day 17. The fecal abundance of Bifidobacterium was significantly reduced in the DSS group compared with that in the control group, but it was recovered by lily bulb intake. Cecal butyrate, fecal mucins, and alkaline phosphatase (ALP) activity were significantly higher in the DSS group than in the control group. Dietary lily bulb potentiated the increase in cecal butyrate, fecal mucins, and the ALP activity caused by DSS treatment. These results indicate that lily bulb attenuates DSS-induced colitis by modulating colonic microflora, organic acids, mucins, and ALP activity in HF diet-fed rats. PMID:27465728

  1. Anti-PD1-induced collagenous colitis in a melanoma patient.

    PubMed

    Baroudjian, Barouyr; Lourenco, Nelson; Pagès, Cécile; Chami, Ichrak; Maillet, Marianne; Bertheau, Philippe; Bagot, Martine; Gornet, Jean-Marc; Lebbé, Céleste; Allez, Matthieu

    2016-06-01

    Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab. PMID:26990271

  2. Prevention of Chronic Experimental Colitis Induced by Dextran Sulphate Sodium (DSS) in Mice Treated with FR91

    PubMed Central

    Lombardi, Valter R. M.; Etcheverría, Ignacio; Carrera, Iván; Cacabelos, Ramón; Chacón, Antonio R.

    2012-01-01

    One of the main treatments currently used in humans to fight cancer is chemotherapy. A huge number of compounds with antitumor activity are present in nature, and many of their derivatives are produced by microorganisms. However, the search for new drugs still represents a main objective for cancer therapy, due to drug toxicity and resistance to multiple chemotherapeutic drugs. In animal models, a short-time oral administration of dextran sulfate sodium (DSS) induces colitis, which exhibits several clinical and histological features similar to ulcerative colitis (UC). However, the pathogenic factors responsible for DSS-induced colitis and the subsequent colon cancer also remain unclear. We investigated the effect of FR91, a standardized lysate of microbial cells belonging to the Bacillus genus which has been previously shown to have significant immunomodulatory effects, against intestinal inflammation. Colitis was induced in mice during 5 weeks by oral administration 2% (DSS). Morphological changes in the colonic mucosa were evaluated by hematoxylin-eosin staining and immunohistochemistry methods. Adenocarcinoma and cryptal cells of the dysplastic epithelium showed cathenin-β, MLH1, APC, and p53 expression, together with increased production of IFN-γ. In our model, the optimal dose response was the 20% FR91 concentration, where no histological alterations or mild DSS-induced lesions were observed. These results indicate that FR91 may act as a chemopreventive agent against inflammation in mice DSS-induced colitis. PMID:22619498

  3. Development of novel budesonide pellets based on CODESTM technology: In vitro/in vivo evaluation in induced colitis in rats

    PubMed Central

    Varshosaz, J.; Emami, J.; Tavakoli, N.; Minaiyan, M.; Rahmani, N.; Dorkoosh, F.; Mahzouni, P.

    2011-01-01

    Background and the purpose of the study Budesonide is the drug of choice for treatment of active inflammatory bowel disease (IBD). The aim of this study was to develop budesonide pellets based on a novel colon drug delivery system (CODES). Methods Pellet cores containing lactulose or mannitol were prepared by extrusion/spheronization and coated with an acid soluble polymer (Eudragit E100), hydroxypropylmethyl cellulose (HPMC) and an enteric coat (Eudragit FS 30D) sequentially. In vitro drug release of coated pellets was studied using USP dissolution apparatus type II in buffers of pH 1.2 (2 hrs), pH of 7.4 (4 hrs) and pH of 6.8 containing 8% rat cecal contents (RCC) (18 hrs). The efficacy of the optimized formulation (containing 50% lactulose coated with Eudragit E (30% w/w) and Eudragit FS 30D (12% w/w)) was evaluated against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Results The results of the kind of bacteria in vitro dissolution tests indicated absence of drug release in pHs of 1.2 and 7.4 and controlled release in buffer of pH 6.8 containing RCC. It was found that release rate was controlled by the type and amount of polysaccharide and the thickness of the acid soluble layer. The prepared formulation showed promising results in alleviating the conditions of experimental model of colitis. Conclusion The results of this study suggest that pellets based on CODES technology could be useful for colonic delivery of budesonide. PMID:22615647

  4. Effects of Guchang Capsule on Dextran Sulphate Sodium-Induced Experimental Ulcerative Colitis in Mice

    PubMed Central

    Liu, Baoshan; Liu, Tong; Wang, Xiaohong; Zheng, Xin; Wang, Hong; Ma, Lin

    2016-01-01

    Guchang capsule (GC) is a Chinese materia medica standardized product extracted from 15 Chinese traditional medical herbs and it has been clinically used in the treatment of intestinal disease. In this study, in order to extend the research of GC in intestinal disease, we were aiming to evaluate potential effects of GC on dextran sulphate sodium- (DSS-) induced murine experimental colitis and to elucidate the underlying mechanisms. GC treatment attenuated DSS-induced body weight loss and reduced the mortality. Moreover, GC treatment prevented DSS-induced colonic pathological damage; meanwhile it inhibited proinflammatory cytokines production in colon tissues. In vitro, GC significantly reduced LPS-induced proinflammatory cytokines production via inhibiting the activation of NF-κB in macrophage cells, and the expressions of several long noncoding RNAs (lncRNAs) which were reported in regulating NF-κB signaling pathway were obviously affected by adding GC into culture medium. In conclusion, our data suggested that administration of GC exhibits therapeutic effects on DSS-induced colitis partially through regulating the expression of NF-κB related lncRNAs in infiltrating immune cells. PMID:27313642

  5. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

    PubMed Central

    Liu, Weicheng; Chen, Yunzi; Golan, Maya Aharoni; Annunziata, Maria L.; Du, Jie; Dougherty, Urszula; Kong, Juan; Musch, Mark; Huang, Yong; Pekow, Joel; Zheng, Changqing; Bissonnette, Marc; Hanauer, Stephen B.; Li, Yan Chun

    2013-01-01

    The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn’s disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4+CD45RBhi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions. PMID:23945234

  6. Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.

    PubMed Central

    Breuer, R I; Soergel, K H; Lashner, B A; Christ, M L; Hanauer, S B; Vanagunas, A; Harig, J M; Keshavarzian, A; Robinson, M; Sellin, J H; Weinberg, D; Vidican, D E; Flemal, K L; Rademaker, A W

    1997-01-01

    BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. CONCLUSIONS: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit. PMID:9176076

  7. Anti-inflammatory effects of Lactococcus lactis NCDO 2118 during the remission period of chemically induced colitis

    PubMed Central

    2014-01-01

    Background Many probiotic bacteria have been described as promising tools for the treatment and prevention of inflammatory bowel diseases (IBDs). Most of these bacteria are lactic acid bacteria, which are part of the healthy human microbiota. However, little is known about the effects of transient bacteria present in normal diets, including Lactococcus lactis. Methods In the present study, we analysed the immunomodulatory effects of three L. lactis strains in vitro using intestinal epithelial cells. L. lactis NCDO 2118 was administered for 4 days to C57BL/6 mice during the remission period of colitis induced by dextran sodium sulphate (DSS). Results Only one strain, L. lactis NCDO 2118, was able to reduce IL-1β-induced IL-8 secretion in Caco-2 cells, suggesting a potential anti-inflammatory effect. Oral treatment using L. lactis NCDO 2118 resulted in a milder form of recurrent colitis than that observed in control diseased mice. This protective effect was not attributable to changes in secretory IgA (sIgA); however, NCDO 2118 administration was associated with an early increase in IL-6 production and sustained IL-10 production in colonic tissue. Mice fed L. lactis NCDO 2118 had an increased number of regulatory CD4+ T cells (Tregs) bearing surface TGF-β in its latent form (Latency-associated peptide-LAP) in the mesenteric lymph nodes and spleen. Conclusions Here, we identified a new probiotic strain with a potential role in the treatment of IBD, and we elucidated some of the mechanisms underlying its anti-inflammatory effect. PMID:25110521

  8. Plant-derived polysaccharide supplements inhibit dextran sulfate sodium-induced colitis in the rat.

    PubMed

    Koetzner, Lee; Grover, Gary; Boulet, Jamie; Jacoby, Henry I

    2010-05-01

    Several plant-derived polysaccharides have been shown to have anti-inflammatory activity in animal models. Ambrotose complex and Advanced Ambrotose are dietary supplements that include aloe vera gel, arabinogalactan, fucoidan, and rice starch, all of which have shown such activity. This study was designed to evaluate these formulations against dextran sulfate sodium (DSS)-induced colitis in rats and to confirm their short-term safety after 14 days of daily dosing. Rats were dosed daily orally with vehicle, Ambrotose or Advanced Ambrotose. On day six groups of rats received tap water or 5% Dextran Sulfate sodium. Ambrotose and Advanced Ambrotose significantly lowered the disease scores and partially prevented the shortening of colon length. An increase in monocyte count was induced by dextran sulfate sodium and inhibited by Ambrotose and Advanced Ambrotose. There were no observable adverse effects after 14-day daily doses. The mechanism of action of the formulations against DSS-induced colitis may be related to its effect on monocyte count. PMID:19513840

  9. IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

    PubMed Central

    Bahri, Rajia; Pateras, Ioannis S; D’Orlando, Orietta; Goyeneche-Patino, Diego A; Campbell, Michelle; Polansky, Julia K; Sandig, Hilary; Papaioannou, Marilena; Evangelou, Kostas; Foukas, Periklis G; Gorgoulis, Vassilis G; Bulfone-Paus, Silvia

    2015-01-01

    IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15−/− and Il15rα−/− mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15−/− but not Il15rα−/− mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15−/− mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFNγ, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu. PMID:26405589

  10. Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway

    PubMed Central

    Zhang, Jingjing; Zhang, Eryun; Sun, Aning; Ding, Lili; Wei, Xiaohui; Chou, Guixin; Mani, Sridhar; Wang, Zhengtao

    2013-01-01

    Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways. PMID:24232001

  11. Mulberry fruit prevents LPS-induced NF-κB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice.

    PubMed

    Qian, Zhengjiang; Wu, Zhiqin; Huang, Lian; Qiu, Huiling; Wang, Liyan; Li, Li; Yao, Lijun; Kang, Kang; Qu, Junle; Wu, Yonghou; Luo, Jun; Liu, Johnson J; Yang, Yi; Yang, Wancai; Gou, Deming

    2015-01-01

    Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials. PMID:26615818

  12. Mulberry fruit prevents LPS-induced NF-κB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice

    PubMed Central

    Qian, Zhengjiang; Wu, Zhiqin; Huang, Lian; Qiu, Huiling; Wang, Liyan; Li, Li; Yao, Lijun; Kang, Kang; Qu, Junle; Wu, Yonghou; Luo, Jun; Liu, Johnson J.; Yang, Yi; Yang, Wancai; Gou, Deming

    2015-01-01

    Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2−/− mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2−/− mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials. PMID:26615818

  13. Impact of dextran sulphate sodium-induced colitis on the intestinal transport of the colon carcinogen PhIP.

    PubMed

    Nicken, Petra; von Keutz, Anne; Willenberg, Ina; Ostermann, Annika I; Schebb, Nils Helge; Giovannini, Samoa; Kershaw, Olivia; Breves, Gerhard; Steinberg, Pablo

    2016-05-01

    Colorectal cancer is one of the most frequent cancers in Western countries. Chronic intestinal diseases such as Crohn's disease and ulcerative colitis, in which the intestinal barrier is massively disturbed, significantly raise the risk of developing a colorectal tumour. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a genotoxic heterocyclic aromatic amine that is formed after strongly heating fish and meat. In this study, the hypothesis that PhIP uptake in the gut is increased during chronic colitis was tested. Chronic colitis was induced by oral administration of dextran sulphate sodium (DSS) to Fischer 344 rats. The transport of PhIP in eight different rat intestinal segments was examined in Ussing chambers. The tissues were incubated with 10 µM PhIP for 90 min, and the concentration of PhIP was determined in the mucosal and serosal compartments of the Ussing chambers as well as in the clamped tissues by LC-MS. Although chronic colitis was clearly induced in the rats, no differences in the intestinal transport of PhIP were observed between control and DSS-treated animals. The hypothesis that in the course of chronic colitis more PhIP is taken up by the intestinal epithelium, thereby increasing the risk of developing colorectal cancer, could not be confirmed in the present report. PMID:26070365

  14. Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation

    PubMed Central

    Liu, Xiaowei; He, Haiyue; Huang, Tingting; Lei, Zhen; Liu, Fuquan; An, Guangyu; Wen, Tao

    2016-01-01

    Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils. PMID:26881040

  15. Lactobacillus casei prevents the development of dextran sulphate sodium-induced colitis in Toll-like receptor 4 mutant mice.

    PubMed

    Chung, Y W; Choi, J H; Oh, T-Y; Eun, C S; Han, D S

    2008-01-01

    Probiotics, defined as live or attenuated bacteria or bacterial products, confer a significant health benefit to the host. Recently, they have been shown to be useful in the treatment of chronic inflammatory bowel disease and infectious colitis. In this study, we investigated the effect of probiotics on the development of experimental colitis using Toll-like receptor 4 (TLR-4) mutant (lps-/lps-) mice. TLR-4(lps-/lps-) and wild-type (WT) mice were given 2.5% dextran sulphate sodium (DSS) in drinking water to induce colitis with or without Lactobacillus casei pretreatment. Clinical and histological activity of DSS-colitis was attenuated markedly both in TLR-4(lps-/lps-) and WT mice pretreated with L. casei. Interestingly, histological activity was less severe in TLR-4(lps-/lps-) mice than in WT mice. The levels of myeloperoxidase activity and interleukin (IL)-12p40 were attenuated in pretreated TLR-4(lps-/lps-) mice after DSS administration. By contrast, transforming growth factor (TGF)-beta and IL-10 mRNA and protein expressions were increased markedly in pretreated TLR-4(lps-/lps-) mice. The current results suggest that L. casei has a preventive effect in the development of acute DSS-induced colitis and its action depends largely upon TLR-4 status. L. casei modulates the expression of inflammatory cytokines and down-regulates neutrophilic infiltration in the case of incomplete TLR-4 complex signalling. PMID:18005362

  16. β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon

    PubMed Central

    Schippers, A; Muschaweck, M; Clahsen, T; Tautorat, S; Grieb, L; Tenbrock, K; Gaßler, N; Wagner, N

    2016-01-01

    Leukocyte recruitment is pivotal for the initiation and perpetuation of inflammatory bowel disease (IBD) and controlled by the specificity and interactions of chemokines and adhesion molecules. Interactions of the adhesion molecules α4β7-integrin and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) promote the accumulation of pathogenic T-cell populations in the inflamed intestine. We aimed to elucidate the significance of β7-integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that β7-integrin deficiency protects recombination-activating gene-2 (RAG-2)-deficient mice from dextran sodium sulfate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that β7-integrin is expressed on most CD11b+CD64lowLy6C+ bone marrow progenitors and contributes to colonic recruitment of these proinflammatory monocytes. Importantly, adoptive transfer of CD115+ wild-type (WT) monocytes partially restored the susceptibility of RAG-2/β7-integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of β7-integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4β7-integrin–MAdCAM-1 interactions as drivers of colitis by directing inflammatory monocytes into the colon. PMID:26349655

  17. BTLA associates with increased Foxp3 expression in CD4(+) T cells in dextran sulfate sodium-induced colitis.

    PubMed

    Zhang, Han-Xian; Zhu, Bin; Fu, Xiao-Xia; Zeng, Jin-Cheng; Zhang, Jun-Ai; Wang, Wan-Dang; Kong, Bin; Xiang, Wen-Yu; Zhong, Jixin; Wang, Cong-Yi; Zheng, Xue-Bao; Xu, Jun-Fa

    2015-01-01

    Ulcerative colitis (UC) is an inflammatory bowel disease, and its pathogenesis involves a variety of genetic, environmental, and immunological factors such as T helper cells and their secreted cytokines. B and T lymphocyte attenuator (BTLA) is an immunoregulatory receptor that has a strong suppressive effect on T-cell function. However the role of BTLA in UC remains poorly understood. Here we demonstrated that the frequency of BTLA-expressing CD3(+) T cells, especially CD4(+) T cells, increased in blood and mucosa in mice with DSS-induced colitis. The frequency of Foxp3-expressing cells in BTLA+ CD4(+) T cell from lamina propria mononuclear cells (LPMCs) was much higher in DSS-treated mice than that in controls. Similarly, the proportion of IL-17+ cells in BTLA+ CD4(+) T cells from LPMCs in DSS-treated mice is much higher than that in controls, while no perceptible difference for the proportion of IFN-γ+ cells in BTLA+ CD4(+) T cells was noted between DSS-treated mice and controls. Treatment of mesalazine, an anti-ulcerative colitis drug, down-regulated Foxp3 and IL-17 expression in BTLA positive T cells along with attenuated severity for colitis. Our findings indicate that BTLA may be involved in the control of inflammatory responses through increasing Foxp3 expression, rather than attenuating IL-17 production, in DSS-induced colitis. PMID:25973010

  18. Inhibitory effect of the gallotannin corilagin on dextran sulfate sodium-induced murine ulcerative colitis.

    PubMed

    Xiao, Hai-Tao; Lin, Cheng-Yuan; Ho, Derek H H; Peng, Jiao; Chen, Yan; Tsang, Siu-Wai; Wong, Michael; Zhang, Xiao-Jun; Zhang, Man; Bian, Zhao-Xiang

    2013-11-22

    The therapeutic effect of corilagin (1) was evaluated in an acute colitis model induced by dextran sulfate sodium (DSS) in mice, and the mechanism of action was investigated in this study. Animals were challenged with 2% DSS drinking water for 5 consecutive days and then intraperitoneally treated with 1 (7.5, 15, and 30 mg/kg) daily for 7 days. It was found that 1 significantly decreased the disease activity index, inhibited the shortening of colon length, reduced colon tissue damage, and suppressed myeloperoxidase activity. Moreover, 1 greatly suppressed the secretion of TNF-α, IL-6, and IL-1β, inhibited the degradation of IκB α, and down-regulated expression of cleaved caspase-3 and cleaved caspase-9 in colon tissues of DSS-treated mice. These findings demonstrated that 1 exerts a protective effect on DSS-induced colitis, and its underlying mechanisms are associated with inhibition of the NF-κB pathway that mitigates colon inflammatory responses and apoptosis of intestinal epithelial cells. PMID:24200352

  19. Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice

    SciTech Connect

    Kanbe, Takamasa |; Murai, Rie; Mukoyama, Tomoyuki; Murawaki, Yoshiyuki |; Hashiguchi, Ko-ichi; Yoshida, Yoko; Tsuchiya, Hiroyuki; Kurimasa, Akihiro; Harada, Ken-ichi; Yashima, Kazuo; Nishimuki, Eiji; Shabana, Noriko; Kishimoto, Yukihiro; Kojyo, Haruhiko; Miura, Kunihiko; Kawasaki, Hironaka; Murawaki, Yoshikazu; Shiota, Goshi . E-mail: gshiota@grape.med.tottori-u.ac.jp

    2006-07-14

    Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SR{alpha} promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes.

  20. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

    PubMed Central

    2011-01-01

    Background This study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines. Methods Mice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \\ groups (control, colitis, HFD and colitis + HFD). Results Obesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group. Conclusion Our results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream. PMID:22073943

  1. Involvement of 5HT3 Receptors in Anti-Inflammatory Effects of Tropisetron on Experimental TNBS-Induced Colitis in Rat

    PubMed Central

    Motavallian, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Andalib, Sasan; Mahzouni, Parvin

    2013-01-01

    Introduction: There is a pressing need for research leading to the development of new effective drugs with lower side effects and more efficacy for treating inflammatory bowel disease (IBD). The analgesic and anti-inflammatory properties of 5-Hydroxytryptamine (5-HT)-3 receptor antagonists have been shown in in vivo and in vitro studies. The present study was designed to investigate the effects of tropisetron, a 5-HT3 receptor antagonist, on an immune-based animal model of IBD. Methods: In the present study, the trinitrobenzenesulfonic acid (TNBS) model of colitis in the rat was used. Two hours after induction of colitis in rats, tropisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT3 receptor agonist, or tropisetron + mCPBG were intraperitoneally (i.p.) administrated for 6 days. Animals were then sacrificed; macroscopic, histological, biochemical (myeloperoxidase [MPO]) assessments and ELISA test (tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta) were performed on distal colon samples. Results: Tropisetron or dexamethasone treatment significantly reduced macroscopic and microscopic colonic damages. In addition, a significant reduction in MPO activity and colonic levels of inflammatory cytokines was seen. The beneficial effects of tropisetron were antagonized by concurrent administration of mCPBG. Conclusion: The present study indicates that the protective effects of tropisetron on TNBS-induced colitis can be mediated by 5-HT3 receptors. PMID:24455480

  2. Monocolonization of germ-free mice with Bacteroides fragilis protects against dextran sulfate sodium-induced acute colitis.

    PubMed

    Chiu, Chien-Chao; Ching, Yung-Hao; Wang, Yu-Chih; Liu, Ju-Yun; Li, Yen-Peng; Huang, Yen-Te; Chuang, Hsiao-Li

    2014-01-01

    Ulcerative colitis is inflammatory conditions of the colon caused by interplay of genetic and environmental factors. Previous studies indicated that the gut microflora may be involved in the colonic inflammation. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to the colonic symbiotic. We aimed to investigate the protective role of BF in a colitis model induced in germ-free (GF) mice by dextran sulfate sodium (DSS). GF C57BL/6JNarl mice were colonized with BF for 28 days before acute colitis was induced by DSS. BF colonization significantly increased animal survival by 40%, with less reduction in colon length, and decreased infiltration of inflammatory cells (macrophages and neutrophils) in colon mucosa following challenge with DSS. In addition, BF could enhance the mRNA expression of anti-inflammatory-related cytokine such as interleukin 10 (IL-10) with polymorphism cytokine IL-17 and diminish that of proinflammatory-related tumor necrosis factor α with inducible nitric oxide synthase in the ulcerated colon. Myeloperoxidase activity was also decreased in BF-DSS mice. Taking these together, the BF colonization significantly ameliorated DSS-induced colitis by suppressing the activity of inflammatory-related molecules and inducing the production of anti-inflammatory cytokines. BF may play an important role in maintaining intestinal immune system homeostasis and regulate inflammatory responses. PMID:24971344

  3. Monocolonization of Germ-Free Mice with Bacteroides fragilis Protects against Dextran Sulfate Sodium-Induced Acute Colitis

    PubMed Central

    Liu, Ju-Yun; Li, Yen-Peng; Huang, Yen-Te; Chuang, Hsiao-Li

    2014-01-01

    Ulcerative colitis is inflammatory conditions of the colon caused by interplay of genetic and environmental factors. Previous studies indicated that the gut microflora may be involved in the colonic inflammation. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to the colonic symbiotic. We aimed to investigate the protective role of BF in a colitis model induced in germ-free (GF) mice by dextran sulfate sodium (DSS). GF C57BL/6JNarl mice were colonized with BF for 28 days before acute colitis was induced by DSS. BF colonization significantly increased animal survival by 40%, with less reduction in colon length, and decreased infiltration of inflammatory cells (macrophages and neutrophils) in colon mucosa following challenge with DSS. In addition, BF could enhance the mRNA expression of anti-inflammatory-related cytokine such as interleukin 10 (IL-10) with polymorphism cytokine IL-17 and diminish that of proinflammatory-related tumor necrosis factor α with inducible nitric oxide synthase in the ulcerated colon. Myeloperoxidase activity was also decreased in BF-DSS mice. Taking these together, the BF colonization significantly ameliorated DSS-induced colitis by suppressing the activity of inflammatory-related molecules and inducing the production of anti-inflammatory cytokines. BF may play an important role in maintaining intestinal immune system homeostasis and regulate inflammatory responses. PMID:24971344

  4. Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses

    PubMed Central

    Chen, Qian-Qian; Yan, Li; Wang, Chang-Zheng; Wang, Wei-Hua; Shi, Hui; Su, Bin-Bin; Zeng, Qing-Huan; Du, Hai-Tao; Wan, Jun

    2013-01-01

    AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4+CD25+Foxp3

  5. Alpinetin attenuates inflammatory responses by suppressing TLR4 and NLRP3 signaling pathways in DSS-induced acute colitis.

    PubMed

    He, Xuexiu; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Fu, Yunhe; Yang, Zhengtao

    2016-01-01

    Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment. PMID:27321991

  6. Alpinetin attenuates inflammatory responses by suppressing TLR4 and NLRP3 signaling pathways in DSS-induced acute colitis

    PubMed Central

    He, Xuexiu; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Fu, Yunhe; Yang, Zhengtao

    2016-01-01

    Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment. PMID:27321991

  7. Anti-inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection on TNBS-Induced Colitis in a Murine Model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To model the protective mechanism of helminth infection on colitis-induced changes in immune and epithelial cell function, BALB/c mice received intra-rectal saline or TNBS (2 mg/mouse; 40% ETOH) and were studied 4 days (d) later. Separate groups of mice received oral Heligmosomoides polygyrus follow...

  8. Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote Th2 while suppressing Th1 and Th17 cytokine responses. We investigated the contribution of endogenous IL-25 to DSS-induced colitis in mice. Mice were exposed to DSS in drinking water ad li...

  9. Immunological mechanisms involved in probiotic-mediated protection against Citrobacter rodentium-induced colitis.

    PubMed

    Jiang, Y; Yang, G; Meng, F; Yang, W; Hu, J; Ye, L; Shi, C; Wang, C

    2016-06-01

    Inflammatory bowel disease is a group of chronic, incurable inflammatory disorders of the gastrointestinal tract that cause severe diarrhoea, intestinal inflammation, pain, fatigue and weight loss. In this study, we first developed a model of Citrobacter rodentium-induced colitis and then evaluated the protective effects of selected probiotics on inflammation. The results showed that administration of a combination of probiotics including Lactobacillus rhamnosus ATCC 53103, Lactobacillus acidophilus ATCC 4356 and Lactobacillus plantarum A significantly increased the production of CD11c(+) dendritic cells in the spleen (3.62% vs phosphate buffered saline (PBS)-treated control, P<0.01) and mesenteric lymph nodes (MLNs). In addition, the presence of probiotics significantly up-regulated the development of CD4(+)/CD25(+)/Foxp3(+) regulatory T cells in MLNs by approximately 2.07% compared to the effect observed in the PBS-treated control (P<0.01) and down-regulated the expression of inflammatory cytokines, including interleukin-17, tumour necrosis factor-α and interferon-γ, by 0.11, 0.11 and 0.15%, respectively, compared to the effect observed in the PBS-treated control (P<0.01).These effects conferred protection against colitis, as shown by histopathological analyses. PMID:26925601

  10. Treatment of dextran sodium sulfate-induced experimental colitis by adoptive transfer of peritoneal cells

    PubMed Central

    Liu, Ting; Ren, Jun; Wang, Wei; Wei, Xia-wei; Shen, Guo-bo; Liu, Yan-tong; Luo, Min; Xu, Guang-chao; Shao, Bin; Deng, Sen-yi; He, Zhi-yao; Liang, Xiao; Liu, Yu; Wen, Yan-Zhu; Xiang, Rong; Yang, Li; Deng, Hong-xin; Wei, Yu-quan

    2015-01-01

    The adoptive transfer of the natural regulatory B cells and macrophages should be a useful treatment for inflammation and autoimmune disease. However, it is usually difficult to isolate these cells from the tissues and expand them. Here, we investigated the feasibility of adoptively transferring peritoneal cells (PCs) as a treatment for DSS-induced colitis. We found that peritoneal cavity can provide an easily accessible site for harvesting enough number of PCs, namely, two-dose PCs for the treatment from a mouse in one operation. Adoptive therapy of these cells from healthy mice or those with disease is effectively in reducing the disease activity score. The natural B cells and macrophages of the infused PCs can selectively migrate to lesion sites and regulate the expression of Stat3, NF−κB, Smad3 and Smad7. Additionally, PCs exert dual activity of IL-10 and TGF-β secreted spontaneously by both peritoneal B cells and macrophages, which in turn enhance the induction of regulatory B cells and Macrophages in microenvironment of inflammation. Moreover, PCs can re-establish immunological tolerance in the OVA-immunized mice. Thus, our findings provide a new strategy for colitis therapy and could be of importance in additional exploration of other inflammation and autoimmune diseases therapy. PMID:26565726

  11. IL-10/microRNA-155/SHIP-1 signaling pathway is crucial for commensal bacteria induced spontaneous colitis.

    PubMed

    Li, Yi; Tian, Yun; Zhu, Weiming; Gong, Jianfeng; Guo, Zhen; Guo, Feilong; Gu, Lili; Li, Jieshou

    2016-09-15

    Interleukin 10 (IL-10) microRNA-155 (miR-155)/Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) signaling pathway plays an important role in maintaining immune homeostasis. We aimed to determine and characterize the changes induced by commensal bacteria on the IL-10/miR-155/SHIP-1 signaling pathway, as well as the potential therapeutic effects of anti-miR-155 on colitis in IL-10 deficient (IL-10(-)/(-)) mice. Age- and sex-matched C57BL/6 IL-10(-)/(-) and wild type mice were transferred from a germ-free environment to a specific pathogen free condition. Part of IL-10(-)/(-) mice were then treated with anti-miR-155. IL-10/miR-155/SHIP-1 signaling pathway was evaluated and the therapeutic effects of anti-miR-155 treatment on colitis in IL-10(-)/(-) mice was assessed. The expression and the relationship of IL-10, miR-155, and SHIP-1 were also measured in patients with active Crohn's colitis. IL-10/miR-155/SHIP-1 signaling pathway was activated in IL-10(-)/(-) mice transferring from a germ-free environment to a specific pathogen free condition. Anti-miR-155 treatment significantly ameliorated the severity of colitis in IL-10(-)/(-) mice. Additionally, administration of anti-miR-155 was associated with a restoration of SHIP-1 signaling pathway. The relationship of IL-10, miR-155, and SHIP-1 was confirmed in human study using samples from patients with active Crohn's colitis. IL-10/miR-155/SHIP-1 pathways play a critical role in commensal bacteria induced colitis and miR-155 may be a potential therapeutic target for human inflammatory bowel disease. PMID:27395764

  12. Different Effects of Three Selected Lactobacillus Strains in Dextran Sulfate Sodium-Induced Colitis in BALB/c Mice

    PubMed Central

    Cui, Yi; Wei, Hongyun; Lu, Fanggen; Liu, Xiaowei; Liu, Deliang; Gu, Li; Ouyang, Chunhui

    2016-01-01

    Aim To analyze the changes of different Lactobacillus species in ulcerative colitis patients and to further assess the therapeutic effects of selected Lactobacillus strains on dextran sulfate sodium (DSS)-induced experimental colitis in BALB/c mice. Methods Forty-five active ulcerative colitis (UC) patients and 45 population-based healthy controls were enrolled. Polymerase chain reaction (PCR) amplification and real-time PCR were performed for qualitative and quantitative analyses, respectively, of the Lactobacillus species in UC patients. Three Lactobacillus strains from three species were selected to assess the therapeutic effects on experimental colitis. Sixty 8-week-old BALB/c mice were divided into six groups. The five groups that had received DSS were administered normal saline, mesalazine, L. fermentum CCTCC M206110 strain, L. crispatus CCTCC M206119 strain, or L. plantarum NCIMB8826 strain. We assessed the severity of colitis based on disease activity index (DAI), body weight loss, colon length, and histologic damage. Results The detection rate of four of the 11 Lactobacillus species decreased significantly (P < 0.05), and the detection rate of two of the 11 Lactobacillus species increased significantly (P < 0.05) in UC patients. Relative quantitative analysis revealed that eight Lactobacillus species declined significantly in UC patients (P < 0.05), while three Lactobacillus species increased significantly (P < 0.05). The CCTCC M206110 treatment group had less weight loss and colon length shortening, lower DAI scores, and lower histologic scores (P < 0.05), while the CCTCC M206119 treatment group had greater weight loss and colon length shortening, higher histologic scores, and more severe inflammatory infiltration (P < 0.05). NCIMB8826 improved weight loss and colon length shortening (P < 0.05) with no significant influence on DAI and histologic damage in the colitis model. Conclusions Administration of an L. crispatus CCTCC M206119 supplement aggravated

  13. A Picrorhiza kurroa Derivative, Picroliv, Attenuates the Development of Dextran-Sulfate-Sodium-Induced Colitis in Mice

    PubMed Central

    Zhang, De-Kui; Yu, Jian-Jie; Li, Yu-Min; Wei, Li-Na; Yu, Yi; Feng, Yan-Hu; Wang, Xiang

    2012-01-01

    Background. Free radicals and proinflammatory cytokines have been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Picroliv, a Picrorhiza kurroa derivative, has been demonstrated to have antioxidant and anti-inflammatory effect. The purpose of the study was to investigate the effects of picroliv on experimental model of UC in mice. Materials and Methods. Picroliv was administrated orally by gavage to mice with colitis induced by dextran sulfate sodium (DSS). Disease activity index (DAI), colon length, and histology score were observed. Myeloperoxidase (MPO) activity, and SOD, MDA concentrations were measured by enzyme-linked immunosorbent assay (ELISA) while the expression of cytokine mRNAs was studied by real-time-quantitative polymerase chain reaction and also ELISA. The expression of NF-κB p65 was observed by immunohistochemistry staining and western blotting. Results. A significant improvement was observed in DAI and histological score in mice treated with picroliv, and incerased MPO activity, MDA concentrations, and the expression of IL-1β, TNF-α, and NF-κB p65 in mice with DSS-induced colitis were significantly reduced while decreased SOD level increased following administration of picroliv. Conclusion. The administration of picroliv leads to an amelioration of DSS-induced colitis, suggesting administration of picroliv may provide a therapeutic approach for UC. PMID:23125487

  14. Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages.

    PubMed

    Meshkibaf, Shahab; Martins, Andrew J; Henry, Garth T; Kim, Sung Ouk

    2016-02-01

    Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine best known for its role in promoting the generation and function of neutrophils. G-CSF is also found to be involved in macrophage generation and immune regulation; however, its in vivo role in immune homeostasis is largely unknown. Here, we examined the role of G-CSF in dextran sulfate sodium (DSS)-induced acute colitis using G-CSF receptor-deficient (G-CSFR(-/-)) mice. Mice were administered with 1.5% DSS in drinking water for 5days, and the severity of colitis was measured for the next 5days. GCSFR(-/-) mice were more susceptible to DSS-induced colitis than G-CSFR(+/+) or G-CSFR(-/+) mice. G-CSFR(-/-) mice harbored less F4/80(+) macrophages, but a similar number of neutrophils, in the intestine. In vitro, bone marrow-derived macrophages prepared in the presence of both G-CSF and macrophage colony-stimulating factor (M-CSF) (G-BMDM) expressed higher levels of regulatory macrophage markers such as programmed death ligand 2 (PDL2), CD71 and CD206, but not in arginase I, transforming growth factor (TGF)-β, Ym1 (chitinase-like 3) and FIZZ1 (found in inflammatory zone 1), and lower levels of inducible nitric oxide synthase (iNOS), CD80 and CD86 than bone marrow-derived macrophages prepared in the presence of M-CSF alone (BMDM), in response to interleukin (IL)-4/IL-13 and lipopolysaccharide (LPS)/interferon (IFN)-γ, respectively. Adoptive transfer of G-BMDM, but not BMDM, protected G-CSFR(-/-) mice from DSS-induced colitis, and suppressed expression of tumor necrosis factor (TNF)-α, IL-1β and iNOS in the intestine. These results suggest that G-CSF plays an important role in preventing colitis, likely through populating immune regulatory macrophages in the intestine. PMID:26687628

  15. Evaluation of a new type of nano-sized carbon monoxide donor on treating mice with experimentally induced colitis.

    PubMed

    Nagao, Saori; Taguchi, Kazuaki; Miyazaki, Yuri; Wakayama, Tomohiko; Chuang, Victor Tuan Giam; Yamasaki, Keishi; Watanabe, Hiroshi; Sakai, Hiromi; Otagiri, Masaki; Maruyama, Toru

    2016-07-28

    Low concentrations of exogenous carbon monoxide (CO) have been reported to be useful for the treatment of various disorders related to inflammation and oxidative stress. However, a number of obstacles make it difficult to use CO in vivo. Among these are, at high concentrations, it is toxic and the fact that it is difficult to control its delivery in the body. Hemoglobin-encapsulated liposomes, Hemoglobin-vesicles (HbV), have the potential for use as a new type of nano-sized CO donor, referred to as CO-bound HbV (CO-HbV). In this study, we investigated the potential of CO-HbV as a CO donor in terms of toxicity and therapeutic efficacy using an experimental colitis model. Toxicological assessments of CO-HbV showed no severe adverse effects including death, and clinical laboratory tests and histopathological changes remained normal for 28days after the administration of doses up to 1400mgHb/kg. We then evaluated the therapeutic efficacies of CO-HbV on dextran sulfate sodium (DSS)-induced colitis model mice. A single administration of CO-HbV at 3days from beginning of the DSS treatment dramatically improved colitis symptoms, colonic histopathological changes and the duration of survival compared to both saline and HbV administration. In addition, the therapeutic effects of CO-HbV on colitis can be attributed to a decreased level of neutrophil infiltration, the production of pro-inflammatory cytokines and oxidative injuries. Interestingly, it appears that an increase in anti-inflammatory cytokine production contributes, in part, to therapeutic effects of CO-HbV in the treatment of colitis. These safety and efficacy profiles of CO-HbV suggest that it has the potential for use as a drug for treating, not only colitis but also a variety of other disorders associated with inflammation and oxidative stress. PMID:27173944

  16. Andrographolide derivative AL-1 ameliorates TNBS-induced colitis in mice: involvement of NF-кB and PPAR-γ signaling pathways

    PubMed Central

    Yang, Yali; Yan, Hui; Jing, Mei; Zhang, Zaijun; Zhang, Gaoxiao; Sun, Yewei; Shan, Luchen; Yu, Pei; Wang, Yuqiang; Xu, Lipeng

    2016-01-01

    Andrographolide is a traditional herb medicine, widely used in Asia for conditions involving inflammation. The andrographlide-lipoic acid conjugate, AL-1, has been found being able to alleviate inflammation in our previous reports. Although the anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve inflammatory bowel disease (IBD) and the underlying mechanisms of its action remain largely unknown. In this study, we investigated the anti-inflammatory effects of AL-1 in C57BL/6 mice with trinitrobenzenesulfonic acid (TNBS)-induced colitis. The body weight loss and length change of colon after TNBS instillation were more severe than those in normal mice. AL-1 treatment led to significant reductions in disease activity index (DAI), macroscopic score and colon mucosa damage index (CMDI) associated with TNBS administration. AL-1 inhibited the inflammatory response via lowering the level of inflammatory cytokines and myeloperoxidase (MPO) activity. AL-1 attenuated the expression of p-p65, p-IκBα and COX-2 in the colitis mice. The alleviation of colon injury by AL-1 treatment was also evidenced by the increased expression of PPAR-γ. These results indicated that AL-1 could protect intestinal tract from the injury induced by TNBS in mice, suggesting that AL-1 may have potential in treatment for IBD. PMID:27435110

  17. Andrographolide derivative AL-1 ameliorates TNBS-induced colitis in mice: involvement of NF-кB and PPAR-γ signaling pathways.

    PubMed

    Yang, Yali; Yan, Hui; Jing, Mei; Zhang, Zaijun; Zhang, Gaoxiao; Sun, Yewei; Shan, Luchen; Yu, Pei; Wang, Yuqiang; Xu, Lipeng

    2016-01-01

    Andrographolide is a traditional herb medicine, widely used in Asia for conditions involving inflammation. The andrographlide-lipoic acid conjugate, AL-1, has been found being able to alleviate inflammation in our previous reports. Although the anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve inflammatory bowel disease (IBD) and the underlying mechanisms of its action remain largely unknown. In this study, we investigated the anti-inflammatory effects of AL-1 in C57BL/6 mice with trinitrobenzenesulfonic acid (TNBS)-induced colitis. The body weight loss and length change of colon after TNBS instillation were more severe than those in normal mice. AL-1 treatment led to significant reductions in disease activity index (DAI), macroscopic score and colon mucosa damage index (CMDI) associated with TNBS administration. AL-1 inhibited the inflammatory response via lowering the level of inflammatory cytokines and myeloperoxidase (MPO) activity. AL-1 attenuated the expression of p-p65, p-IκBα and COX-2 in the colitis mice. The alleviation of colon injury by AL-1 treatment was also evidenced by the increased expression of PPAR-γ. These results indicated that AL-1 could protect intestinal tract from the injury induced by TNBS in mice, suggesting that AL-1 may have potential in treatment for IBD. PMID:27435110

  18. Therapeutic effect of a hydroxynaphthoquinone fraction on dextran sulfate sodium-induced ulcerative colitis

    PubMed Central

    Zhang, Zi-Liang; Fan, Hua-Ying; Yang, Ming-Yan; Zhang, Zuo-Kai; Liu, Ke

    2014-01-01

    AIM: To evaluate the therapeutic effect of hydroxynaphthoquinone mixture (HM) on dextran sulfate sodium (DSS)-induced colitis and explore the underlying mechanisms. METHODS: BALB/c mice received 3.5% DSS for 6 d to induce ulcerative colitis. Groups of mice were orally administered HM 3.5, 7 and 14 mg/kg and mesalazine 200 mg/kg per day for 7 d. During the experiment, clinical signs and body weight, stool consistency and visible fecal blood were monitored and recorded daily. A disease activity index score was calculated for each animal. At the conclusion of the experiment, the colonic histopathological lesions were evaluated. Myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) levels were determined. Protein expression levels of TNF-α, nuclear factor-κB (NF-κB) p65, inhibitor of κB (IκB) and phosphorylation of IκB (p-IκB) were analyzed by Western blot analysis. RESULTS: Administration of 3.5% DSS for 6 d successfully induced acute colitis associated with soft stool, diarrhea, rectal bleeding, and colon shortening, as well as a loss of body weight. Administration of HM effectively attenuated the severity of colonic mucosa injury. For histopathological analysis, HM treatment improved histological alterations and lowered pathological scores compared with the DSS only group. This manifested as a reduction in the extent of colon injury and inflammatory cell infiltration, as well as the degree of mucosal destruction. In addition, HM at doses of 7 and 14 mg/kg significantly decreased MPO activity in colonic tissue (0.98 ± 0.22 U/g vs 1.32 ± 0.24 U/g, 0.89 ± 0.37 U/g vs 1.32 ± 0.24 U/g tissue, P < 0.05) and serum TNF-α levels (68.78 ± 7.34 ng/L vs 88.98 ± 17.79 ng/L, 64.13 ± 14.13 ng/L vs 88.98 ± 17.79 ng/L, P < 0.05). Furthermore, HM down-regulated the expression of TNF-α, NF-κB p65 and p-IκBα in colonic tissue while up-regulating IκBα protein expression. These results suggest that the significant anti-inflammatory effect of HM may be

  19. Neutralization of IL-6 and TNF-α ameliorates intestinal permeability in DSS-induced colitis.

    PubMed

    Xiao, Yong-Tao; Yan, Wei-Hui; Cao, Yi; Yan, Jun-Kai; Cai, Wei

    2016-07-01

    The cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been implicated as important mediators of the inflammatory reaction in patients with intestinal inflammation. The present study was designed to investigate the roles of these cytokines on mucosal barrier function in a mouse model of acute colitis with using anti-cytokine strategies. Mice received 3% dextran sulfate sodium (DSS) in their drinking water for 7days showed morphological alteration of mucosa and increase of intestinal permeability. Administration of IL-6 monoclonal antibody (mAb) or TNF-α mAb significantly attenuated intestinal permeability. IL-6 mAb and TNF-α mAb treatment also effectively suppressed the expression of claudin-2 and myosin light chain kinase (MLCK). Taken together, we indicated that anti-IL-6 and anti-TNF-α therapy prevent intestinal permeability induced by intestinal inflammation. PMID:27155817

  20. Probiotic bacteria lactobacillus and bifidobacterium attenuate inflammation in dextran sulfate sodium-induced experimental colitis in mice.

    PubMed

    Toumi, R; Soufli, I; Rafa, H; Belkhelfa, M; Biad, A; Touil-Boukoffa, C

    2014-01-01

    It is widely accepted that inflammatory Bowel disease (IBD) arises from a dysregulated mucosal immune response to the enteric microbiota in the gut of a genetically susceptible individual. No definitive therapies are available for this inflammatory disorder. Therefore it became imperative to develop new strategies for treating this disease. Probiotics have emerged as a potential new therapeutic strategy for IBD, however their exact mechanisms of action is still poorly defined. In this study, we address the potential effect of a probiotic cocktail (Ultrabiotique®) composed of four live bacterial strains (L. acidophilus, L. plantarum, B. lactis and B.breve) to promote recovery from acute colitis. Probiotic was given to mice by oral gavage after the onset of colitis and the establishment of dextran sulfate sodium (DSS)-induced intestinal injury. Clinical parameters were monitored daily, histological scores of colitis and the production of nitric oxide (NO) and interferon-γ (IFN-γ) were determined. In addition, TLR4, NF-κB and iNOS colonic expression were examined. Probiotic treatment ameliorated clinical symptoms and histological scores. NO and IFN-γ production in plasma were decreased by probiotic. These results were associated with reduced TLR4, iNOS and NF-кB expression in colonic tissue. In conclusion, probiotic exerted anti-inflammatory effects and contributed to a rapid recovery of DSS-induced acute colitis. PMID:25572742

  1. Lactobacillus fermentum BR11, a potential new probiotic, alleviates symptoms of colitis induced by dextran sulfate sodium (DSS) in rats.

    PubMed

    Geier, Mark S; Butler, Ross N; Giffard, Philip M; Howarth, Gordon S

    2007-03-20

    Current treatments for inflammatory bowel disease (IBD) are relatively ineffective. Recently, probiotics have emerged as a potential treatment modality for numerous gastrointestinal disorders, including IBD. Few probiotics, however, have undergone appropriate preclinical screening in vivo. The current study compared the effects of four candidate probiotics on development of dextran sulfate sodium (DSS)-induced colitis in rats. Sprague Dawley rats were gavaged 1 mL of the potential probiotic (1 x 10(10) CFU/mL), or vehicle, twice daily for 14 days. Strains tested were Lactobacillus rhamnosus GG (LGG), Streptococcus thermophilus TH-4 (TH-4), Bifidobacterium lactis Bb12 (Bb12) and Lactobacillus fermentum BR11 (BR11). Colitis was induced from day 7 to 14 via administration of 2% DSS in drinking water. Disease activity index (DAI) was monitored daily until rats were killed at day 14. DAI decreased in DSS+Bb12 and DSS+BR11 compared to DSS+Vehicle. Colon length increased in DSS+BR11 (10%) and DSS+LGG (10%) compared to DSS+Vehicle. DSS+Bb12 and DSS+BR11 prevented the distal colon crypt hyperplasia evident in DSS+Vehicle, DSS+LGG and DSS+TH-4. BR11 was most effective at reducing colitic symptoms. Bb12 had minimal effects, whilst TH-4 did not prevent DSS-colitis and LGG actually exacerbated some indicators of colitis. Further studies into the potential benefits of L. fermentum BR11 are indicated. PMID:17150273

  2. Modified Pulsatilla decoction attenuates oxazolone-induced colitis in mice through suppression of inflammation and epithelial barrier disruption

    PubMed Central

    Wang, Xuewei; Fan, Fugang; Cao, Qin

    2016-01-01

    Inflammatory bowel diseases (IBDs) are chronic inflammatory gastrointestinal disorders caused by a dysregulated mucosal immune response and epithelial barrier disruption. Conventional treatment of IBD is currently limited to overcoming patient symptoms and is often associated with severe adverse effects from the drugs used. Modified Pulsatilla decoction has been used previously to treat ulcerative colitis (UC) in clinical practice in China, however, the underlying mechanism in the treatment of UC remains to be elucidated. In the present study, the efficiency and mechanisms of modified Pulsatilla decoction in the treatment of oxazolone-induced colitis were investigated. Assessment of clinical colitis and histological examination found that the administration of modified Pulsatilla decoction attenuated the severity of oxazolone-induced colitis in mice. Measurement of cytokine concentration, western blotting and reverse transcription-quantitative polymerase chain reaction demonstrated modified Pulsatilla decoction treatment significantly reduced the secretion of pro-inflammatory cytokines and restored alterations in tight junction proteins in the colon tissues. In addition, modified Pulsatilla decoction suppressed the activation of the nuclear factor-κB signaling pathway. Thus, the findings of the present study demonstrated that modified Pulsatilla decoction offers an effective therapeutic approach for the treatment of IBD and revealed the underlying mechanisms of action offered by modified Pulsatilla decoction. PMID:27278299

  3. Maternal Exposure to Low Levels of Corticosterone during Lactation Protects against Experimental Inflammatory Colitis-Induced Damage in Adult Rat Offspring

    PubMed Central

    Petrella, Carla; Giuli, Chiara; Agostini, Simona; Bacquie, Valérie; Zinni, Manuela; Theodorou, Vassilia; Broccardo, Maria; Casolini, Paola; Improta, Giovanna

    2014-01-01

    Opposing emotional events (negative/trauma or positive/maternal care) during the postnatal period may differentially influence vulnerability to the effects of stress later in life. The development and course of intestinal disorders such as inflammatory bowel disease are negatively affected by persistent stress, but to date the role of positive life events on these pathologies has been entirely unknown. In the present study, the effect of early life beneficial experiences in the development of intestinal dysfunctions, where inflammation and stress stimuli play a primary role, was investigated. As a “positive” experimental model we used adult male rat progeny nursed by mothers whose drinking water was supplemented with moderate doses of corticosterone (CORT) (0.2 mg/ml) during the lactation period. Such animals have been generally shown to cope better with different environmental situations during life. The susceptibility to inflammatory experimental colitis induced by intracolonic infusion of TNBS (2,4,6-trinitrobenzenesulphonic acid) was investigated in CORT-nursed rats in comparison with control rats. This mild increase in maternal corticosterone during lactation induced, in CORT-nursed rats, a long lasting protective effect on TNBS-colitis, characterized by improvements in some indices of the disease (increased colonic myeloperoxidase activity, loss of body weight and food intake) and by the involvement of endogenous peripheral pathways known to participate in intestinal disorder development (lower plasma corticosterone levels and colonic mast cell degranulation, alterations in the colonic expression of both corticotrophin releasing factor/CRF and its receptor/CRH-1R). All these findings contribute to suggesting that the reduced vulnerability to TNBS-colitis in CORT-nursed rats is due to recovery from the colonic mucosal barrier dysfunction. Such long lasting changes induced by mild hormonal manipulation during lactation, making the adult also better adapted

  4. Effects of AP‑1 and NF‑κB inhibitors on colonic endocrine cells in rats with TNBS‑induced colitis.

    PubMed

    El-Salhy, Magdy; Umezawa, Kazuo

    2016-08-01

    Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)‑1 and nuclear factor (NF)‑κB inhibitors on inflammation‑induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)‑induced colitis only (TNBS group), TNBS‑induced colitis with 3‑[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM‑G) treatment (DTCM‑G group), and TNBS‑induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM‑G group received DTCM‑G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image‑analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM‑G or DHMEQ groups. All of the colonic

  5. Effects of AP-1 and NF-κB inhibitors on colonic endocrine cells in rats with TNBS-induced colitis

    PubMed Central

    El-Salhy, Magdy; Umezawa, Kazuo

    2016-01-01

    Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)-1 and nuclear factor (NF)-κB inhibitors on inflammation-induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)-induced colitis only (TNBS group), TNBS-induced colitis with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) treatment (DTCM-G group), and TNBS-induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM-G group received DTCM-G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image-analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM-G or DHMEQ groups. All of the colonic endocrine cell types were affected in

  6. Long-Term Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Dextran Sulfate Sodium-Induced Murine Chronic Colitis

    PubMed Central

    Lee, Hyun Jung; Oh, Sun-Hee; Jang, Hui Won; Kwon, Ji-Hee; Lee, Kyoung Jin; Kim, Chung Hee; Park, Soo Jung; Hong, Sung Pil; Cheon, Jae Hee; Kim, Tae Il; Kim, Won Ho

    2016-01-01

    Background/Aims Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown beneficial effects in experimental colitis models, but the underlying mechanisms are not fully understood. We investigated the long-term effects of BM-MSCs, particularly in mice with chronic colitis. Methods Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in a series of three cycles. BM-MSCs were injected intravenously into DSS-treated mice three times during the first cycle. On day 33, the therapeutic effects were evaluated with clinicopathologic profiles and histological scoring. Inflammatory mediators were measured with real-time polymerase chain reaction. Results Systemic infusion of BM-MSCs ameliorated the severity of colitis, and body weight restoration was significantly promoted in the BM-MSC-treated mice. In addition, BM-MSC treatment showed a sustained beneficial effect throughout the three cycles. Microscopic examination revealed that the mice treated with BM-MSCs had fewer inflammatory infiltrates, a lesser extent of inflammation, and less crypt structure damage compared with mice with DSS-induced colitis. Anti-inflammatory cytokine levels of interleukin-10 were significantly increased in the inflamed colons of BM-MSC-treated mice compared with DSS-induced colitis mice. Conclusions Systemic infusion of BM-MSCs at the onset of disease exerted preventive and rapid recovery effects, with long-term immunosuppressive action in mice with repeated DSS-induced chronic colitis. PMID:27114436

  7. PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner

    PubMed Central

    Wei, Fanhua; Zhang, Yuying; Jian, Jinlong; Mundra, Jyoti Joshi; Tian, Qingyun; Lin, Jiqiang; Lafaille, Juan Jose; Tang, Wei; Zhao, Weiming; Yu, Xiuping; Liu, Chuan-Ju

    2014-01-01

    This study was aimed to determine the role and regulation of progranulin (PGRN) in the pathogenesis of inflammatory bowel diseases (IBD). Dextran sulfate sodium (DSS)−, picrylsulfonic acid (TNBS)-induced, bone marrow chimera and CD4+CD45Rbhi T cell transfer colitis model were established and analyzed in wild-type and several genetically-modified mice, including PGRN, IL-10 and TNFR2 deficient mice. Elevated levels of PGRN were found in colitis samples from human IBD patients and mouse colitis models in comparison to the corresponding controls. PGRN-deficient mice became highly susceptible to DSS- and TNBS-induced colitis, whereas recombinant PGRN ameliorated the pathology and reduced the histological score in both DSS and TNBS colitis models. In addition, hematopoietic-derived PGRN was critical for protection against DSS-induced colitis, and lack of PGRN signaling in CD4+ T cells also exacerbated experimental colitis. PGRN-mediated protective effect in colitis was compromised in the absence of IL-10 signaling. In addition, PGRN's effect was also largely lost in the TNFR2-deficient colitis model. Collectively, these findings not only provide the new insight into PGRN's anti-inflammatory action in vivo, but may also present PGRN and its derivatives as novel biological agent for treating IBD. PMID:25387791

  8. Porcine β-defensin 2 attenuates inflammation and mucosal lesions in dextran sodium sulfate-induced colitis.

    PubMed

    Han, Feifei; Zhang, Haiwen; Xia, Xi; Xiong, Haitao; Song, Deguang; Zong, Xin; Wang, Yizhen

    2015-02-15

    Intestinal permeability plays a critical role in the etiopathogenesis of ulcerative colitis. Defensins, including porcine β-defensin (pBD)2, are crucial antimicrobial peptides for gut protection owing to their antibacterial and immunomodulatory activities. The purpose of this study was to investigate the protective effects of pBD2 on mucosal injury and the disruption of the epithelial barrier during the pathological process of dextran sodium sulfate (DSS)-induced colitis. The effects and mechanism of pBD2 were evaluated both using a DSS-induced C57BL/6 mouse model and, in vitro, using Caco-2 and RAW264.7 cells. DSS-induced colitis was characterized by higher disease activity index, shortened colon length, elevated activities of myeloperoxidase and eosinophil peroxidase, histologic evidence of inflammation, and increased expression levels of TNF-α, IL-6, and IL-8. pBD2 increased the expression of zonula occludens-1, zonula occludens-2, claudin-1, mucin-1, and mucin-2 mRNA and proteins, and it decreased permeability to FITC-D, as well as apoptosis, in DSS-treated mice. pBD2 also decreased inflammatory infiltrates of the colon epithelium. In Caco-2 cells, pBD2 increased transepithelial electrical resistance and mucin mRNA expression, and it decreased the permeability of FITC-D while preserving the structural integrity of the tight junctions. The effects of pBD2 appeared to be through upregulation of the expression of genes associated with tight junctions and mucins, and by suppressing DSS-induced increases in inflammation, inducible NO synthase, cyclooxygenase-2, and apoptosis. These results show that pBD2 improves DSS-induced changes in mucosal lesions and paracellular permeability, possibly by affecting the activation of NF-κB signaling. The present study demonstrates that intrarectal administration of pBD2 may be a novel preventive option for ulcerative colitis. PMID:25601921

  9. Protective Effect of Calculus Bovis Sativus on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice

    PubMed Central

    Li, Xiping; Xu, Yanjiao; Zhang, Chengliang; Deng, Li; Chang, Mujun; Yu, Zaoqin; Liu, Dong

    2015-01-01

    Calculus Bovis Sativus (CBS) is a commonly used traditional Chinese medicine, which has been reported to exhibit antispasmodic, fever-reducing, anti-inflammatory, and gallbladder-repairing effects. The present study aims to investigate the protective effect of CBS on dextran sulphate sodium- (DSS-) induced ulcerative colitis (UC) in mice. C57BL/6 male mice were exposed to 5% DSS in drinking water. CBS was given orally at 50 and 150 mg/kg once per day for 7 days. Body weight, disease activity index (DAI), colon length, colonic myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and nitric oxide (NO) levels were measured. Administration of CBS significantly reserved these changes, decreased the MPO activity and MDA and NO level, and increased the SOD activity in the colon tissue. Histological observation suggested that CBS alleviated edema, mucosal damage, and inflammatory cells infiltration induced by DSS in the colon. Moreover, CBS significantly downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β and IL-6 in the colon tissue. Our data suggested that CBS exerted protective effect on DSS-induced UC partially through the antioxidant and anti-inflammatory activities. PMID:26579201

  10. Protective Effect of Calculus Bovis Sativus on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice.

    PubMed

    Li, Xiping; Xu, Yanjiao; Zhang, Chengliang; Deng, Li; Chang, Mujun; Yu, Zaoqin; Liu, Dong

    2015-01-01

    Calculus Bovis Sativus (CBS) is a commonly used traditional Chinese medicine, which has been reported to exhibit antispasmodic, fever-reducing, anti-inflammatory, and gallbladder-repairing effects. The present study aims to investigate the protective effect of CBS on dextran sulphate sodium- (DSS-) induced ulcerative colitis (UC) in mice. C57BL/6 male mice were exposed to 5% DSS in drinking water. CBS was given orally at 50 and 150 mg/kg once per day for 7 days. Body weight, disease activity index (DAI), colon length, colonic myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and nitric oxide (NO) levels were measured. Administration of CBS significantly reserved these changes, decreased the MPO activity and MDA and NO level, and increased the SOD activity in the colon tissue. Histological observation suggested that CBS alleviated edema, mucosal damage, and inflammatory cells infiltration induced by DSS in the colon. Moreover, CBS significantly downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β and IL-6 in the colon tissue. Our data suggested that CBS exerted protective effect on DSS-induced UC partially through the antioxidant and anti-inflammatory activities. PMID:26579201

  11. Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition.

    PubMed

    Guo, Wenjie; Hu, Shasha; Elgehama, Ahmed; Shao, Fenli; Ren, Ren; Liu, Wen; Zhang, Wenjing; Wang, Xinlei; Tan, Renxiang; Xu, Qiang; Sun, Yang; Jiao, Ruihua

    2015-10-01

    In the present study, the effect of Fumigaclavine C, a fungal metabolite, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of Fumigaclavine C dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco was also significantly reduced by Fumigaclavine C treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1β and IL-17A, were markedly suppressed by Fumigaclavine C. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in Fumigaclavine C -treated mice which suggested that the NLRP3 inflammasome activation was suppressed. Furthermore, in the LPS plus ATP cell model, we found that Fumigaclavine C dose-dependent inhibited IL-1β release and caspase-1 activation. Taken together, our results demonstrate the ability of Fumigaclavine C to inhibit NLRP3 inflammasome activation and give some evidence for its potential use in the treatment of inflammatory bowel diseases. PMID:26320672

  12. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice.

    PubMed

    Mouzaoui, Souad; Rahim, Ibtissem; Djerdjouri, Bahia

    2012-01-01

    The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response. PMID:22036766

  13. Lactobacillus casei secreting alpha-MSH induces the therapeutic effect on DSS-induced acute colitis in Balb/c Mice.

    PubMed

    Yoon, Sun-Woo; Lee, Chul-Ho; Kim, Jeong-Yoon; Kim, Jie-Youn; Sung, Moon-Hee; Poo, Haryoung

    2008-12-01

    The neuropeptide alpha-melanocyte-stimulating hormone (alpha- MSH) has anti-inflammatory property by downregulating the expressions of proinflammatory cytokines. Because alpha-MSH elicits the anti-inflammatory effect in various inflammatory disease models, we examined the therapeutic effect of oral administration of recombinant Lactobacillus casei, which secretes alpha-MSH (L. casei-alpha-MSH), on dextran sulfate sodium (DSS)-induced colitis in Balb/c mice. Thus, we constructed the alpha-MSH-secreting Lactobacillus casei by the basic plasmid, pLUAT-ss, which was composed of a PldhUTLS promoter and alpha-amylase signal sequence from Streptococcus bovis strain. Acute colitis was induced by oral administration of 5% DSS in drinking water for 7 days. To investigate the effect of L. casei-alpha-MSH on the colitis, L. casei or L. casei-alpha-MSH was orally administered for 7 days and their effects on body weight, mortality rate, cytokine production, and tissue myeloperoxidase (MPO) activity were observed. Administration of L. casei-alpha-MSH reduced the symptom of acute colitis as assessed by body weight loss (DSS alone: 14.45+/-0. 2 g; L. casei-alpha- MSH: 18.2+/-0.12 g), colitis score (DSS alone: 3.6+/-0.4; L. casei-alpha-MSH: 1.4+/-0.6), MPO activity (DSS alone: 42.7+/-4.5 U/g; L. casei-alpha-MSH: 10.25+/-0.5 U/g), survival rate, and histological damage compared with the DSS alone mice. L. casei-alpha-MSH-administered entire colon showed reduced in vitro production of proinflammatory cytokines and NF-kappaB activation. The alpha-MSH-secreting recombinant L. casei showed significant anti-inflammatory effects in the murine model of acute colitis and suggests a potential therapeutic role for this agent in clinical inflammatory bowel diseases. PMID:19131702

  14. Biofilm-associated bacterial amyloids dampen inflammation in the gut: oral treatment with curli fibres reduces the severity of hapten-induced colitis in mice

    PubMed Central

    Oppong, Gertrude O; Rapsinski, Glenn J; Tursi, Sarah A; Biesecker, Steven G; Klein-Szanto, Andres JP; Goulian, Mark; McCauley, Christine; Healy, Catherine; Wilson, R Paul; Tükel, Cagla

    2015-01-01

    BACKGROUND/OBJECTIVES A disruption of epithelial barrier function can lead to intestinal inflammation. Toll-like receptor (TLR) 2 activation by microbial products promotes intestinal epithelial integrity and overall gut health. Several bacterial species, including enteric bacteria, actively produce amyloid proteins as a part of their biofilms. Recognition of amyloid fibres found in enteric biofilms, termed curli, by the Toll-like receptor (TLR)2/1 complex reinforces barrier function. Here, we investigated the effect of purified curli fibres on inflammation in a mouse model of acute colitis. METHODS Bone marrow–derived macrophages as well as lamina propria cells were treated with curli fibres of both pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli Nissle 1917 biofilms. Mice were given 0.1 or 0.4 mg of purified curli orally 1 day post administration of 1% 2,4,6-trinitrobenzene sulphonic acid (TNBS) enema. Histopathological analysis was performed on distal colonic tissue taken 6 days post TNBS enema. RNA extracted from colonic tissue was subjected to RT-PCR. RESULTS Here we show that curli fibres of both pathogenic and commensal bacteria are recognised by TLR2 leading to the production of IL-10, immunomodulatory cytokine of intestinal homeostasis. Treatment of mice with a single dose of curli heightens transcript levels of Il10 in the colon and ameliorates the disease pathology in TNBS-induced colitis. Curli treatment is comparable to the treatment with anti-tumour necrosis factor alpha (anti-TNFα) antibodies, a treatment known to reduce the severity of acute colitis in humans and mice. CONCLUSION These results suggest that the bacterial amyloids had a role in helping to maintain immune homeostasis in the intestinal mucosa via the TLR2/IL-10 axis. Furthermore, bacterial amyloids may be a potential candidate therapeutic to treat intestinal inflammatory disorders owing to their remarkable immunomodulatory activity. PMID:26855788

  15. Social stress-enhanced severity of Citrobacter rodentium-induced colitis is CCL2-dependent and attenuated by probiotic Lactobacillus reuteri.

    PubMed

    Mackos, A R; Galley, J D; Eubank, T D; Easterling, R S; Parry, N M; Fox, J G; Lyte, M; Bailey, M T

    2016-03-01

    Psychological stressors are known to affect colonic diseases but the mechanisms by which this occurs, and whether probiotics can prevent stressor effects, are not understood. Because inflammatory monocytes that traffic into the colon can exacerbate colitis, we tested whether CCL2, a chemokine involved in monocyte recruitment, was necessary for stressor-induced exacerbation of infectious colitis. Mice were exposed to a social disruption stressor that entails repeated social defeat. During stressor exposure, mice were orally challenged with Citrobacter rodentium to induce a colonic inflammatory response. Exposure to the stressor during challenge resulted in significantly higher colonic pathogen levels, translocation to the spleen, increases in colonic macrophages, and increases in inflammatory cytokines and chemokines. The stressor-enhanced severity of C. rodentium-induced colitis was not evident in CCL2(-/-) mice, indicating the effects of the stressor are CCL2-dependent. In addition, we tested whether probiotic intervention could attenuate stressor-enhanced infectious colitis by reducing monocyte/macrophage accumulation. Treating mice with probiotic Lactobacillus reuteri reduced CCL2 mRNA levels in the colon and attenuated stressor-enhanced infectious colitis. These data demonstrate that probiotic L. reuteri can prevent the exacerbating effects of stressor exposure on pathogen-induced colitis, and suggest that one mechanism by which this occurs is through downregulation of the chemokine CCL2. PMID:26422754

  16. Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1).

    PubMed

    Kanthesh, Basalingappa M; Sandle, Geoffrey I; Rajendran, Vazhaikkurichi M

    2013-11-01

    Defective colonic Na(+) and Cl(-) absorption is a feature of active ulcerative colitis (UC), but little is known about changes in colonic K(+) transport. We therefore investigated colonic K(+) transport in a rat model of dextran sulfate-induced colitis. Colitis was induced in rat distal colon using 5% dextran sulfate sodium (DSS). Short-circuit current (Isc, indicating electrogenic ion transport) and (86)Rb (K(+) surrogate) fluxes were measured in colonic mucosa mounted in Ussing chambers under voltage-clamp conditions in the presence of mucosal orthovanadate (a P-type ATPase inhibitor). Serum aldosterone was measured by immunoassay. Control animals exhibited zero net K(+) flux. By contrast, DSS-treated animals exhibited active K(+) secretion, which was inhibited by 98, 76, and 22% by Ba(2+) (nonspecific K(+) channel blocker), iberiotoxin (IbTX; BK channel blocker), and TRAM-34 (IK channel blocker), respectively. Apical BK channel α-subunit mRNA abundance and protein expression, and serum aldosterone levels in DSS-treated animals, were enhanced 6-, 3-, and 6-fold respectively, compared with controls. Increasing intracellular Ca(2+) with carbachol (CCH), or intracellular cAMP with forskolin (FSK), stimulated both active Cl(-) secretion and active K(+) secretion in controls but had no or little effect in DSS-treated animals. In DSS-induced colitis, active K(+) secretion involves upregulation of apical BK channel expression, which may be aldosterone-dependent, whereas Cl(-) secretion is diminished. Since similar ion transport abnormalities occur in patients with UC, diarrhea in this disease may reflect increased colonic K(+) secretion (rather than increased Cl(-) secretion), as well as defective Na(+) and Cl(-) absorption. PMID:23986198

  17. Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase.

    PubMed

    Zucker, Stephen D; Vogel, Megan E; Kindel, Tammy L; Smith, Darcey L H; Idelman, Gila; Avissar, Uri; Kakarlapudi, Ganesh; Masnovi, Michelle E

    2015-11-15

    Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression. PMID:26381705

  18. Chloroform fraction of Solanum tuberosum L. cv Jayoung epidermis suppresses LPS-induced inflammatory responses in macrophages and DSS-induced colitis in mice.

    PubMed

    Lee, Seung-Jun; Shin, Ji-Sun; Choi, Hye-Eun; Lee, Kyoung-Goo; Cho, Young-Wuk; An, Hyo-Jin; Jang, Dae Sik; Jeong, Jin-Cheol; Kwon, Oh-Keun; Nam, Jung-Hwan; Lee, Kyung-Tae

    2014-01-01

    In this study, the authors investigated the molecular mechanism underlying the antiinflammatory effects of the chloroform fraction of the peel of 'Jayoung' (CFPJ), a color-fleshed potato, on lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and in mice with dextran sulfate sodium (DSS)-induced colitis. CFPJ inhibited the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the transcription level, and attenuated the transcriptional activity of nuclear factor-κB (NF-κB) by reducing the translocation of NF-κB depending on degradation of inhibitory κB-α (IκB-α). Furthermore, CFPJ attenuated the phosphorylations of mitogen-activated protein kinase kinases3/6 (MKK3/6) and of p38. In colitis model, CFPJ significantly reduced the severity of colitis and the productions and protein levels of pro-inflammatory mediators in colonic tissue. These results suggest that the anti-inflammatory effects of CFPJ are associated with the suppression of NF-κB and p38 activation in macrophages, and support its possible therapeutic role for the treatment of colitis. PMID:24184733

  19. Oral Feeding of Probiotic Bifidobacterium infantis: Colonic Morphological Changes in Rat Model of TNBS-Induced Colitis

    PubMed Central

    Javed, Najma H.; Alsahly, Musaad B.; Khubchandani, Jagdish

    2016-01-01

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. It has been proposed that modifying the bacterial flora in intestine with probiotics may decrease the inflammatory process and prevent relapses in UC. We investigated the possible protective and therapeutic effects of a single strand of probiotic, Bifidobacterium infantis (BI), on colonic inflammation, in rats with regular feedings. Two groups of Lewis rats were prepared (n = 8). The first group was the control, sham-fed group (n = 4). The other group was the experimental BI-fed group (n = 4). Colitis was induced in both groups by intrarectal administration of TNBS under light anesthesia. The sham-fed colitis induced groups received a daily oral gavage feeding of 1.0 mL distilled water, whereas the B. infantis-fed group received 0.205 g of B. infantis dissolved in 1.0 mL distilled water daily. The change in body weight and food and water intake was recorded over the course of each study and analyzed. The rats were euthanized and tissues from the descending colon were harvested and analyzed microscopically and histologically. Results of our study indicated significant reduction in inflammation, mucosal damage, and preservation of goblet cells, as compared to the control animals. Modulation of gastrointestinal (GI) flora suggests a promising field in developing strategies for prevention and treatment of inflammatory bowel diseases by dietary modifications. PMID:27127686

  20. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium.

    PubMed

    Zhang, Qianpeng; Wu, Yanqiu; Wang, Jing; Wu, Guojun; Long, Wenmin; Xue, Zhengsheng; Wang, Linghua; Zhang, Xiaojun; Pang, Xiaoyan; Zhao, Yufeng; Zhao, Liping; Zhang, Chenhong

    2016-01-01

    Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn't induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates. PMID:27264309

  1. Oral Feeding of Probiotic Bifidobacterium infantis: Colonic Morphological Changes in Rat Model of TNBS-Induced Colitis.

    PubMed

    Javed, Najma H; Alsahly, Musaad B; Khubchandani, Jagdish

    2016-01-01

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. It has been proposed that modifying the bacterial flora in intestine with probiotics may decrease the inflammatory process and prevent relapses in UC. We investigated the possible protective and therapeutic effects of a single strand of probiotic, Bifidobacterium infantis (BI), on colonic inflammation, in rats with regular feedings. Two groups of Lewis rats were prepared (n = 8). The first group was the control, sham-fed group (n = 4). The other group was the experimental BI-fed group (n = 4). Colitis was induced in both groups by intrarectal administration of TNBS under light anesthesia. The sham-fed colitis induced groups received a daily oral gavage feeding of 1.0 mL distilled water, whereas the B. infantis-fed group received 0.205 g of B. infantis dissolved in 1.0 mL distilled water daily. The change in body weight and food and water intake was recorded over the course of each study and analyzed. The rats were euthanized and tissues from the descending colon were harvested and analyzed microscopically and histologically. Results of our study indicated significant reduction in inflammation, mucosal damage, and preservation of goblet cells, as compared to the control animals. Modulation of gastrointestinal (GI) flora suggests a promising field in developing strategies for prevention and treatment of inflammatory bowel diseases by dietary modifications. PMID:27127686

  2. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium

    PubMed Central

    Zhang, Qianpeng; Wu, Yanqiu; Wang, Jing; Wu, Guojun; Long, Wenmin; Xue, Zhengsheng; Wang, Linghua; Zhang, Xiaojun; Pang, Xiaoyan; Zhao, Yufeng; Zhao, Liping; Zhang, Chenhong

    2016-01-01

    Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn’t induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates. PMID:27264309

  3. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis.

    PubMed

    Ahmad, R; Chaturvedi, R; Olivares-Villagómez, D; Habib, T; Asim, M; Shivesh, P; Polk, D B; Wilson, K T; Washington, M K; Van Kaer, L; Dhawan, P; Singh, A B

    2014-11-01

    Expression of claudin-2, a tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Notably, claudin-2 has also been implicated in the regulation of intestinal epithelial proliferation. However, precise role of claudin-2 in regulating colonic homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic mice, that increased colonic claudin-2 expression augments mucosal permeability as well as colon and crypt length. Most notably, despite leaky colon, Cl-2TG mice were significantly protected against experimental colitis. Importantly, claudin-2 expression increased colonocyte proliferation and provided protection against colitis-induced colonocyte death in a PI-3Kinase/Bcl-2-dependent manner. However, Cl-2TG mice also demonstrated marked suppression of colitis-induced increases in immune activation and associated signaling, suggesting immune tolerance. Accordingly, colons from naive Cl-2TG mice harbored significantly increased numbers of regulatory (CD4(+)Foxp3(+)) T cells than WT littermates. Furthermore, macrophages isolated from Cl-2TG mouse colon exhibited immune anergy. Importantly, these immunosuppressive changes were associated with increased synthesis of the immunoregulatory cytokine TGF-β by colonic epithelial cells in Cl-2TG mice compared with WT littermates. Taken together, our findings reveal a critical albeit complex role of claudin-2 in intestinal homeostasis by regulating epithelial permeability, inflammation and proliferation and suggest novel therapeutic opportunities. PMID:24670427

  4. Anti-Colitic Effects of Kanjangs (Fermented Soy Sauce and Sesame Sauce) in Dextran Sulfate Sodium-Induced Colitis in Mice

    PubMed Central

    Song, Jia-Le; Choi, Jung-Ho; Seo, Jae-Hoon; Lim, Yaung-Iee

    2014-01-01

    Abstract This study was conducted to investigate the preventive effects of different kanjangs (Korean soy sauces), including acid-hydrolyzed soy sauce (AHSS), fermented soy sauce (FSS), and fermented sesame sauce (FSeS), on 2% dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice. The fermented sauces, particularly FSeS, significantly suppressed DSS-induced body weight loss, increased colon length, and decreased colon weight/length ratios. Histological observations suggested that the fermented sauces prevented edema, mucosal damage, and the loss of crypts induced by DSS compared to the control mice and animals fed AHSS. FSeS and FSS decreased the serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6, and IL-17α. mRNA expression of these cytokines as well as that of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon mucosa was also inhibited by the two sauces. Our results suggest that fermented sauces, especially FSeS, exert an anticolitic effect partially by reducing the serum levels of proinflammatory cytokines and inhibiting the mRNA expression of these factors in the colon tissue of mice treated with DSS. However, AHSS did not protect against DSS-induced colitis. In addition, low-dose treatment (4 mL/kg) with the fermented sauces resulted in greater anticolitic effects than consumption of a high quantity (8 mL/kg) of the sauces. PMID:25188463

  5. Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium-Induced Colitis.

    PubMed

    Zhang, Jun; Cao, Lijuan; Wang, Hong; Cheng, Xuefang; Wang, Lin; Zhu, Lin; Yan, Tingting; Xie, Yang; Wu, Yuzheng; Zhao, Min; Ma, Sijing; Wu, Mengqiu; Wang, Guangji; Hao, Haiping

    2015-08-01

    Pregnane X receptor (PXR) activation exhibits anti-inflammatory effects via repressing nuclear factor-κB (NF-κB); however, its overactivation may disrupt homeostasis of various enzymes and transporters. Here we found that ginsenosides restore PXR/NF-κB signaling in inflamed conditions without disrupting PXR function in normal conditions. The effects and mechanisms of ginsenosides in regulating PXR/NF-κB signals were determined both in vitro and in vivo. Ginsenosides significantly inhibited NF-κB activation and restored the expression of PXR target genes in tumor necrosis factor-α-stimulated LS174T cells. Despite not being PXR agonists, ginsenosides repressed NF-κB activation in a PXR-dependent manner. Ginsenosides significantly increased the physical association between PXR and the NF-κB p65 subunit and thereby decreased the nuclear translocation of p65. Ginsenoside Rb1 and compound K (CK) were major bioactive compounds in the regulating PXR/NF-κB signaling. Consistently, ginsenosides significantly attenuated dextran sulfate sodium-induced experimental colitis, which was associated with restored PXR/NF-κB signaling. This study indicates that ginsenosides may elicit anti-inflammatory effects via targeting PXR/NF-κB interaction without disrupting PXR function in healthy conditions. Ginsenoside Rb1 and CK may serve as leading compounds in the discovery of new drugs that target PXR/NF-κB interaction in therapy for inflammatory bowel disease. PMID:25986850

  6. Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis.

    PubMed

    Beloqui, Ana; Coco, Régis; Alhouayek, Mireille; Solinís, María Ángeles; Rodríguez-Gascón, Alicia; Muccioli, Giulio G; Préat, Véronique

    2013-10-01

    The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200 nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment. PMID:23694806

  7. Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis

    PubMed Central

    Hoda, Raschid M.; Scharl, Michael; Keely, Stephen J.; McCole, Declan F.

    2010-01-01

    The purpose of this study was to investigate whether luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Monolayers of human intestinal T84 epithelial cells and a rat model of chemotherapy-induced enterocolitis were used. Cells were treated with leptin and mounted in Ussing chambers to measure basal and secretagogue-induced changes in transepithelial short-circuit current (Isc). Furthermore, the role of MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating responses to leptin was investigated. Acute colitis in Sprague-Dawley rats was induced by intraperitoneal injection of 40 mg/kg methotrexate. Leptin (100 ng/ml) induced a time-dependent increase in basal Isc in T84 intestinal epithelial cells (P < 0.01). Moreover, pretreatment of T84 cells with leptin for up to 1 h significantly potentiated carbachol- and forskolin-induced increases in Isc. Pretreatment with an inhibitor of MAPK abolished the effect of leptin on basal, carbachol- and forskolin-induced chloride secretion (P < 0.05). However, the PI3K inhibitor, wortmannin, only blunted the effect of leptin on forskolin-induced increases in Isc. Furthermore, leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T84 cells. In the rat model, luminal leptin induced significant increases in Isc across segments of proximal and, to a lesser extent, distal colon (P < 0.05). We conclude that luminal leptin is likely an intestinal chloride secretagogue, particularly when present at elevated concentrations and/or in the setting of inflammation. Our findings may provide a mechanistic explanation, at least in part, for the clinical condition of secretory diarrhea both in hyperleptinemic obese patients and in patients with chemotherapy-induced intestinal inflammation. PMID:20203064

  8. Ulcerative Colitis Impairs the Acylethanolamide-Based Anti-Inflammatory System Reversal by 5-Aminosalicylic Acid and Glucocorticoids

    PubMed Central

    Suárez, Juan; Romero-Zerbo, Yanina; Márquez, Lucia; Rivera, Patricia; Iglesias, Mar; Bermúdez-Silva, Francisco J.; Andreu, Montserrat; de Fonseca, Fernando Rodríguez

    2012-01-01

    Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages. PMID:22662201

  9. [Pseudomembranous colitis caused by antibiotics].

    PubMed

    Meyer, B; Geering, P

    1978-11-11

    A case of antibiotic-induced pseudomembranous colitis is presented. Following resection of a carcinoma of the colon, an 81-year old man was treated with clindamycin for 9 days and with epicillin for another 9 days. One week after discontinuation of antibiotics the patient developed progressively severe diarrhea. Death from central pulmonary embolism ensued 10 days after the onset of diarrhea. Autopsy revealed severe pseudomembranous colitis of the entire large intestine. Pseudomembranous colitis is often observed as a complication after the administration of different antibiotics. The Anglo-American literature contains several recent reports of clindamycin-induced pseudomembranous colitis. The etiopathology of this drug-induced disease is still unclear. A possible interpretation is an antibiotic-induced change in the intestinal flora. Recent observations suggest that toxin-producing clostridia are responsible for the pseudomembranous colitis. PMID:568308

  10. Anti-inflammatory effects of ginsenoside Rg1 and its metabolites ginsenoside Rh1 and 20(S)-protopanaxatriol in mice with TNBS-induced colitis.

    PubMed

    Lee, Sang-Yun; Jeong, Jin-Ju; Eun, Su-Hyeon; Kim, Dong-Hyun

    2015-09-01

    Ginsenoside Rg1, one of the main constituents of Panax ginseng, exhibits anti-inflammatory effect. In a preliminary study, it was observed that ginsenoside Rg1 was metabolized to 20(S)-protopanaxtriol via ginsenosides Rh1 and F1 by gut microbiota. We further investigated the anti-inflammatory effects of ginsenoside Rg1 and its metabolites in vitro and in vivo. Ginsenosides Rg1, Rh1, and 20(S)-protopanaxtriol inhibited the activation of NF-κB activation, phosphorylation of transforming growth factor beta-activated kinase 1 and interleukin (IL)-1 receptor-associated kinase, and expression of tumor necrosis factor-α and IL-1β in lipopolysaccharide (LPS)-stimulated macrophages. They also inhibited the binding of LPS to toll-like receptor 4 on the macrophages. Orally administered ginsenoside Rg1, Rh1, or 20(S)-protopanaxtriol inhibited 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colon shortening, myeloperoxidase activity, and expression of IL-1β, IL-17, and tumor necrosis factor-α in mice with TNBS-induced colitis. They did not only inhibit TNBS-induced NF-κB activation, but also restored TNBS-induced Th17/Treg imbalance. They restored IL-10 and Foxp3 expression. Moreover, they inhibited Th17 cell differentiation in vitro. Of these metabolites, in vitro and in vivo anti-inflammatory effect of 20(S)-protopanaxtriol was the most potent, followed by Rh1. These findings suggest that ginsenoside Rg1 is metabolized to 20(S)-protopanaxtriol via ginsenosides Rh1 and F1 and these metabolites particularly 20(S)-protopanaxtriol, may ameliorate inflammatory disease such as colitis by inhibiting the binding of LPS to TLR4 on macrophages and restoring the Th17/Treg imbalance. PMID:26054809

  11. Microscopic colitis.

    PubMed

    Pardi, Darrell S

    2014-02-01

    Microscopic colitis is a frequent cause of chronic watery diarrhea, especially in older persons. Common associated symptoms include abdominal pain, arthralgias, and weight loss. The incidence of microscopic colitis had been increasing, although more recent studies have shown a stabilization of incidence rates. The diagnosis is based on characteristic histologic findings in a patient with diarrhea. Microscopic colitis can occur at any age, including in children, but it is primarily seen in the elderly. Several treatment options exist to treat the symptoms of microscopic colitis, although only budesonide has been well studied in randomized clinical trials. PMID:24267602

  12. Parthenolide induces apoptosis in colitis-associated colon cancer, inhibiting NF-κB signaling

    PubMed Central

    KIM, SE LIM; LIU, YU CHUAN; SEO, SEUNG YOUNG; KIM, SEONG HUN; KIM, IN HEE; LEE, SEUNG OK; LEE, SOO TEIK; KIM, DAE-GHON; KIM, SANG WOOK

    2015-01-01

    Recently, the nuclear factor (NF)-κB inhibitor parthenolide (PT) was identified as a promising anticancer agent for the promotion of cancer cell apoptosis. Additionally, our previous study demonstrated that PT administration suppresses tumor growth in a xenograft model of colorectal cancer cells via regulation of the B-cell lymphoma-2 (Bcl-2) family. However, the role of PT in the development of colitis-associated colon cancer (CAC) is poorly understood. Therefore, the aim of the present study was to investigate the effects of PT administration on CAC using a murine model. Azoxymethane (AOM) and dextran sulfate sodium (DSS) were administered to induce experimental CAC in the following three groups of treated mice: i) AOM and DSS plus vehicle; ii) AOM, DSS and 2 mg/kg PT; and iii) AOM, DSS and 4 mg/kg PT. It was demonstrated that the histological acuteness of AOM/DSS-induced CAC was significantly reduced following the administration of PT, resulting in decreased NF-κB p65 expression levels via a blockade of phosphorylation and subsequent degradation of inhibitor of κB-α (IκBα). Furthermore, PT administration appeared to enhance the process of carcinogenesis via the downregulation of the antiapoptotic proteins Bcl-2 and Bcl-extra large, mediated by inhibition of NF-κB activation. Apoptosis and caspase-3 expression were markedly increased in the PT-treated group. These findings indicate that PT inhibits IκBα phosphorylation and NF-κB activation, resulting in the initiation of apoptosis and the eventual suppression of CAC development. The beneficial effects of PT treatment observed in the experimental CAC model indicate the potential chemopreventive and therapeutic role of PT in CAC. PMID:26137027

  13. Vitamin D Regulates the Gut Microbiome and Protects Mice from Dextran Sodium Sulfate–Induced Colitis123

    PubMed Central

    Ooi, Jot Hui; Li, Yunfei; Rogers, Connie J.; Cantorna, Margherita T.

    2013-01-01

    The active form of vitamin D [1,25-dihydroxycholecalciferol, 1,25(OH)2D3] and the vitamin D receptor (VDR) regulate susceptibility to experimental colitis. The effect of the bacterial microflora on the susceptibility of C57BL/6 mice to dextran sodium sulfate–induced colitis was determined. Mice that cannot produce 1,25(OH)2D3 [Cyp27b1 (Cyp) knockout (KO)], VDR KO as well as their wild-type littermates were used. Cyp KO and VDR KO mice had more bacteria from the Bacteroidetes and Proteobacteria phyla and fewer bacteria from the Firmicutes and Deferribacteres phyla in the feces compared with wild-type. In particular, there were more beneficial bacteria, including the Lactobacillaceae and Lachnospiraceae families, in feces from Cyp KO and VDR KO mice than in feces from wild-type. Helicobacteraceae family member numbers were elevated in Cyp KO compared with wild-type mice. Depletion of the gut bacterial flora using antibiotics protected mice from colitis. 1,25(OH)2D3 treatment (1.25 μg/100 g diet) of Cyp KO mice decreased colitis severity and reduced the numbers of Helicobacteraceae in the feces compared with the numbers in the feces of untreated Cyp KO mice. The mechanisms by which the dysbiosis occurs in VDR KO and Cyp KO mice included lower expression of E-cadherin on gut epithelial and immune cells and fewer tolerogenic dendritic cells that resulted in more gut inflammation in VDR and Cyp KO mice compared with wild-type mice. Increased host inflammation has been shown to provide pathogens with substrates to out-compete more beneficial bacterial species. Our data demonstrate that vitamin D regulates the gut microbiome and that 1,25(OH)2D3 or VDR deficiency results in dysbiosis, leading to greater susceptibility to injury in the gut. PMID:23966330

  14. Anti-inflammatory effect of elemental diets with different fat composition in experimental colitis.

    PubMed

    Papada, E; Kaliora, A C; Gioxari, A; Papalois, A; Forbes, A

    2014-04-14

    The aim of the present study was to evaluate the effectiveness of two isoenergetic elemental formulae with different fat content in the rat model of trinitrobenzene sulphonic acid (TNBS) colitis that mimics human inflammatory bowel disease. A total of forty-five male Wistar rats were assigned to five groups: (1) control group; (2) TNBS-induced colitis group; (3) TNBS-induced colitis group fed a long-chain TAG (LCT)-rich diet; (4) TNBS-induced colitis group fed a medium-chain TAG (MCT)-rich diet; (5) TNBS-induced colitis group fed a baseline diet and administered infliximab. Nutritional management lasted 12 d before and 4 d after rectal administration of TNBS. Subsequently, the rats were killed, and colonic tissue samples were collected for the assessment of histology, inflammation and oxidative stress. The MCT-rich diet decreased IL-6, IL-8 and intercellular adhesion molecule-1 (ICAM-1) levels and glutathione S-transferase (GST) activity, while the LCT-rich diet reduced only ICAM-1 levels and GST activity (P<0.05). Neither elemental formula affected IL-10 levels. Infliximab reduced IL-8 and ICAM-1 levels and GST activity and increased IL-10 levels (P<0.05). No significant differences were detected in oxidative stress. Histological damage scores differed significantly only between the control and the TNBS-induced colitis group. A MCT-rich formula seems to exert stronger anti-inflammatory effects than a LCT-rich formula in TNBS colitis. PMID:24229480

  15. Effects of Malva sylvestris and Its Isolated Polysaccharide on Experimental Ulcerative Colitis in Rats.

    PubMed

    Hamedi, Azadeh; Rezaei, Hossein; Azarpira, Negar; Jafarpour, Mehrnaz; Ahmadi, Fatemeh

    2016-01-01

    Malva sylvestris is an edible plant that is consumed as a herbal supplement for its antiulcer and colon cleansing properties in traditional Persian medicine. This study was designed to evaluate its effects on ulcerative colitis, which is a chronic gastrointestinal inflammation. Colitis was induced by rectal instillation of acetic acid solution. Rats in different groups received aqueous, n-hexane, or ethanolic fractions of the plant before induction of colitis. Isolated polysaccharide of plant was also tested in 2 groups before and after induction of colitis. Macroscopic and microscopic evaluation of colitis showed that the aqueous fraction was very effective in preventing the inflammation and efficacy was lower for ethanolic and n-hexane fractions. Polysaccharide was effective in reducing signs of inflammation, especially as pretreatment. These beneficial effects provide evidences that this plant can be suggested for patients with this disease to improve their health condition or to reduce adverse effects of their medication. PMID:26045553

  16. The Sasa quelpaertensis Leaf Extract Inhibits the Dextran Sulfate Sodium-induced Mouse Colitis Through Modulation of Antioxidant Enzyme Expression

    PubMed Central

    Yeom, Yiseul; Kim, Yuri

    2015-01-01

    Background: Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease. The objective of this study is to investigate the protective effect of Sasa quelpaertensis leaf extract (SQE) against oxidative stress in mice with dextran sulfate sodium (DSS)-induced colitis. Methods: Mice were treated with SQE (100 mg/kg or 300 mg/kg body weight) by gavage in advance two weeks before inflammation was induced. Then, the mice were administered with 2.5% DSS in drinking water for 7 days and normal drinking water for 7 days between two DSS treatment. Disease activity index values, gut motility, and severity of the resulting oxidative DNA damage were analyzed. The antioxidant effect of SQE was evaluated by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) activity in plasma samples. Catalase activity and expressions levels of glutathione peroxidase 1 (Gpx1), SOD1, and SOD2 were also detected in colon tissues. Results: Administration of SQE significantly reduced the severity of DSS-induced colitis compared to the control (Ctrl) group. Levels of 8-oxo-dG, an oxidative DNA damage marker, were significantly lower in the SQE group compared to the untreated DSS Ctrl group. In the SQE (300 mg/kg) group, MDA levels were significantly lower, while SOD and catalase activity levels in the plasma samples were significantly higher compared with the DSS Ctrl group. The expression levels of the antioxidant enzymes, SOD2 and Gpx1, were significantly higher, while the levels of SOD 1 expression were lower, in the colon tissues of the DSS Ctrl group compared with those of the Ctrl group. In contrast, administration of SQE significantly down-regulated SOD2 and Gpx1 expressions and up-regulated SOD1 expression. Conclusions: These results indicate that SQE efficiently suppresses oxidative stress in DSS-induced colitis in mice, and its action is associated with the regulation of antioxidant enzymes. PMID:26151047

  17. Mice Overexpressing β-1,4-Galactosyltransferase I Are Resistant to TNF-Induced Inflammation and DSS-Induced Colitis

    PubMed Central

    Vanhooren, Valerie; Vandenbroucke, Roosmarijn E.; Dewaele, Sylviane; Van Hamme, Evelien; Haigh, Jody J.; Hochepied, Tino; Libert, Claude

    2013-01-01

    Glycosylation is an essential post-translational modification, which determines the function of proteins and important processes such as inflammation. β-1,4-galactosyltransferase I (βGalT1) is a key enzyme involved in the addition of galactose moieties to glycoproteins. Intestinal mucins are glycoproteins that protect the gut barrier against invading pathogens and determine the composition of the intestinal microbiota. Proper glycosylation of mucus is important in this regard. By using ubiquitously expressing βGalT1 transgenic mice, we found that this enzyme led to strong galactosylation of mucus proteins, isolated from the gut of mice. This galactosylation was associated with a drastic change in composition of gut microbiota, as TG mice had a significantly higher Firmicutes to Bacteroidetes ratio. TG mice were strongly protected against TNF-induced systemic inflammation and lethality. Moreover, βGalT1 transgenic mice were protected in a model of DSS-induced colitis, at the level of clinical score, loss of body weight, colon length and gut permeability. These studies put βGalT1 forward as an essential protective player in exacerbated intestinal inflammation. Optimal galactosylation of N-glycans of mucus proteins, determining the bacterial composition of the gut, is a likely mechanism of this function. PMID:24339869

  18. Mice overexpressing β-1,4-Galactosyltransferase I are resistant to TNF-induced inflammation and DSS-induced colitis.

    PubMed

    Vanhooren, Valerie; Vandenbroucke, Roosmarijn E; Dewaele, Sylviane; Van Hamme, Evelien; Haigh, Jody J; Hochepied, Tino; Libert, Claude

    2013-01-01

    Glycosylation is an essential post-translational modification, which determines the function of proteins and important processes such as inflammation. β-1,4-galactosyltransferase I (βGalT1) is a key enzyme involved in the addition of galactose moieties to glycoproteins. Intestinal mucins are glycoproteins that protect the gut barrier against invading pathogens and determine the composition of the intestinal microbiota. Proper glycosylation of mucus is important in this regard. By using ubiquitously expressing βGalT1 transgenic mice, we found that this enzyme led to strong galactosylation of mucus proteins, isolated from the gut of mice. This galactosylation was associated with a drastic change in composition of gut microbiota, as TG mice had a significantly higher Firmicutes to Bacteroidetes ratio. TG mice were strongly protected against TNF-induced systemic inflammation and lethality. Moreover, βGalT1 transgenic mice were protected in a model of DSS-induced colitis, at the level of clinical score, loss of body weight, colon length and gut permeability. These studies put βGalT1 forward as an essential protective player in exacerbated intestinal inflammation. Optimal galactosylation of N-glycans of mucus proteins, determining the bacterial composition of the gut, is a likely mechanism of this function. PMID:24339869

  19. Functional and protein-protein interaction network analysis of colorectal cancer induced by ulcerative colitis

    PubMed Central

    DAI, YONG; JIANG, JIN-BO; WANG, YAN-LEI; JIN, ZU-TAO; HU, SAN-YUAN

    2015-01-01

    Colorectal cancer (CRC) is a well-recognized complication of ulcerative colitis (UC), and patients with UC have a higher incidence of CRC, compared with the general population. However, the properties of CRC induced by UC have not been clarified using an interaction network to analyze and compare gene sets. In the present study, six microarray datasets of CRC and UC were extracted from the Array Express database, and gene signatures were identified using the genome-wide relative significance (GWRS) method. Functional analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Prediction of the genes and microRNA were performed using a hypergeometric method. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/proteins, and clusters were obtained through the Molecular Complex Detection algorithm. Topological centrality and a novel analyzing method, based on the rank value of GWGS, were used to characterize the biological importance of the clusters. A total of 217 differentially expressed (DE) genes of CRC were identified, 341 DE genes were identified in UC, and 62 common genes existed in the two. Several KEGG pathways were the same in CRC and UC. Collagenase, progesterone, heparin, urokinase, nadh and adenosine drugs demonstrated potential for use in treatment of CRC and UC. In the PPI network of CRC, 210 nodes and 752 edges were observed, wheras 314 nodes and 882 edges were identified in UC. Cluster 3 in UC had the highest GWGS, while the topological centrality of Cluster 3 in UC had the lowest degree and betweenness. PPI network analysis provided an effective way to estimate and understand the likelihood of the potential connections between proteins/genes. The results obtained following the use of GWGS to analyze differences between clusters did not agree with the topological degree and betweenness centrality, which indicated that gene fold change based GWGS was

  20. Role of hypoxia-inducible factor-1α in pathogenesis and disease evaluation of ulcerative colitis

    PubMed Central

    XU, CHUNMEI; DONG, WEIGUO

    2016-01-01

    The main aim of the present study was to measure hypoxia-inducible factor-1α (HIF-1α) in serum and colonic mucosa of ulcerative colitis (UC) patients and to analyze its role in the pathogenesis, disease activity and severity of UC. A total of 47 UC patients and 13 UC in remission patients were recruited for the present study. Ten healthy subjects were also included to serve as controls. HIF-1α in the serum was measured using ELISA. The citrate-microwave-SP immunohistochemical method was used to measure the expression of HIF-1α in colonic mucosa. The results showed that, HIF-1α in serum was notably higher in UC patients (73.21±28.65) than UC in remission patients (44.54±14.75) and controls (42.83±15.49). The difference between UC patients and UC in remission patients was significant (P<0.05). A correlation analysis revealed that, the HIF-1α level in serum was positively associated with disease activity, disease severity and endoscopic grade. The expression of HIF-1α in colonic mucosa of UC patients was (58.05±13.83) higher than that in UC in remission patients (3.00±2.72) and controls (3.04±2.69) and this difference was statistically significant (P<0.05). A positive correlation was identified between the expression of HIF-1α in colonic mucosa and the disease activity, severity and endoscopic grade. Thus, the present findings indicated that, HIF-1α is likely to play an important role in the pathogenesis of UC and may serve as a biomarker to evaluate disease activity and severity in UC patients. PMID:27073444

  1. Deficient Production of Reactive Oxygen Species Leads to Severe Chronic DSS-Induced Colitis in Ncf1/p47phox-Mutant Mice

    PubMed Central

    Rodrigues-Sousa, Tiago; Ladeirinha, Ana Filipa; Santiago, Ana Raquel; Carvalheiro, Helena; Raposo, Bruno; Alarcão, Ana; Cabrita, António; Holmdahl, Rikard; Carvalho, Lina; Souto-Carneiro, M. Margarida

    2014-01-01

    Background Colitis is a common clinical complication in chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis. Methods Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS), intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry. Results Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A) and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2). Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+T and B cells. Conclusion This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD. PMID:24873968

  2. Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation.

    PubMed

    Melgar, Silvia; Karlsson, Agneta; Michaëlsson, Erik

    2005-06-01

    Exposure to dextran sulfate sodium (DSS) induces acute colitis, which is normally resolved after DSS removal. To study chronicity, mice are typically subjected to three to five cycles of weekly DSS exposures, each followed by a 1- to 2-wk rest period. Here, we describe a novel and convenient way of inducing chronic, progressive colitis by a single exposure to DSS. C57BL/6 mice exposed to DSS for 5 days developed acute colitis that progressed to severe chronic inflammation. The plasma haptoglobin levels remained high during the chronic phase, showing that the inflammation was active. Surprisingly, the mice regained their original weight along with the progression of colitis, and the only apparent symptom was loose feces. Histopathological changes 4 wk after DSS removal were dense infiltrates of mononuclear cells, irregular epithelial structure, and persistent deposits of collagen. A progressive production of the cytokines IL-1beta, IL-12 p70, and IL-17 correlated with the extensive cellular infiltration, whereas high IFN-gamma production was mainly found late in the chronic phase. Similar to C57BL/6 mice, BALB/c mice exposed to 5 days of DSS developed acute colitis as previously described. The acute colitis was accompanied by elevated plasma levels of haptoglobin and increased colonic levels of IL-1alpha/beta, IL-6, IL-18, and granulocyte colony-stimulating factor. However, soon after DSS removal, BALB/c mice recovered and were symptom free within 2 wk and completely recovered 4 wk after DSS removal in terms of histopathology, haptoglobin levels, and local cytokine production. In summary, these data stress the effect of genetic background on the outcome of DSS provocation. We believe that the present protocol to induce chronic colitis in C57BL/6 mice offers a robust model for validating future therapies for treatment of inflammatory bowel disease. PMID:15637179

  3. The effect of methylsulfonylmethane on the experimental colitis in the rat

    SciTech Connect

    Amirshahrokhi, K.; Bohlooli, S.; Chinifroush, M.M.

    2011-06-15

    Methylsulfonylmethane (MSM), naturally occurring in green plants, fruits and vegetables, has been shown to exert anti-inflammatory and antioxidant effects. MSM is an organosulfur compound and a normal oxidative metabolite of dimethyl sulfoxide. This study was carried out to investigate the effect of MSM in a rat model of experimental colitis. Colitis was induced by intracolonic instillation of 1 ml of 5% of acetic acid. Rats were treated with MSM (400 mg/kg/day, orally) for 4 days. Animals were euthanized and distal colon evaluated histologically and biochemically. Tissue samples were used to measurement of malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), glutathione (GSH) and proinflammatory cytokine (TNF-{alpha} and IL-1{beta}) levels. Results showed that MSM decreased macroscopic and microscopic colonic damage scores caused by administration of acetic acid. MSM treatment also significantly reduced colonic levels of MDA, MPO and IL-1{beta}, while increased the levels of GSH and CAT compared with acetic acid-induced colitis group. It seems that MSM as a natural product may have a protective effect in an experimental ulcerative colitis. - Research Highlights: > Methylsulfonylmethane occurs naturally in some green plants, fruits and vegetables. > Methylsulfonylmethane (MSM) has anti-inflammatory and antioxidant effects. > We evaluated the effects of MSM in a rat model of experimental ulcerative colitis. > MSM has protective effect against acetic acid-induced colitis in rat.

  4. Anti-inflammatory effects of Lactobacillus brevis K65 on RAW 264.7 cells and in mice with dextran sulphate sodium-induced ulcerative colitis.

    PubMed

    Liu, Y-W; Ong, W-K; Su, Y-W; Hsu, C-C; Cheng, T-H; Tsai, Y-C

    2016-06-01

    Lactic acid bacteria (LAB) with anti-inflammatory effects may be beneficial to the prevention or treatment for inflammation-related diseases, such as inflammatory bowel diseases. In an in vitro assay, heat-killed Lactobacillus brevis K65 (K65) reduced lipopolysaccharide-induced production of nitric oxide, tumour necrosis factor (TNF)-α and prostaglandin E2 in RAW 264.7 cells. In RAW 264.7 cells stably expressing an ind=ucible nitric oxide synthase (iNOS) reporter, viable K65 showed greater inhibition of iNOS production than its heat-killed form. In order to further examine the in vivo anti-inflammatory effect of K65, viable K65 was orally administered to BALB/c mice before and during the period of dextran sulphate sodium (DSS)-induced ulcerative colitis (UC). K65 improved UC symptoms, including reduced the levels of the pro-inflammatory cytokines, TNF-α, interleukin (IL)-6 and IL-1β, and lowered the activity of myeloperoxidase. Furthermore, K65 inhibited TNF-α, cyclo-oxygenase 2, forkhead box P3, and Toll-like receptor 4 mRNA expression in the colonic tissue of DSS-induced UC mice. Taken together, K65, a LAB with in vitro anti-inflammatory activity showed preventive effects on mice with DSS-induced UC by lowering the expression of inflammatory molecules. PMID:26925602

  5. Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice

    PubMed Central

    Reichmann, Florian; Hassan, Ahmed Mostafa; Farzi, Aitak; Jain, Piyush; Schuligoi, Rufina; Holzer, Peter

    2015-01-01

    Psychological stress causes disease exacerbation and relapses in inflammatory bowel disease (IBD) patients. Since studies on stress processing during visceral inflammation are lacking, we investigated the effects of experimental colitis as well as psychological stress on neurochemical and neuroendocrine changes as well as behaviour in mice. Dextran sulfate sodium (DSS)-induced colitis and water avoidance stress (WAS) were used as mouse models of colitis and mild psychological stress, respectively. We measured WAS-associated behaviour, gene expression and proinflammatory cytokine levels within the amygdala, hippocampus and hypothalamus as well as plasma levels of cytokines and corticosterone in male C57BL/6N mice. Animals with DSS-induced colitis presented with prolonged immobility during the WAS session, which was associated with brain region-dependent alterations of neuropeptide Y (NPY), NPY receptor Y1, corticotropin-releasing hormone (CRH), CRH receptor 1, brain-derived neurotrophic factor and glucocorticoid receptor gene expression. Furthermore, the combination of DSS and WAS increased interleukin-6 and growth regulated oncogene-α levels in the brain. Altered gut-brain signalling in the course of DSS-induced colitis is thought to cause the observed distinct gene expression changes in the limbic system and the aberrant molecular and behavioural stress responses. These findings provide new insights into the effects of stress during IBD. PMID:26066467

  6. Extraintestinal Helminth Infection Limits Pathology and Proinflammatory Cytokine Expression during DSS-Induced Ulcerative Colitis: A Role for Alternatively Activated Macrophages and Prostaglandins

    PubMed Central

    Ledesma-Soto, Yadira; Callejas, Blanca E.; Terrazas, César A.; Reyes, Jose L.; Espinoza-Jiménez, Arlett; González, Marisol I.; León-Cabrera, Sonia; Morales, Rosario; Olguín, Jonadab E.; Saavedra, Rafael; Oghumu, Steve; Satoskar, Abhay R.; Terrazas, Luis I.

    2015-01-01

    Chronic inflammation of the intestinal mucosa is characteristic of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Helminth parasites have developed immunomodulatory strategies that may impact the outcome of several inflammatory diseases. Therefore, we investigated whether Taenia crassiceps infection is able to decrease the inflammatory effects of dextran sulfate sodium- (DSS-) induced ulcerative colitis in BALB/c and C57BL/6 mice. Preinfection significantly reduced the manifestations of DSS-induced colitis, as weight loss and shortened colon length, and decreased the disease activity index independently of the genetic background of the mice. Taenia infection decreased systemic levels of proinflammatory cytokines while increasing levels of IL-4 and IL-10, and the inflammatory infiltrate into the colon was also markedly reduced. RT-PCR assays from colon showed that T. crassiceps-infected mice displayed increased expression of Arginase-1 but decreased expression of iNOS compared to DSS-treated uninfected mice. The percentages of T regulatory cells were not increased. The adoptive transfer of alternatively activated macrophages (AAMФs) from infected mice into mice with DSS-induced colitis reduced the severity of colon inflammation. Administration of indomethacin abrogated the anticolitic effect of Taenia. Thus, T. crassiceps infection limits the pathology of ulcerative colitis by suppressing inflammatory responses mechanistically associated with AAMФs and prostaglandins. PMID:26090422

  7. Heligmosomoides induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut Tcell responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Immunological diseases like inflammatory bowel disease (IBD) are infrequent in less developed countries possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides bakeri (Hb) prevents colitis. It was determined if Hb mediated IBD pro...

  8. Ischemic colitis induced by the newly reformulated multicomponent weight-loss supplement Hydroxycut®

    PubMed Central

    Sherid, Muhammed; Samo, Salih; Sulaiman, Samian; Gaziano, Joseph H

    2013-01-01

    Ischemic colitis accounts for 6%-18% of causes of acute lower gastrointestinal bleeding. It is more often multifactorial and more common in elderly. Drugs are considered important causative agents of this disease with different mechanisms. In this paper, we describe a 37-year-old otherwise healthy female presented with sudden onset diffuse abdominal pain and bloody stool. Radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her only suspected factor was hydroxycut which she had been taking for a period of 1 mo prior to her presentation. Her condition improved uneventfully after cessation of hydroxycut, bowel rest, intravenous hydration, and antibiotics. This is a first case of ischemic colitis with clear relationship with hydroxycut use (Naranjo score of 7). Our case demonstrates the importance of questioning patients regarding the usage of dietary supplements; especially since many patients consider them safe and do not disclose their use voluntarily to their physicians. Hydroxycut has to be considered as a potential trigger for otherwise unexplained ischemic colitis. PMID:23596542

  9. Proteomic profiling of dextran sulfate sodium induced acute ulcerative colitis mice serum exosomes and their immunomodulatory impact on macrophages.

    PubMed

    Wong, Wing-Yan; Lee, Magnolia Muk-Lan; Chan, Brandon Dow; Kam, Richard Kin-Tin; Zhang, Ge; Lu, Ai-Ping; Tai, William Chi-Shing

    2016-04-01

    Macrophages are essential for the maintenance of intestinal homeostasis, and their activation has been proposed to be critical to the pathogenesis of inflammatory bowel disease (IBD). Although there are many recognized mediators of macrophage activation, increasing evidence suggests that macrophages respond to exosome stimulation. Exosomes are 40-150 nm microvesicles released from different cell types and are found in a variety of physiological fluids, including serum. As studies have shown that circulating exosomes participate in intercellular communication and can mediate the immune response, we hypothesized that exosomes may play a role in the pathogenesis of IBD though modulation of macrophage activity. In this study, we used the dextran sulfate sodium (DSS) induced acute colitis mice model to investigate the effect of serum exosomes on macrophages and identify exosome proteins potentially involved in macrophage activation. We treated RAW264.7 macrophages with serum exosomes isolated from dextran sulfate sodium induced mice and found that treatment induced phosphorylation of p38 and ERK and production of tumor necrosis factor α when compared to treatment with exosomes isolated from control mice. Subsequent proteomic analysis identified 56 differentially expressed proteins, a majority of which were acute-phase proteins and immunoglobulins. Bioinformatics analysis suggested these proteins were mainly involved in the complement and coagulation cascade, which has been implicated in macrophage activation. Our findings provide new insight into the role of circulating serum exosomes in acute colitis and contribute to the understanding of macrophage activation in the pathogenesis of IBD. PMID:26806198

  10. CD103+CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis

    PubMed Central

    Wenzel, Ulf A.; Jonstrand, Caroline; Hansson, Gunnar C.; Wick, Mary Jo

    2015-01-01

    Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+CD11b- DCs and increased CD103-CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+CD11b+ DCs in the distal colon. CD103+CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103-CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis. PMID:26121642

  11. The role of cholinergic anti-inflammatory pathway in acetic acid-induced colonic inflammation in the rat.

    PubMed

    Kolgazi, Meltem; Uslu, Unal; Yuksel, Meral; Velioglu-Ogunc, Ayliz; Ercan, Feriha; Alican, Inci

    2013-09-01

    The "cholinergic anti-inflammatory pathway" provides neurological modulation of cytokine synthesis to limit the magnitude of the immune response. This study aimed to evaluate the impact of the cholinergic anti-inflammatory pathway on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. Colitis was induced by intrarectal administration of 5% acetic acid (1ml) to Sprague-Dawley rats (200-250g; n=7-8 per group). Control group received an equal volume of saline intrarectally. The rats were treated with either nicotine (1mg/kg/day) or huperzine A (0.1mg/kg/day) intraperitoneally for 3 days. After decapitation, the distal colon was scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Formation of reactive oxygen species was monitored by using chemiluminescence (CL). Nuclear factor (NF)-κB expression was evaluated in colonic samples via immunohistochemical analysis. Trunk blood was collected for the assessment of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10, resistin and visfatin levels. Both nicotine and huperzine A reduced the extent of colonic lesions, increased colonic MDA level, high MPO activity and NF-κB expression in the colitis group. Elevation of serum IL-1β level due to colitis was also attenuated by both treatments. Additionally, huperzine A was effective to reverse colitis-induced high lucigenin-enhanced CL values and serum TNF-α levels. Colitis group revealed decreased serum visfatin levels compared to control group which was completely reversed by nicotine. In conclusion, modulation of the cholinergic system either by nicotine or ACh esterase inhibition improved acetic acid-induced colonic inflammation as confirmed by macroscopic and microscopic examination and biochemical assays. PMID:23810507

  12. The Algal Meroterpene 11-Hydroxy-1′-O-Methylamentadione Ameloriates Dextran Sulfate Sodium-Induced Colitis in Mice

    PubMed Central

    Zbakh, Hanaa; Talero, Elena; Avila, Javier; Alcaide, Antonio; de los Reyes, Carolina; Zubía, Eva; Motilva, Virginia

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1′-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD. PMID:27527191

  13. The Algal Meroterpene 11-Hydroxy-1'-O-Methylamentadione Ameloriates Dextran Sulfate Sodium-Induced Colitis in Mice.

    PubMed

    Zbakh, Hanaa; Talero, Elena; Avila, Javier; Alcaide, Antonio; de Los Reyes, Carolina; Zubía, Eva; Motilva, Virginia

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1'-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD. PMID:27527191

  14. Polyglycolic acid induced inflammation

    PubMed Central

    Ceonzo, Kathleen; Gaynor, Anne; Shaffer, Lisa; Kojima, Koji; Vacanti, Charles A.; Stahl, Gregory L.

    2005-01-01

    Tissue and organ replacement have quickly outpaced available supply. Tissue bioengineering holds the promise for additional tissue availability. Various scaffolds are currently used, whereas polyglycolic acid (PGA), which is currently used in absorbable sutures and orthopedic pins, provides an excellent support for tissue development. Unfortunately, PGA can induce a local inflammatory response following implantation, so we investigated the molecular mechanism of inflammation in vitro and in vivo. Degraded PGA induced an acute peritonitis, characterized by neutrophil (PMN) infiltration following intraperitoneal injection in mice. Similar observations were observed using the metabolite of PGA, glycolide. Dissolved PGA or glycolide, but not native PGA, activated the classical complement pathway in human sera, as determined by classical complement pathway hemolytic assays, C3a and C5a production, C3 and immunoglobulin deposition. To investigate whether these in vitro observations translated to in vivo findings, we used genetically engineered mice. Intraperitoneal administration of glycolide or dissolved PGA in mice deficient in C1q, factor D, C1q and factor D or C2 and factor B demonstrated significantly reduced PMN infiltration compared to congenic controls (WT). Mice deficient in C6 also demonstrated acute peritonitis. However, treatment of WT or C6 deficient mice with a monoclonal antibody against C5 prevented the inflammatory response. These data suggest that the hydrolysis of PGA to glycolide activates the classical complement pathway. Further, complement is amplified via the alternative pathway and inflammation is induced by C5a generation. Inhibition of C5a may provide a potential therapeutic approach to limit the inflammation associated with PGA derived materials following implantation. PMID:16548688

  15. Ulcerative Colitis

    MedlinePlus

    Ulcerative colitis (UC) is a disease that causes inflammation and sores, called ulcers, in the lining of the rectum and colon. It is one of a group of diseases called inflammatory bowel disease. UC can happen at ...

  16. Ulcerative colitis

    MedlinePlus

    ... of nonhospitalized ulcerative colitis: the Toronto consensus. Gastroenterology . 2015;148(5):1035-58. PMID: 25747596 www.ncbi.nlm.nih.gov/pubmed/25747596 . Burger D, Travis S. Conventional medical management of inflammatory bowel ...

  17. Serotonin-Exacerbated DSS-Induced Colitis Is Associated with Increase in MMP-3 and MMP-9 Expression in the Mouse Colon

    PubMed Central

    Gao, Lei; Feng, Dandan; Jiang, Yalin; Jin, Jianjun

    2016-01-01

    Background. 5-HT enhances dextran sulfate sodium- (DSS-) induced colitis and is involved in inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) play roles in the process of intestinal inflammation. Aims. To examine whether 5-HT induces MMPs expression in mouse colon to enhance DSS-induced colitis. Materials and Methods. C57BL/6J (B6) mice were treated with either low-dose (1.0 mg/kg) or high-dose (2.0 mg/kg) 5-HT by enema, low-dose (1.0%) or high-dose (2.5%) DSS, or combined low-dose (1.0%) DSS and (1.0 mg/kg) 5-HT. Mouse colitis was analyzed. MMPs and tissue inhibitors of MMPs (TIMPs) mRNA were measured by real-time quantitative RT-PCR in mouse colon and in human Caco-2 cells and neutrophils. MMP-3 and MMP-9 protein levels were quantified from immunohistochemistry (IHC) images of mouse colons. Results. 5-HT exacerbated DSS-induced colitis, low-dose 5-HT induces both MMP-3 and MMP-9, and high-dose 5-HT only increased MMP-3 mRNA expression in mouse colon. Mouse colon MMP-3 and MMP-9 protein levels were also elevated by 5-HT treatment. The MMP-2, TIMP-1, and TIMP-2 mRNA levels were increased in the inflamed colon. 5-HT induced MMP-3 and MMP-9 mRNA expression in Caco-2 and human neutrophils, respectively, in vitro. Conclusion. 5-HT induced MMP-3 and MMP-9 expression in mouse colon; these elevated MMPs may contribute to DSS-induced colitis. PMID:27478308

  18. Pseudomembranous Colitis

    PubMed Central

    Farooq, Priya D.; Urrunaga, Nathalie H.; Tang, Derek M.; von Rosenvinge, Erik C.

    2015-01-01

    Pseudomembranous colitis is an inflammatory condition of the colon characterized by elevated yellow-white plaques that coalesce to form pseudomembranes on the mucosa. Patients with the condition commonly present with abdominal pain, diarrhea, fever, and leukocytosis. Because pseudomembranous colitis is often associated with C. difficile infection, stool testing and empiric antibiotic treatment should be initiated when suspected. When results of C. difficile testing are negative and symptoms persist despite escalating empiric treatment, early gastroenterology consultation and lower endoscopy would be the next step in the appropriate clinical setting. If pseudomembranous colitis is confirmed endoscopically, colonic biopsies should be obtained, as histology can offer helpful clues to the underlying diagnosis. The less common non-C. difficile causes of pseudomembranous colitis should be entertained, as a number of etiologies can result in this condition. Examples include Behcet’s disease, collagenous colitis, inflammatory bowel disease, ischemic colitis, other infections organisms (e.g. bacteria, parasites, viruses), and a handful of drugs and toxins. Pinpointing the correct underlying etiology would better direct patient care and disease management. Surgical specialists would be most helpful in colonic perforation, gangrenous colon, or severe disease. PMID:25769243

  19. Curcumin represses the activity of inhibitor-κB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation.

    PubMed

    Kao, Ning-Jo; Hu, Jia-Yuan; Wu, Chien-Sheng; Kong, Zwe-Ling

    2016-09-01

    In this study, we investigated the preventive effects of curcumin using dextran sulfate sodium (DSS)-induced colitis and the potential role of curcumin in regulation of anti-inflammation through S-nitrosylation. After curcumin treatment for 6days, the body weight and disease activity index of DSS-induced mice was alleviated and the colonic length was also rescued. Western blot presented that the protein expression of iNOS can be reduced by curcumin. Consistently, mRNA level of iNOS and pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, was also repressed. Moreover, Curcumin reduced the amount of nitrite in DSS-induced colitis but not affected total S-nitrosylation level on proteins on day 6, indicating that curcumin inhibited NO oxidation. Furthermore, the protection of S-nitrosylation on IKKβ in DSS-induced colitis for 6days by curcumin caused the repression of IκB phosphorylation and NF-κB activation. In conclusion, this study verified that curcumin-mediated S-nitrosylation may be as an important regulator for anti-inflammation in DSS-induced colitis of mice. PMID:27233000

  20. Metabolite profiling of plasma and urine from rats with TNBS-induced acute colitis using UPLC-ESI-QTOF-MS-based metabonomics--a pilot study.

    PubMed

    Zhang, Xiaojun; Choi, Franky F K; Zhou, Yan; Leung, Feung P; Tan, Shun; Lin, Shuhai; Xu, Hongxi; Jia, Wei; Sung, Joseph J Y; Cai, Zongwei; Bian, Zhaoxiang

    2012-07-01

    The incidence of inflammatory bowel disease, a relapsing intestinal condition whose precise etiology is still unclear, has continually increased over recent years. Metabolic profiling is an effective method with high sample throughput that can detect and identify potential biomarkers, and thus may be useful in investigating the pathogenesis of inflammatory bowel disease. In this study, using a metabonomics approach, a pilot study based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) was performed to characterize the metabolic profile of plasma and urine samples of rats with experimental colitis induced by 2,4,6-trinitrobenzene sulfonic acid. Acquired metabolic profile data were processed by multivariate data analysis for differentiation and screening of potential biomarkers. Five metabolites were identified in urine: two tryptophan metabolites [4-(2-aminophenyl)-2,4-dioxobutanoic acid and 4,6-cihydroxyquinoline], two gut microbial metabolites (phenyl-acetylglycine and p-cresol glucuronide), and the bile acid 12α-hydroxy-3-oxocholadienic acid. Seven metabolites were identified in plasma: three members of the bile acid/alcohol group (cholic acid, 12α-hydroxy-3-oxocholadienic acid and cholestane-3,7,12,24,25-pentol) and four lysophosphatidylcholines [LysoPC(20:4), LysoPC(16:0), LysoPC(18:1) and LysoPC(18:0)]. These metabolites are associated with damage of the intestinal barrier function, microbiota homeostasis, immune modulation and the inflammatory response, and play important roles in the pathogenesis of inflammatory bowel disease. Our results positively support application of the metabonomic approach in study of the pathophysiological mechanism of inflammatory bowel disease. PMID:22520047

  1. Dietary polydextrose prevents inflammatory bowel disease in trinitrobenzenesulfonic acid model of rat colitis.

    PubMed

    Witaicenis, Aline; Fruet, Andréa C; Salem, Letícia; Di Stasi, Luiz C

    2010-12-01

    Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder that involves interactions among the immune system, genetic susceptibility, and environmental factors, especially the bacterial flora. Polydextrose, a polysaccharide constituted by 90% nondigestible and nonabsorbable soluble fibers, has several physiological effects consistent with those of dietary fibers, including proliferation of colon microflora. Because sulfasalazine presents serious side effects through long-term use at high doses, the aim of the present study was to evaluate the preventative effect of polydextrose on trinitrobenzenesulfonic acid-induced intestinal inflammation and its effects on the intestinal anti-inflammatory activity of sulfasalazine. Results indicated that polydextrose and its association with sulfasalazine present an anti-inflammatory effect that reduces myeloperoxidase activity, counteracts glutathione content, and promotes reductions in lesion extension and colonic weight/length ratio. PMID:21091252

  2. Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages.

    PubMed

    Ke, Ping; Shao, Bo-Zong; Xu, Zhe-Qi; Wei, Wei; Han, Bin-Ze; Chen, Xiong-Wen; Su, Ding-Feng; Liu, Chong

    2016-01-01

    Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages. PMID:27611972

  3. The ANXA1 released from intestinal epithelial cells alleviate DSS-induced colitis by improving NKG2A expression of Natural Killer cells.

    PubMed

    Zou, Z; Zuo, D; Yang, J; Fan, H

    2016-09-01

    Inflammatory bowel disease (IBD) arises when intestinal immune homeostasis is broken, the maintenance of such homeostasis is principally controlled by cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). IECs can prevent the contact between luminal bacteria with immune cells through the formation of a physical barrier and the expression of antimicrobial peptides to maintain intestinal immune homeostasis. During Colitis the IECs can express increased ANXA1, which is important for regeneration of intestinal mucosa and function as a potent anti-inflammatory protein. Natural Killer (NK) cells can also suppress the progression of colitis. It is uncertain about the effect of the cross-talk between injured IECs and recruited NK cells during colitis. In this study, the expression of ANXA1 in IECS from DSS treated mice was increased, and more NK cells were recruited to intestinal mucosa. In addition, the expression of NKG2A was upregulated when co-cultured with NK cells. The results further proved that overexpression of NKG2A in NK cells was important for inhibiting the recruitment and activity of neutrophils to alleviate DSS-induced colitis. Here, we provide a new anti-inflammation mechanism about ANXA1 secreted from injured IECs, where ANXA1 can stimulate the expression of NKG2A in NK cells that affect the recruitment and activity of neutrophils necessary for pathology of colitis. PMID:27435504

  4. Camel's milk ameliorates TNBS-induced colitis in rats via downregulation of inflammatory cytokines and oxidative stress.

    PubMed

    Arab, Hany H; Salama, Samir A; Eid, Ahmed H; Omar, Hany A; Arafa, El-Shaimaa A; Maghrabi, Ibrahim A

    2014-07-01

    Current treatment strategies for inflammatory bowel diseases (IBD) are associated with several adverse effects, and thus, the search for effective agents with minimal side effects merits attention. Camel's milk (CM) is endowed with antioxidant/anti-inflammatory features and has been reported to protect against diabetes and hepatic injury, however, its effects on IBD have not been previously explored. In the current study, we aimed to investigate the potential alleviating effects of CM against TNBS-induced colitis in rats. CM (10 ml/kg b.i.d. by oral gavage) effectively suppressed the severity of colon injury as evidenced by amelioration of macroscopic damage, colon weight/length ratio, histopathological alterations, leukocyte influx and myeloperoxidase activity. Administration of CM mitigated the colonic levels of TNF-α and IL-10 cytokines. The attenuation of CM to colon injury was also associated with suppression of oxidative stress via reduction of lipid peroxides and nitric oxide along with boosting the antioxidant defenses through restoration of colon glutathione and total anti-oxidant capacity. In addition, caspases-3 activity, an apoptotic marker, was inhibited. Together, our study highlights evidences for the promising alleviating effects of CM in colitis. Thus, CM may be an interesting complementary approach for the management of IBD. PMID:24788059

  5. Lactobacillus curvatus WiKim38 isolated from kimchi induces IL-10 production in dendritic cells and alleviates DSS-induced colitis in mice.

    PubMed

    Jo, Sung-Gang; Noh, Eui-Jeong; Lee, Jun-Young; Kim, Green; Choi, Joo-Hee; Lee, Mo-Eun; Song, Jung-Hee; Chang, Ji-Yoon; Park, Jong-Hwan

    2016-07-01

    Probiotics such as lactobacilli and bifidobacteria have healthpromoting effects by immune modulation. In the present study, we examined the immunomodulatory properties of Lactobacillus curvatus WiKim38, which was newly isolated from baechu (Chinese cabbage) kimchi. The ability of L. curvatus WiKim38 to induce cytokine production in bone marrow-derived dendritic cells (BMDCs) was determined by enzyme-linked immunosorbent assay. To evaluate the molecular mechanisms underlying L. curvatus Wikim38-mediated IL-10 production, Western blot analyses and inhibitor assays were performed. Moreover, the in vivo anti-inflammatory effects of L. curvatus WiKim38 were examined in a dextran sodium sulfate (DSS)-induced colitis mouse model. L. curvatus WiKim38 induced significantly higher levels of IL-10 in BMDCs compared with that induced by LPS. NF-κB and ERK were activated by L. curvatus WiKim38, and an inhibitor assay revealed that these pathways were required for L. curvatus WiKim38-induced production of IL-10 in BMDCs. An in vivo experiment showed that oral administration of L. curvatus WiKim38 increased the survival rate of mice with DSS-induced colitis and improved clinical signs and histopathological severity in colon tissues. Taken together, these results indicate that L. curvatus Wikim38 may have health-promoting effects via immune modulation, and may thus be applicable for therapy of various inflammatory diseases. PMID:27350616

  6. Dextran sulfate sodium administered orally is depolymerized in the stomach and induces cell cycle arrest plus apoptosis in the colon in early mouse colitis.

    PubMed

    Araki, Yoshio; Bamba, Tadao; Mukaisho, Ken-ichi; Kanauchi, Osamu; Ban, Hiromitsu; Bamba, Shigeki; Andoh, Akira; Fujiyama, Yoshihide; Hattori, Takanori; Sugihara, Hiroyuki

    2012-11-01

    The mechanisms responsible for human inflammatory bowel disease remain poorly understood. The pathogenic factors for dextran sulfate sodium (DSS)-induced colitis, one of the experimental animal colitis models, also remain unknown. Furthermore, detailed studies on DSS metabolism in the gut lumen have not been reported. Therefore, we investigated DSS metabolism in the mouse gut lumen and report the mechanisms which induce colitis. DSS was labeled with 2-aminopyridine (pyridylamino-DSS, PA-DSS). PA-DSS was administered orally to male BALB/cA Jcl mice. The metabolites and histological findings were observed using HPLC and light or fluorescence microscopy. PA-DSS with Mr 5000 was depolymerized rapidly in the gastric lumen, and the depolymerized PA-DSS was absorbed in the small intestine. Therefore, the majority of the PA-DSS in the cecal contents returned to Mr 5000 PA-DSS, escaping absorption in the small intestine. Mr 5000 DSS induced severe colitis, and immunostaining using an anti-mouse Ki-67 antibody and the TUNEL assay showed that DSS arrested the cell cycle at the G0 phase and induced apoptosis of the colonic epithelium. Mr 2500 PA-DSS, however, induced these same effects weakly. During these processes, we observed that the epithelial cells can depolymerize DSS themselves. An in vitro study using Caco-2 cells also showed similar effects. Mr 5000 DSS was depolymerized in the gut lumen and epithelial cells. Therefore, the molecular mass distribution of the DSS differed between each part in the lumen. As an early stage event, DSS induced colitis through cell cycle arrest and apoptosis according to its molecular mass. PMID:22895560

  7. Sarcodon aspratus Extract Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mouse Colon and Mesenteric Lymph Nodes.

    PubMed

    Chung, Min-Yu; Hwang, Jin-Taek; Kim, Jin Hee; Shon, Dong-Hwa; Kim, Hyun-Ku

    2016-05-01

    Mushrooms have been previously investigated for their immune-modulating and anti-inflammatory properties. We examined whether the anti-inflammatory properties of Sarcodon aspratus ethanol extract (SAE) could elicit protective effects against dextran sulfate sodium (DSS)-induced colitis in vivo. Male C57/BL6 mice were randomly assigned to 1 of 4 treatment groups: control (CON; n = 8), DSS-treated (DSS; n = 9), DSS+SAE at 50 mg/kg BW (SAE50; n = 8), and DSS+SAE at 200 mg/kg BW groups (SAE200; n = 9). DSS treatment induced significant weight loss, which was significantly recovered by SAE200. Although SAE did not affect DSS-mediated reductions in colon length, it improved diarrhea and rectal bleeding induced by DSS. SAE at 200 mg/kg BW significantly attenuated IL-6 and enhanced IL-10 expression in mesenteric lymph nodes (MLN), and significantly reduced IL-6 levels in splenocytes. SAE200 also significantly attenuated DSS-induced increase in IL-6 and IL-1β, and reductions in IL-10 in colon tissue. High levels of SAE were also observed to significantly decrease inflammatory COX-2 expression that was upregulated by DSS in mice colon. These findings may have relevance for novel therapeutic strategies to mitigate inflammatory bowel disease-relevant inflammatory responses, via the direct and indirect anti-inflammatory activity of SAE. We also found that SAE harbors significant quantities of total fiber and β-glucan, suggesting a possible role for these components in protection against DSS-mediated colitis. PMID:27074537

  8. The Src kinase Fyn is protective in acute chemical-induced colitis and promotes recovery from disease.

    PubMed

    Lopes, Fernando; Wang, Arthur; Smyth, David; Reyes, Jose-Luis; Doering, Axinia; Schenck, L Patrick; Beck, Paul; Waterhouse, Christopher; McKay, Derek M

    2015-06-01

    Despite progress in understanding enteric inflammation, current therapies, although effective in many patients with inflammatory bowel disease (IBD), have significant side-effects, and, in many patients, it is refractory to treatment. The Src kinase Fyn mediated IFN-γ-induced increased permeability in model epithelia, and so we hypothesized that inhibition of Fyn kinase would be anti-colitic. Mice [B6.129SF2/J wild-type (WT), Fyn KO, or chimeras] received 2.5% dextran sodium sulfate (DSS) or normal water for 10 d and were necropsied immediately or 3 d later. Gut permeability was assessed by FITC-dextran flux, colitis by macroscopic and histologic parameters, and immune cell status by cytokine production and CD4(+) T cell Foxp3 expression. Fyn KO mice consistently displayed significantly worse DSS-induced disease than WT, correlating with decreased IL-10 and increased IL-17 in splenocytes and the gut; Fyn KO mice failed to thrive after removal of the DSS water. Analysis of chimeric mice indicated that the increased sensitivity to DSS was due to the lack of Fyn kinase in hematopoietic, but not stromal, cells, in accordance with Fyn(+) T cell increases in WT mice exposed to DSS and Fyn KO mice having a reduced number of CD4(+)Foxp3(+) cells in baseline or colitic conditions and a reduced capacity to induce Foxp3 expression in vitro. Other experiments suggest that the colonic microbiota in Fyn KO mice is not preferentially colitogenic. Contrary to our expectation, the absence of Fyn kinase resulted in greater DSS-induced disease, and analysis of chimeric mice indicated that leukocyte Fyn kinase is beneficial in limiting colitis. PMID:25877924

  9. Preventive and therapeutic effects of blueberry (Vaccinium corymbosum) extract against DSS-induced ulcerative colitis by regulation of antioxidant and inflammatory mediators.

    PubMed

    Pervin, Mehnaz; Hasnat, Md Abul; Lim, Ji-Hong; Lee, Yoon-Mi; Kim, Eun Ok; Um, Byung-Hun; Lim, Beong Ou

    2016-02-01

    Inflammatory bowel disease (IBD) is an inflammatory disorder caused by hyperactivation of effector immune cells that produce high levels of proinflammatory cytokines. The aims of our study were to determine whether orally administered blueberry extract (BE) could attenuate or prevent the development of experimental colitis in mice and to elucidate the mechanism of action. Female Balb/C mice (n=7) were randomized into groups differing in treatment conditions (prevention and treatment) and dose of BE (50 mg/kg body weight). Acute ulcerative colitis was induced by oral administration of 3% dextran sodium sulfate for 7 days in drinking water. Colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. BE significantly decreased disease activity index and improved the macroscopic and histological score of colons when compared to the colitis group (P<.05). BE markedly attenuated myeloperoxidase accumulation (colitis group 54.97±2.78 nmol/mg, treatment group 30.78±1.33 nmol/mg) and malondialdehyde in colon and prostaglandin E2 level in serum while increasing the levels of superoxide dismutase and catalase (colitis group 11.94±1.16 U/ml, BE treatment group 16.49±0.39 U/ml) compared with the colitis group (P<.05). mRNA levels of the cyclooxygenase (COX)-2, interferon-γ, interleukin (IL)-1β and inducible nitric oxide synthase cytokines were determined by reverse transcriptase polymerase chain reaction. Immunohistochemical analysis showed that BE attenuates the expression of COX-2 and IL-1β in colonic tissue. Moreover, BE reduced the nuclear translocation of nuclear transcription factor kappa B (NF-κB) by immunofluorescence analysis. Thus, the anti-inflammatory effect of BE at colorectal sites is a result of a number of mechanisms: antioxidation, down-regulation of the expression of inflammatory mediators and inhibition of the nuclear translocation of NF-κB. PMID:26878787

  10. Versatile methods for synthesizing organic acid salts of quaternary berberine-type alkaloids as anti-ulcerative colitis agents.

    PubMed

    Zhang, Zhi-Hui; Li, Jing; Zhang, Hai-Jing; Deng, An-Jun; Wu, Lian-Qiu; Li, Zhi-Hong; Song, Hong-Rui; Wang, Wen-Jie; Qin, Hai-Lin

    2016-06-01

    Two versatile methods to synthesize kinds of organic acid salts of quaternary berberine-type alkaloids were investigated in order to determine which is more efficient to improve the liposolubility of the target compounds and to explore the efficacy of the target compounds as anti-ulcerative colitis (UC) agents. Overall evaluation according to the reaction results and yields of the final products indicated that the synthetic method using tertiary (±)-8-acylmethyldihydroberberine-type alkaloids as key intermediates is superior to that of using tertiary dihydroberberine-type alkaloids as intermediates. Ten target compounds were synthesized using quaternary berberine chloride and quaternary coptisine chloride as starting materials, respectively, and the anti-UC activity of some target compounds was evaluated in an in vitro x-box-binding protein 1 (XBP1) transcriptional activity assay using dual luciferase reporter detection. At 10 μM, the tested compounds were found to activate the transcription of XBP1 target at almost the same level as that of quaternary coptisine chloride. The synthesized target compounds were also found to share higher liposolubility than the inorganic acid salts of quaternary berberine-type alkaloid. PMID:27097666

  11. Simultaneous determination of six short-chain fatty acids in colonic contents of colitis mice after oral administration of polysaccharides from Chrysanthemum morifolium Ramat by gas chromatography with flame ionization detector.

    PubMed

    Tao, Jin-Hua; Duan, Jin-Ao; Jiang, Shu; Guo, Jian-Ming; Qian, Yi-Yun; Qian, Da-Wei

    2016-09-01

    Short-chain fatty acids (SCFAs) produced by the intestinal bacteria are very critical for the intestinal barrier, mucosal cytoprotection and normal intestinal biology. However, accumulation of SCFAs promoted by the polysaccharides from Chrysanthemum morifolium Ramat remains unknown. Thus, it is necessary to investigate SCFAs in the colonic contents of dextran sulfate sodium (DSS) induced colitis mice after oral administration of the polysaccharides from C. morifolium Ramat which is very helpful to unravel how it works. In this study, a rapid and reliable gas chromatographic method with flame ionization detector (GC-FID) for simultaneous determination of six SCFAs such as acetic acid (AA), propionic acid (PA), butyric acid (BA), isobutyric acid (IBA), valeric acid (VA) and isovaleric acid (IVA) has been developed and validated. Under the optimized chromatographic conditions and sample extraction procedure, good separation for 6 target compounds was obtained on a HP-INNOWAX column within 12min. Results revealed that polysaccharides from C. morifolium Ramat positively affected the SCFAs intestinal production. The polysaccharides group had greater SCFAs concentration in colonic content than the DSS-treated group (P<0.05), which was decreased remarkably compared to the normal group (P<0.01). With the decrease of the polysaccharides dosage, the contents of AA, PA and VA increased gradually, while the change of BA concentration was the opposite. There was no significant difference in the content of IBA at the different administration concentrations. And the content of IVA reached the highest concentration 0.953mg/g at lower dose of the polysaccharides. Additionally, oral administration of the polysaccharides prominently attenuated the body weight loss, reduced the disease activity index, rectal bleeding and stool consistency, improved colon shortening and macroscopic score of colitis. Our results indicated that the polysaccharides of C. morifolium Ramat might be used as

  12. Efficacy of oral administration of lactic acid bacteria isolated from cocoa in a fermented milk preparation: reduction of colitis in an experimental rat model.

    PubMed

    Dos Santos, T F; Melo, T A; Santos, D S; Rezende, R P; Dias, J C T; Romano, C C

    2016-01-01

    We investigated the probiotic potential of lactic acid bacteria (LAB) obtained from cocoa fermentation using an experimental rat model of colitis. Cocoa beans were collected from fermentation boxes every 12 h for 5 days to isolate the microorganisms. Strains were isolated by serial dilution and plating on MRS agar. Gram-positive and catalase-negative rods were subjected to DNA extraction, polymerase chain reaction, and sequencing. Ten strains were randomly pooled and used to prepare a fermented milk drink that was used to treat the experimental colitis. A parallel group was treated with a single strain drink. Serum concentrations of cytokines and IgA, total and differential counts of blood leukocytes, and histological appearance were compared with the untreated control colitis group. Eighty strains of LAB were identified as Lactobacillus fermentum (68) and Lactobacillus plantarum (12). The multi-strain LAB pool significantly reduced the total number of leukocytes. There was a significant reduction in the percentage of neutrophils and monocytes compared with the control colitis group. IFN-γ concentration was downregulated in animals treated with the LAB pool. IL-10 and IgA increased significantly in the group treated with the strains. Histological analysis showed that the LAB pool reduced the inflammatory infiltrate and restored tissue architecture. The group treated with the single strain LAB drink (L. fermentum) showed no signs of inflammation remission. The results confirm the probiotic action of cocoa-derived LAB in the treatment of experimental colitis. Studies using isogenic models and humans will clarify the mechanisms of immune response modulation in inflammatory bowel disease. PMID:27525878

  13. Investigation of pulmonary involvement in inflammatory bowel disease in an experimental model of colitis

    PubMed Central

    Aydin, Bunyamin; Songur, Yıldıran; Songur, Necla; Aksu, Oğuzhan; Senol, Altug; Ciris, I. Metin; Sutcu, Recep

    2016-01-01

    Background/Aims: Inflammatory bowel disease (IBD) may also involve various extra-intestinal organs. Clinical studies have found asymptomatic/symptomatic pulmonary involvement in 1% to 6% of patients with IBD. The present study histopathologically investigated pulmonary involvement in an experimental model of colitis in order to demonstrate pulmonary tissue involvement in IBD and to expose potential etiological factors. It also explored the relation between inflammation and tissue concentrations of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α). Methods: The study comprised 24 male Wistar albino rats. The rats were divided into four groups of six rats each. Acute colitis was induced in two separate groups using either the dextran sulphate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) method, while the other two groups were used as controls for each model of colitis. Wallace scoring was used for macroscopic assessment of colitis, and the lungs were histopathologically examined. Concentrations of VEGF and TNF-α in pulmonary tissue were measured by the enzyme-linked immunosorbent assay method. Results: The number of animals that had alveolar hemorrhage was significantly higher in the TNBS-induced colitis and DSS-induced colitis groups compared to their own control groups (p = 0.015 and p = 0.015, respectively). VEGF and TNF-α concentrations in pulmonary tissues were significantly increased in both the TNBS colitis and DSS colitis groups compared to their own control groups (p = 0.002 and p = 0.004, respectively; and p = 0.002 and p = 0.002, respectively). Conclusions: The present study demonstrated that significant and serious histopathological changes directly associated with colitis occur in the lungs in IBD. PMID:27539446

  14. Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice.

    PubMed

    Murphy, Stephen F; Rhee, Lesley; Grimm, Wesley A; Weber, Christopher R; Messer, Jeannette S; Lodolce, James P; Chang, Jonathan E; Bartulis, Sarah J; Nero, Thomas; Kukla, Renata A; MacDougall, Gordon; Binghay, Charles; Kolodziej, Lauren E; Boone, David L

    2014-11-01

    Tumor necrosis factor-induced protein 3 (TNFAIP3; also known as A20) negatively regulates NF-κB and MAPK signals to control inflammatory responses. TNFAIP3 also protects against TNF-induced cell death. Intestinal epithelial cell (IEC) expression of TNFAIP3 improves barrier function and tight junction integrity and prevents dextran sulfate sodium (DSS)-induced IEC death and colitis. We therefore investigated the effects of TNFAIP3 expression in IEC on immune homeostasis in the intestines of immune-compromised mice. Villin-TNFAIP3 (v-TNFAIP3) transgenic mice were interbred with IL-10(-/-) mice (v-TNFAIP3 × IL-10(-/-)) and incidence, onset, and severity of colitis was assessed. v-TNFAIP3 × IL-10(-/-) mice displayed severe, early onset, and highly penetrant colitis that was not observed in IL-10(-/-) or v-TNFAIP3 mice. V-TNFAIP3 mice displayed altered expression of mucosal cytokines, increased numbers of mucosal regulatory T cells, and altered expression of mucosal antimicrobial peptides (AMPs). Microbial colonization of the inner mucus layer of v-TNFAIP3 mice was observed, along with alterations in the microbiome, but this was not sufficient to induce colitis in v-TNFAIP3 mice. The relative sterility of the inner mucus layer observed in wild-type and IL-10(-/-) mice was lost in v-TNFAIP3 × IL-10(-/-) mice. Thus IEC-derived factors, induced by signals that are inhibited by TNFAIP3, suppress the onset of inflammatory bowel disease in IL-10(-/-) mice. Our results indicate that IEC expression of TNFAIP3 alters AMP expression and allows microbial colonization of the inner mucus layer, which activates an IL-10-dependent anti-inflammatory process that is necessary to prevent colitis. PMID:25234043

  15. Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice

    PubMed Central

    Murphy, Stephen F.; Rhee, Lesley; Grimm, Wesley A.; Weber, Christopher R.; Messer, Jeannette S.; Lodolce, James P.; Chang, Jonathan E.; Bartulis, Sarah J.; Nero, Thomas; Kukla, Renata A.; MacDougall, Gordon; Binghay, Charles; Kolodziej, Lauren E.

    2014-01-01

    Tumor necrosis factor-induced protein 3 (TNFAIP3; also known as A20) negatively regulates NF-κB and MAPK signals to control inflammatory responses. TNFAIP3 also protects against TNF-induced cell death. Intestinal epithelial cell (IEC) expression of TNFAIP3 improves barrier function and tight junction integrity and prevents dextran sulfate sodium (DSS)-induced IEC death and colitis. We therefore investigated the effects of TNFAIP3 expression in IEC on immune homeostasis in the intestines of immune-compromised mice. Villin-TNFAIP3 (v-TNFAIP3) transgenic mice were interbred with IL-10−/− mice (v-TNFAIP3 × IL-10−/−) and incidence, onset, and severity of colitis was assessed. v-TNFAIP3 × IL-10−/− mice displayed severe, early onset, and highly penetrant colitis that was not observed in IL-10−/− or v-TNFAIP3 mice. V-TNFAIP3 mice displayed altered expression of mucosal cytokines, increased numbers of mucosal regulatory T cells, and altered expression of mucosal antimicrobial peptides (AMPs). Microbial colonization of the inner mucus layer of v-TNFAIP3 mice was observed, along with alterations in the microbiome, but this was not sufficient to induce colitis in v-TNFAIP3 mice. The relative sterility of the inner mucus layer observed in wild-type and IL-10−/− mice was lost in v-TNFAIP3 × IL-10−/− mice. Thus IEC-derived factors, induced by signals that are inhibited by TNFAIP3, suppress the onset of inflammatory bowel disease in IL-10−/− mice. Our results indicate that IEC expression of TNFAIP3 alters AMP expression and allows microbial colonization of the inner mucus layer, which activates an IL-10-dependent anti-inflammatory process that is necessary to prevent colitis. PMID:25234043

  16. Effect of N-acetylcysteine on the murine model of colitis induced by dextran sodium sulfate through up-regulating PON1 activity.

    PubMed

    You, Yu; Fu, Jian-Jiang; Meng, Jun; Huang, Guo-Dong; Liu, Yu-Hui

    2009-08-01

    Reactive oxygen species (ROS) are increased in inflammatory bowel disease (IBD) and have been implicated as mediators of intestinal inflammation. We investigated the hypothesis that N-acetylcysteine (NAC) as a glutathione (GSH) precursor attenuates disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model. A colitis model was induced by adding 5% DSS into the drinking water for 7 days. BALB/c mice were injiciatur enema with saline, 5-ASA, N-acetylcysteine, respectively, and free drinking water as control group. DSS-treated mice developed severe colitis as shown by bloody diarrhea, weight loss, and pathologic involvement. Colon lengths were significantly decreased in DSS-treated mice with decreased GSH activity too (P < 0.01). ROS in the colon, the level of interleukin 1 beta (IL-1 beta) in colonic mucosa, serum tumor necrosis factor a (TNF-alpha), MPO, and MDA were significantly increased in DSS-treated animals (P < 0.01), with decreased PON1 activity (P < 0.01). However, NAC significantly decreased colonic MPO activity, ROS, TNF-alpha and IL-1 beta levels and increased PON1 activity and GSH concentration. Moreover, NAC attenuated the macroscopic colonic damage and the histopathologic changes-induced by DSS while similar to 5-ASA group. These results suggest that NAC may be effective in the treatment of colitis through its up-regulating PON1 and scavenging oxygen-derived free radicals. PMID:19034653

  17. An experimental model of colitis induced by dextran sulfate sodium from acute progresses to chronicity in C57BL/6: correlation between conditions of mice and the environment

    PubMed Central

    Taghipour, Niloofar; Molaei, Mahsa; Mosaffa, Nariman; Rostami-Nejad, Mohammad; Asadzadeh Aghdaei, Hamid; Anissian, Ali; Azimzadeh, Pedram; Zali, Mohammad Reza

    2016-01-01

    Aim: To induce acute colitis progresses to chronicity in C57BL/6 mice by dextran sulfate sodium. Background: Murine models are essential tools to understand IBD pathogenesis. Among different types of chemically induced colitis models, the dextran sulfate sodium (DSS)-induced colitis model is the most common model of IBD, due to its simplicity. Patients and methods: Male C57BL/6 mice 6–8 weeks old, were collected and matched by age with controls. C57BL/6 mice treated with 2 cycles of 3.5% DSS for 4 days and 4 days of pure water between each cycle. After that, mice were sacrificed and the entire colon was removed. Small sections of the colon were fixed in formaldehyde, embedded in paraffin and sectioned with a microtome. Sections were stained with hematoxylin eosin to analyses the degree of inflammation. Results: After the first cycle oral administration of DSS, mice with severe and visible rectal bleeding and diarrhea entered into the acute phase. After day 4-5, bleeding and diarrhea were improved and mice entered into the chronic phase with peak levels of weight loss. Macroscopically, the inflammation was predominantly located in the distal colon. Microscopically, examination of the distal colon sections showed a decrease number of goblet cells, loss of crypts, signs of surface epithelial regeneration and moderate to severe infiltration of inflammatory cells in the mucosa. Conclusion: In order to achieve an experimental colitis model, our protocol is recommended for future therapies in IBD experimental modeling. PMID:26744614

  18. Gingko biloba extract (Ginaton) ameliorates dextran sulfate sodium (DSS)-induced acute experimental colitis in mice via reducing IL-6/STAT3 and IL-23/IL-17

    PubMed Central

    Sun, Yan; Lin, Lian-Jie; Lin, Yan; Sang, Li-Xuan; Jiang, Min; Zheng, Chang-Qing

    2015-01-01

    This study explored the underlying mechanism of Gingko biloba extract (Ginaton) on dextran sulfate sodium (DSS)-induced acute experimental colitis in mice. 40 male C57BL/6 mice were randomly divided into four groups: normal control group, Ginaton group, Ginaton treatment group, and DSS group. After 7 days administration, mice were sacrificed and colons were collected for H-E staining, immunohistochemistry, real-time PCR and Western blot. By observing clinical disease activity and histological damage, we assessed the effect of Ginaton on DSS-induced acute experimental colitis in mice and observed the effect of Ginaton on normal mice. We also explored the specific mechanism of Ginaton on DSS-induced acute experimental colitis in mice through examining the expression of inflammatory related mediators (gp130, STAT3, p-STAT3, ROR-γt) and cytokines (IL-6, IL-17, IL-23). Ginaton-treated DSS mice showed significant improvement over untreated DSS mice. Specifically, Ginaton improved clinical disease activity (DAI score, weight closs, colon shortening, and bloody stool) and histological damage, and reduced the expression of inflammatory-related mediators (p-STAT3, gp130, ROR-γt) and cytokines (IL-6, IL-17, IL-23). In addition, clinical disease activity, histological damage, the expression of inflammatory related mediators (STAT3, p-STAT3, gp130, ROR-t) and cytokines (IL-6, IL-17, IL-23) in mice of Ginaton group were similar to normal control group. In conclusion, Ginaton ameliorates DSS-induced acute experimental colitis in mice by reducing IL-17 production, which is at least partly involved in inhibiting IL-6/STAT3 signaling pathway and IL-23/IL-17 axis. Moreover, Ginaton itself does not cause inflammatory change in normal mice. These results support that Ginaton can be as a potential clinical treatment for ulcerative colitis (UC). PMID:26770316

  19. Ablation of peroxiredoxin II attenuates experimental colitis by increasing FoxO1-induced Foxp3+ regulatory T cells.

    PubMed

    Won, Hee Yeon; Jang, Eun Jung; Lee, Kihyun; Oh, Sera; Kim, Hyo Kyung; Woo, Hyun Ae; Kang, Sang Won; Yu, Dae-Yeul; Rhee, Sue-Goo; Hwang, Eun Sook

    2013-10-15

    Peroxiredoxin (Prx) II is an intracellular antioxidant molecule that eliminates hydrogen peroxide, employing a high substrate-binding affinity. PrxII deficiency increases the levels of intracellular reactive oxygen species in many types of cells, which may increase reactive oxygen species-mediated inflammation. In this study, we investigated the susceptibility of PrxII knockout (KO) mice to experimentally induced colitis and the effects of PrxII on the immune system. Wild-type mice displayed pronounced weight loss, high mortality, and colon shortening after dextran sulfate sodium administration, whereas colonic inflammation was significantly attenuated in PrxII KO mice. Although macrophages were hyperactivated in PrxII KO mice, the amount of IFN-γ and IL-17 produced by CD4(+) T cells was substantially reduced. Foxp3(+) regulatory T (Treg) cells were elevated, and Foxp3 protein expression was increased in the absence of PrxII in vitro and in vivo. Restoration of PrxII into KO cells suppressed the increased Foxp3 expression. Interestingly, endogenous PrxII was inactivated through hyperoxidation during Treg cell development. Furthermore, PrxII deficiency stabilized FoxO1 expression by reducing mouse double minute 2 homolog expression and subsequently activated FoxO1-mediated Foxp3 gene transcription. PrxII overexpression, in contrast, reduced FoxO1 and Foxp3 expression. More interestingly, adoptive transfer of naive CD4(+) T cells from PrxII KO mice into immune-deficient mice attenuated T cell-induced colitis, with a reduction in mouse double minute 2 homolog expression and an increase in FoxO1 and Foxp3 expression. These results suggest that inactivation of PrxII is important for the stability of FoxO1 protein, which subsequently mediates Foxp3(+) Treg cell development, thereby attenuating colonic inflammation. PMID:24048895

  20. Oral administration of fermented wild ginseng ameliorates DSS-induced acute colitis by inhibiting NF-κB signaling and protects intestinal epithelial barrier

    PubMed Central

    Seong, Myeong A; Woo, Jong Kyu; Kang, Ju-Hee; Jang, Yeong Su; Choi, Seungho; Jang, Young Saeng; Lee, Taek Hwan; Jung, Kyung Hoon; Kang, Dong Kyu; Hurh, Byung Seok; Kim, Dae Eung; Kim, Sun Yeou; Oh, Seung Hyun

    2015-01-01

    Ginseng has been widely used for therapeutic and preventive purposes for thousands of years. However, orally administered ginseng has very low bioavailability and absorption in the intestine. Therefore, fermented ginseng was developed to enhance the beneficial effects of ginseng in the intestine. In this study, we investigated the molecular mechanisms underlying the anti-inflammatory activity of fermented wild ginseng (FWG). We found that FWG significantly alleviated the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis mouse model, and decreased expression level of pro-inflammatory cytokines in colonic tissue. Moreover, we observed that FWG suppressed the infiltration of macrophages in DSS-induced colitis. FWG also attenuated the transcriptional activity of nuclear factor-κB (NF-κB) by reducing the translocation of NF-κB into the nucleus. Our data indicate that FWG contains anti-inflammatory activity via NF-κB inactivation and could be useful for treating colitis. [BMB Reports 2015; 48(7): 419-425] PMID:25936779

  1. Resveratrol Pretreatment Ameliorates TNBS Colitis in Rats

    PubMed Central

    Yildiz, Gulserap; Yildiz, Yuksel; Ulutas, Pinar A.; Yaylali, Aslı; Ural, Muruvvet

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar-Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments. PMID:26246013

  2. Resveratrol Pretreatment Ameliorates TNBS Colitis in Rats.

    PubMed

    Yildiz, Gulserap; Yildiz, Yuksel; Ulutas, Pinar A; Yaylali, Asl; Ural, Muruvvet

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar-Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments. PMID:26246013

  3. Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses.

    PubMed

    Li, Yan-Hong; Xiao, Hai-Tao; Hu, Dong-Dong; Fatima, Sarwat; Lin, Cheng-Yuan; Mu, Huai-Xue; Lee, Nikki P; Bian, Zhao-Xiang

    2016-08-01

    Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4(+) cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4(+) cells of spleens and MLNs caused by DSS were significantly

  4. [Ulcerative colitis].

    PubMed

    Lopetuso, Loris; Gasbarrini, Antonio

    2016-06-01

    Inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory disorders of the digestive tract resulting from dysregulated immune responses toward environmental factors in genetically predisposed individuals. This review focus on what is the state of the art of UC pathophysiology, diagnosis, and treatment and how any future findings could drive our clinical practice. PMID:27362722

  5. Iron supplementation increases disease activity and vitamin E ameliorates the effect in rats with dextran sulfate sodium-induced colitis.

    PubMed

    Carrier, Julie; Aghdassi, Elaheh; Cullen, Jim; Allard, Johane P

    2002-10-01

    Inflammatory bowel disease is often associated with iron deficiency anemia and oral iron supplementation may be required. However, iron may increase oxidative stress through the Fenton reaction and thus exacerbate the disease. This study was designed to determine in rats with dextran sulfate sodium (DSS)-induced colitis whether oral iron supplementation increases intestinal inflammation and oxidative stress and whether the addition of an antioxidant, vitamin E, would reduce this detrimental effect. Four groups of rats that consumed 50 g/L DSS in drinking water were studied for 7 d and were fed: a control, nonpurified diet (iron, 270 mg, and dl-alpha-tocopherol acetate, 49 mg/kg); diet + iron (iron, 3000 mg/kg); diet + vitamin E (dl-alpha-tocopherol acetate, 2000 mg/kg) and the diet + both iron and vitamin E, each at the same concentrations as above. Body weight change, rectal bleeding, histological scores, plasma and colonic lipid peroxides (LPO), plasma 8-isoprostane, colonic glutathione peroxidase (GPx) and plasma vitamin E were measured. Iron supplementation increased disease activity as demonstrated by higher histological scores and heavier rectal bleeding. This was associated with an increase in colonic and plasma LPO and plasma 8-isoprostane as well as a decrease in colonic GPx. Vitamin E supplementation decreased colonic inflammation and rectal bleeding but did not affect oxidative stress, suggesting another mechanism for reducing inflammation. In conclusion, oral iron supplementation resulted in an increase in disease activity in this model of colitis. This detrimental effect on disease activity was reduced by vitamin E. Therefore, the addition of vitamin E to oral iron supplementation may be beneficial. PMID:12368409

  6. Mesalizine-Induced Acute Pancreatitis and Interstitial Pneumonitis in a Patient with Ulcerative Colitis

    PubMed Central

    Chung, Min Jae; Lee, Jae Hee

    2015-01-01

    Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease. Mesalizine for the first-line therapy of UC has adverse effects include pancreatitis, pneumonia and pericarditis. UC complicated by two coexisting conditions, however, is very rare. Moreover, drug-related pulmonary toxicity is particularly rare. An 11-year-old male patient was hospitalized for recurring upper abdominal pain after meals with vomiting, hematochezia and exertional dyspnea developing at 2 weeks of mesalizine therapy for UC. The serum level of lipase was elevated. Chest X-ray and thorax computed tomography showed interstitial pneumonitis. Mesalizine was discontinued and steroid therapy was initiated. Five days after admission, symptoms were resolved and mesalizine was resumed after a drop in amylase and lipase level. Symptoms returned the following day, however, accompanied by increased the serum levels of amylase and lipase. Mesalizine was discontinued again and recurring symptoms rapidly improved. PMID:26770905

  7. Herpes simplex induced necrotizing tonsillitis in an immunocompromised patient with ulcerative colitis.

    PubMed

    Jansen, Laura; Vos, Xander G; Löwenberg, Mark

    2016-02-16

    We here present the case of a 22-year-old female of Suriname ethnicity with ulcerative colitis who received treatment with mercaptopurine and infliximab. She presented herself with a severe necrotizing tonsillitis due to herpes simplex virus type-1 (HSV-1). Combination therapy consisting of immunomodulators and anti-tumor necrosis factor (TNF) agents is increasingly being used. Anti-TNF therapy is associated with an increased risk of developing serious infections, and especially patients receiving combination treatment with thiopurines are at an increased risk. We here show that HSV infections can cause a severe tonsillitis in immunocompromised patients. Early recognition is essential when there is no improvement with initial antibiotic therapy within the first 24 to 72 h. HSV infections should be in the differential diagnosis of immunocompromised patients presenting with a necrotizing tonsillitis and can be confirmed by polymerase chain reaction. Early treatment with antiviral agents should be considered especially if antibiotic treatment fails in such patients. PMID:26881193

  8. Herpes simplex induced necrotizing tonsillitis in an immunocompromised patient with ulcerative colitis

    PubMed Central

    Jansen, Laura; Vos, Xander G; Löwenberg, Mark

    2016-01-01

    We here present the case of a 22-year-old female of Suriname ethnicity with ulcerative colitis who received treatment with mercaptopurine and infliximab. She presented herself with a severe necrotizing tonsillitis due to herpes simplex virus type-1 (HSV-1). Combination therapy consisting of immunomodulators and anti-tumor necrosis factor (TNF) agents is increasingly being used. Anti-TNF therapy is associated with an increased risk of developing serious infections, and especially patients receiving combination treatment with thiopurines are at an increased risk. We here show that HSV infections can cause a severe tonsillitis in immunocompromised patients. Early recognition is essential when there is no improvement with initial antibiotic therapy within the first 24 to 72 h. HSV infections should be in the differential diagnosis of immunocompromised patients presenting with a necrotizing tonsillitis and can be confirmed by polymerase chain reaction. Early treatment with antiviral agents should be considered especially if antibiotic treatment fails in such patients. PMID:26881193

  9. Leech Induced Pyoderma Gangrenosum in an Ulcerative Colitis Patient: A Case Report.

    PubMed

    Sadeghi, Anahita; Navabakhsh, Behrouz; Izadi Vahedi, Niloofar

    2016-01-01

    Pyoderma gangrenosum (PG) is a painful skin lesion that results from excessive inflammatory response to a host of traumatic, inflammatory, or neoplastic processes in susceptible individuals. A clear pathogenetic mechanism as well as an exhaustive list of potential triggers for PG is yet to be fully characterized. This case documents the occurrence of pyoderma gangrenosum following leech-therapy in a patient who is a known case of ulcerative colitis and it deserves attention because leeches have been part of medical armamentarium since ancient times and have re-emerged in the last century relying on their ancient charm and modern research revealing potential benefits of several bioactive substances in their saliva. PMID:26933484

  10. Leech Induced Pyoderma Gangrenosum in an Ulcerative Colitis Patient: A Case Report

    PubMed Central

    Sadeghi, Anahita; Navabakhsh, Behrouz; Izadi Vahedi, Niloofar

    2016-01-01

    Pyoderma gangrenosum (PG) is a painful skin lesion that results from excessive inflammatory response to a host of traumatic, inflammatory, or neoplastic processes in susceptible individuals. A clear pathogenetic mechanism as well as an exhaustive list of potential triggers for PG is yet to be fully characterized. This case documents the occurrence of pyoderma gangrenosum following leech-therapy in a patient who is a known case of ulcerative colitis and it deserves attention because leeches have been part of medical armamentarium since ancient times and have re-emerged in the last century relying on their ancient charm and modern research revealing potential benefits of several bioactive substances in their saliva. PMID:26933484

  11. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats

    PubMed Central

    EL-SALHY, MAGDY; UMEZAWA, KAZUO

    2016-01-01

    The aim of the present study was to elucidate the anti-inflammatory effects of the two novel anti-inflammatory substances, 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) and dehydroxymethylepoxyquinomicin (DHMEQ), on DSS-induced colitis in rats. For this purpose, rats with dextran sulfate sodium (DSS)-induced colitis were randomly divided into 3 groups with 10 animals in each group as follows: i) the control group, which received 0.5 ml of 0.5% carboxymethyl cellulose (CMC; vehicle), ii) rats that received DTCM-G (20 mg/kg body weight in 0.5% CMC; the DTCM-G group), and iii) rats that received DHMEQ (15 mg/kg body weight in 0.5% CMC; the DHMEQ group). The animals were sacrificed after the 5-day treatment period, and tissue samples were taken from their colons and sectioned for histological evaluation. The tissue sections were stained with hematoxylin and eosin, and immunostained for leukocytes, lymphocytes, macrophages/monocytes and mast cells. The disease activity index (DAI), histological grading of colitis, and densities of several types of submucosal immune cells were compared between the controls, and the DTCM-G and DHMEQ groups. The DAI values were significantly lower in both the DTCM-G and DHMEQ groups than in the control group. The total scores for the histological grading of colitis were also significantly lower in the DTCM-G and DHMEQ groups than in the control group. The submucosal densities of leucocytes, lymphocytes, macrophages/monocytes and mast cells were significantly lower in the DTCM-G and DHMEQ groups than in the control group. Our findings indicate that the anti-inflammatory and anticancer effects of DTCM-G and DHMEQ, and the absence of any associated toxicity render them excellent therapeutic candidates for clinical use in the treatment of colitis. PMID:27082818

  12. Implication of TNF-alpha convertase (TACE/ADAM17) in inducible nitric oxide synthase expression and inflammation in an experimental model of colitis.

    PubMed

    Colón, A L; Menchén, L A; Hurtado, O; De Cristóbal, J; Lizasoain, I; Leza, J C; Lorenzo, P; Moro, M A

    2001-12-21

    Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-alpha convertase (TACE; ADAM17). TNF-alpha plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-alpha levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-alpha and NOx- levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-alpha. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-alpha release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-alpha release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD. PMID:11884025

  13. Dietary Supplementation with a Low Dose of Polyphenol-Rich Grape Pomace Extract Prevents Dextran Sulfate Sodium-Induced Colitis in Rats.

    PubMed

    Boussenna, Ahlem; Joubert-Zakeyh, Juliette; Fraisse, Didier; Pereira, Bruno; Vasson, Marie-Paule; Texier, Odile; Felgines, Catherine

    2016-08-01

    Evidence from several epidemiological and experimental studies points to a beneficial role of dietary polyphenols in inflammatory bowel disease. In this study, we investigate the protective effect of dietary supplementation with various amounts of a polyphenol-rich grape pomace extract (GPE) on the development of dextran sulfate sodium (DSS)-induced colitis in rats. Rats were fed 21 days on a semisynthetic diet enriched with GPE (0.1%, 0.5%, and 1%), and acute colitis was induced by DSS (40 g/L in the drinking water) administration during the last 7 days. The low GPE content in the diet (0.1%) attenuated clinical signs and colon shortening and limited DSS-induced histological lesions. GPE 0.1% also attenuated the DSS-induced increase in myeloperoxidase activity and improved superoxide dismutase activity. Higher amounts of GPE in the diet induced only weak and nonsignificant protective effects. These results suggest that consumption of a low amount of polyphenol-rich GPE helps protect against colitis development. PMID:27355494

  14. Polyphenol-rich sorghum brans alter colon microbiota and impact species diversity and species richness after multiple bouts of dextran sodium sulfate-induced colitis

    PubMed Central

    Ritchie, Lauren E.; Sturino, Joseph M.; Carroll, Raymond J.; Rooney, Lloyd W.; Azcarate-Peril, M. Andrea; Turner, Nancy D.

    2015-01-01

    The microbiota affects host health, and dysbiosis is involved in colitis. Sorghum bran influences butyrate concentrations during dextran sodium sulfate (DSS) colitis, suggesting microbiota changes. We aimed to characterize the microbiota during colitis, and ascertain if polyphenol-rich sorghum bran diets mitigate these effects. Rats (n = 80) were fed diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins), or Hi Tannin black (both) sorghum bran. Inflammation was induced three times using 3% DSS for 48 h (40 rats, 2 week separation), and the microbiota characterized by pyrosequencing. The Firmicutes/Bacteroidetes ratio was higher in Cellulose DSS rats. Colonic injury negatively correlated with Firmicutes, Actinobacteria, Lactobacillales and Lactobacillus, and positively correlated with Unknown/Unclassified. Post DSS#2, richness was significantly lower in Sumac and Hi Tannin black. Post DSS#3 Bacteroidales, Bacteroides, Clostridiales, Lactobacillales and Lactobacillus were reduced, with no Clostridium identified. Diet significantly affected Bacteroidales, Bacteroides, Clostridiales and Lactobacillus post DSS#2 and #3. Post DSS#3 diet significantly affected all genus, including Bacteroides and Lactobacillus, and diversity and richness increased. Sumac and Hi Tannin black DSS had significantly higher richness compared to controls. Thus, these sorghum brans may protect against alterations observed during colitis including reduced microbial diversity and richness, and dysbiosis of Firmicutes/Bacteroidetes. PMID:25764457

  15. Polyphenol-rich sorghum brans alter colon microbiota and impact species diversity and species richness after multiple bouts of dextran sodium sulfate-induced colitis.

    PubMed

    Ritchie, Lauren E; Sturino, Joseph M; Carroll, Raymond J; Rooney, Lloyd W; Azcarate-Peril, M Andrea; Turner, Nancy D

    2015-03-01

    The microbiota affects host health, and dysbiosis is involved in colitis. Sorghum bran influences butyrate concentrations during dextran sodium sulfate (DSS) colitis, suggesting microbiota changes. We aimed to characterize the microbiota during colitis, and ascertain if polyphenol-rich sorghum bran diets mitigate these effects. Rats (n = 80) were fed diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins), or Hi Tannin black (both) sorghum bran. Inflammation was induced three times using 3% DSS for 48 h (40 rats, 2 week separation), and the microbiota characterized by pyrosequencing. The Firmicutes/Bacteroidetes ratio was higher in Cellulose DSS rats. Colonic injury negatively correlated with Firmicutes, Actinobacteria, Lactobacillales and Lactobacillus, and positively correlated with Unknown/Unclassified. Post DSS#2, richness was significantly lower in Sumac and Hi Tannin black. Post DSS#3 Bacteroidales, Bacteroides, Clostridiales, Lactobacillales and Lactobacillus were reduced, with no Clostridium identified. Diet significantly affected Bacteroidales, Bacteroides, Clostridiales and Lactobacillus post DSS#2 and #3. Post DSS#3 diet significantly affected all genus, including Bacteroides and Lactobacillus, and diversity and richness increased. Sumac and Hi Tannin black DSS had significantly higher richness compared to controls. Thus, these sorghum brans may protect against alterations observed during colitis including reduced microbial diversity and richness, and dysbiosis of Firmicutes/Bacteroidetes. PMID:25764457

  16. Regulation of induced colonic inflammation by Lactobacillus acidophilus deficient in lipoteichoic acid.

    PubMed

    Mohamadzadeh, Mansour; Pfeiler, Erika A; Brown, Jeffrey B; Zadeh, Mojgan; Gramarossa, Matthew; Managlia, Elizabeth; Bere, Praveen; Sarraj, Bara; Khan, Mohammad W; Pakanati, Krishna Chaitanya; Ansari, M Javeed; O'Flaherty, Sarah; Barrett, Terrence; Klaenhammer, Todd R

    2011-03-15

    Imbalance in the regulatory immune mechanisms that control intestinal cellular and bacterial homeostasis may lead to induction of the detrimental inflammatory signals characterized in humans as inflammatory bowel disease. Induction of proinflammatory cytokines (i.e., IL-12) induced by dendritic cells (DCs) expressing pattern recognition receptors may skew naive T cells to T helper 1 polarization, which is strongly implicated in mucosal autoimmunity. Recent studies show the ability of probiotic microbes to treat and prevent numerous intestinal disorders, including Clostridium difficile-induced colitis. To study the molecular mechanisms involved in the induction and repression of intestinal inflammation, the phosphoglycerol transferase gene that plays a key role in lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus NCFM (NCK56) was deleted. The data show that the L. acidophilus LTA-negative in LTA (NCK2025) not only down-regulated IL-12 and TNFα but also significantly enhanced IL-10 in DCs and controlled the regulation of costimulatory DC functions, resulting in their inability to induce CD4(+) T-cell activation. Moreover, treatment of mice with NCK2025 compared with NCK56 significantly mitigated dextran sulfate sodium and CD4(+)CD45RB(high)T cell-induced colitis and effectively ameliorated dextran sulfate sodium-established colitis through a mechanism that involves IL-10 and CD4(+)FoxP3(+) T regulatory cells to dampen exaggerated mucosal inflammation. Directed alteration of cell surface components of L. acidophilus NCFM establishes a potential strategy for the treatment of inflammatory intestinal disorders. PMID:21282652

  17. Effect of venlafaxine on experimental colitis in normal and reserpinised depressed rats

    PubMed Central

    Minaiyan, Mohsen; Hajhashemi, Valiollah; Rabbani, Mohammad; Fattahian, Ehsan; Mahzouni, Parvin

    2015-01-01

    Psychological disorders such as depression have more prevalence in inflammatory bowel disease patients and can exacerbate the clinical course of the disease, so anti-depressant therapy may have a potential to positively impact the disease course. On the other hand several antidepressant drugs have shown anti-inflammatory and immunomodulatory properties. Thus, this study aimed to explore the beneficial effects of venlafaxine on experimental colitis in normal and reserpinised depressed rats. Acetic acid colitis was induced in both reserpinised and non-reserpinised rats. Reserpinised groups received reserpine at dose of 6 mg/kg i.p.1 h prior to colitis induction and then treated with venlafaxine at doses of 10, 20, 40 mg/kg given i.p. 2 h after induction of colitis and daily for 4 consecutive days. Non-reserpinised groups treated with 10, 20, 40 mg/kg venlafaxine i.p. 2 h after the induction of colitis and daily for 4 successive days. Dexamethasone (1 mg/kg, i.p.) was used as reference drug. Colonic inflammation was evaluated using macroscopic, histological and myeloperoxidase activity measurements. Results showed that reserpine at dose of 6 mg/kg exacerbated the colitis damage. Compared to acetic acid control, venlafaxine at dose of 40 mg/kg as well as dexamethasone significantly improved colitis parameters in both reserpinised and non-reserpinised animals. Venlafaxine reduced inflammatory injury in this animal model of induced ulcerative colitis. These effects are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug. PMID:26600857

  18. Genetic Deletion of Klf4 in the Mouse Intestinal Epithelium Ameliorates Dextran Sodium Sulfate–induced Colitis by Modulating the NF-κB Pathway Inflammatory Response

    PubMed Central

    Ghaleb, Amr M.; Laroui, Hamed; Merlin, Didier; Yang, Vincent W.

    2014-01-01

    Background Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor expressed in the differentiated epithelial cells lining of the intestine. Under physiological conditions, KLF4 inhibits cell proliferation. Conversely, KLF4 mediates proinflammatory signaling in macrophages and its overexpression in the esophageal epithelium activates cytokines, leading to inflammation-mediated esophageal squamous cell cancer formation in mice. Here, we tested whether KLF4 has a proinflammatory activity in experimental colitis in mice. Methods Villin-Cre;Klf4fl/fl mice with intestine-specific Klf4 deletion (Klf4ΔIS) and control mice with floxed Klf4 gene (Klf4fl/fl) were treated or not with 3% dextran sodium sulfate (DSS) for 7 days to induce colitis. Additionally, WT mice were administered or not, nanoparticles loaded with scrambled or Klf4-siRNA, and concomitantly given DSS. Results Compared with DSS-treated Klf4fl/fl mice, DSS-treated Klf4ΔIS mice were significantly less sensitive to DSS-induced colitis. DSS treatment of Klf4fl/fl mice induced Klf4 expression in the crypt zone of the colonic epithelium. DSS-treated Klf4ΔIS mice had increased proliferation relative to DSS-treated control mice. DSS treatment induced NF-κB signaling pathway in Klf4fl/fl mice colon but not Klf4ΔIS mice. Additionally, WT mice given DSS and nanoparticle/Klf4-siRNA were less sensitive to colitis and had reduced Klf4 expression and while maintaining the proliferative response in the colonic epithelium. Conclusions Our results indicate that Klf4 is an important mediator of DSS-induced colonic inflammation by modulating NF-κB signaling pathway and could be involved in the pathogenesis and/or propagation of inflammatory bowel disease. Thus, Klf4 may represent a novel therapeutic target in inflammatory bowel disease. PMID:24681655

  19. Tumor necrosis factor-α-induced colitis increases NADPH oxidase 1 expression, oxidative stress, and neutrophil recruitment in the colon: preventive effect of apocynin.

    PubMed

    Mouzaoui, Souad; Djerdjouri, Bahia; Makhezer, Nesrine; Kroviarski, Yolande; El-Benna, Jamel; Dang, Pham My-Chan

    2014-01-01

    Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). Intraperitoneal injection of TNFα (10 μg · kg(-1)) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFα-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFα-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFα challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. PMID:25276054

  20. Tumor Necrosis Factor-α-Induced Colitis Increases NADPH Oxidase 1 Expression, Oxidative Stress, and Neutrophil Recruitment in the Colon: Preventive Effect of Apocynin

    PubMed Central

    Mouzaoui, Souad; Djerdjouri, Bahia; Makhezer, Nesrine; Kroviarski, Yolande; El-Benna, Jamel; Dang, Pham My-Chan

    2014-01-01

    Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). Intraperitoneal injection of TNFα (10 μg · kg−1) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFα-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFα-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFα challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. PMID:25276054

  1. The effect of Hypericum perforatum (St. John's Wort) on experimental colitis in rat.

    PubMed

    Dost, Turhan; Ozkayran, Hakan; Gokalp, Filiz; Yenisey, Cigdem; Birincioglu, Mustafa

    2009-06-01

    The aim of the present study was to investigate the effect of Hypericum perforatum (HP) on the inflammatory and immune response of colonic mucosa in rat with induced inflammatory bowel disease and that on various enzyme activities in blood and bowel tissue. Male Wistar albino rats were divided into three main groups: control, third day, and seventh day of colitis. Third-day and seventh-day groups were divided into four subgroups. Colitis was induced in all groups except the control group by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The colitis group received saline; treatment groups received HP extract (50, 150, and 300 mg/kg/day, respectively). Glutathione (GSH), catalase (CAT), and malondialdehyde (MDA) activities in blood were measured. Catalase, myeloperoxidase (MPO), glutathione peroxidase (GSH-Px), glutathione reductase (GR), malondialdehyde, and nitric oxide (NO) activities were measured from tissue samples. Colonic damage was significantly reduced by HP extract. Macroscopic scoring of colonic damage significantly reduced in groups given HP extract compared with in the colitis group (P < 0.001). Blood catalase levels were reduced in the HP (150 mg/kg/day) compared with the colitis group (P < 0.01). Blood GSH levels significantly increased in groups treated with HP compared with control (P < 0.001) on the third and seventh day. Tissue GR levels reduced in the colitis and HP (50 mg/kg/day) groups compared with control (P < 0.05). Tissue MPO activity increased in the colitis and treatment groups compared with control (P < 0.007). GSH-Px levels increased in the colitis group compared with control at day 3 (P = 0.006). HP has a protective effect on TNBS-induced inflammatory bowel disease (IBD), probably due to an anti-inflammatory and antioxidant mechanism. PMID:18754092

  2. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis

    PubMed Central

    Masterson, Joanne C; McNamee, Eóin N; Fillon, Sophie A; Hosford, Lindsay; Harris, Rachel; Fernando, Shahan D; Jedlicka, Paul; Iwamoto, Ryo; Jacobsen, Elizabeth; Protheroe, Cheryl; Eltzschig, Holger K; Colgan, Sean P; Arita, Makoto; Lee, James J; Furuta, Glenn T

    2015-01-01

    Objective Eosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice. Design Acute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy. Results Eosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration. Conclusions Eosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid

  3. Octreotide effectively decreases mucosal damage in experimental colitis.

    PubMed Central

    Eliakim, R; Karmeli, F; Okon, E; Rachmilewitz, D

    1993-01-01

    The effect of octreotide, a synthetic analogue of somatostatin, on the modulation of the acetic acid model of experimental colitis was examined. Colitis was induced by intracolonic administration of 2 ml of 5% acetic acid. The inflammatory response elicited by the acetic acid resulted in increased colonic synthesis of platelet activating factor, leukotriene B4 and decreased mucosal somatostatin levels. Subcutaneous administration of octreotide (10 micrograms/rat) 1 hour before or immediately after damage induction, as well as 1 and 23 hours after acetic acid application, resulted in a significant reduction in mucosal damage. The protective effect was accompanied by a significant reduction in platelet activating factor activity, leukotriene B4, and vasoactive intestinal peptide concentrations. There were no significant changes in mucosal leukotriene C4 and calcitonin gene related peptide levels. This study shows that acetic acid induced colitis is pharmacologically manipulated by octreotide. The mechanism of action of octreotide has not yet been fully determined. The potential use of octreotide in treating active inflammatory bowel disease remains to be evaluated. Images Figure 5 PMID:8381760

  4. Ischemic Colitis

    PubMed Central

    FitzGerald, James F.; Hernandez III, Luis O.

    2015-01-01

    Most clinicians associate ischemic colitis with elderly patients who have underlying cardiovascular comorbidities. While the majority of cases probably occur in this population, the disease can present in younger patients as a result of different risk factors, making the diagnosis challenging. While a majority of patients respond to medical management, surgery is required in approximately 20% of the cases and is associated with high morbidity and mortality. PMID:26034405

  5. Bifidobacterium longum CCM 7952 Promotes Epithelial Barrier Function and Prevents Acute DSS-Induced Colitis in Strictly Strain-Specific Manner

    PubMed Central

    Srutkova, Dagmar; Schwarzer, Martin; Hudcovic, Tomas; Zakostelska, Zuzana; Drab, Vladimir; Spanova, Alena; Rittich, Bohuslav; Kozakova, Hana; Schabussova, Irma

    2015-01-01

    Background Reduced microbial diversity has been associated with inflammatory bowel disease (IBD) and probiotic bacteria have been proposed for its prevention and/or treatment. Nevertheless, comparative studies of strains of the same subspecies for specific health benefits are scarce. Here we compared two Bifidobacterium longum ssp. longum strains for their capacity to prevent experimental colitis. Methods Immunomodulatory properties of nine probiotic bifidobacteria were assessed by stimulation of murine splenocytes. The immune responses to B. longum ssp. longum CCM 7952 (Bl 7952) and CCDM 372 (Bl 372) were further characterized by stimulation of bone marrow-derived dendritic cell, HEK293/TLR2 or HEK293/NOD2 cells. A mouse model of dextran sulphate sodium (DSS)-induced colitis was used to compare their beneficial effects in vivo. Results The nine bifidobacteria exhibited strain-specific abilities to induce cytokine production. Bl 372 induced higher levels of both pro- and anti-inflammatory cytokines in spleen and dendritic cell cultures compared to Bl 7952. Both strains engaged TLR2 and contain ligands for NOD2. In a mouse model of DSS-induced colitis, Bl 7952, but not Bl 372, reduced clinical symptoms and preserved expression of tight junction proteins. Importantly, Bl 7952 improved intestinal barrier function as demonstrated by reduced FITC-dextran levels in serum. Conclusions We have shown that Bl 7952, but not Bl 372, protected mice from the development of experimental colitis. Our data suggest that although some immunomodulatory properties might be widespread among the genus Bifidobacterium, others may be rare and characteristic only for a specific strain. Therefore, careful selection might be crucial in providing beneficial outcome in clinical trials with probiotics in IBD. PMID:26218526

  6. Oral administration of Lactobacillus paracasei alleviates clinical symptoms of colitis induced by dextran sulphate sodium salt in BALB/c mice.

    PubMed

    Pan, T; Guo, H Y; Zhang, H; Liu, A P; Wang, X X; Ren, F Z

    2014-09-01

    The aim of this study was to investigate the alleviating effect of Lactobacillus paracasei subsp. paracasei LC-01 (LC-01) on the murine model of colitis induced by dextran sulphate sodium (DSS). 50 pathogen-free, 6-week-old male BALB/c mice were divided randomly into 5 groups, including a control group and four DSS-LC-01-treated groups (DSS, DSS-106, DSS-108, and DSS-1010 with 0, 1×106, 1×108 and 1×1010 cfu/ml LC-01, respectively). To test the effectiveness of LC-01 as a prophylactic it was administered for 7 days before the onset of the disease in DSS-LC-01-treated mice. After 7 days, colitis was induced by administration of 2.5% (w/v) DSS in drinking water for a further 7 days. The disease activity index (DAI), histological score, myeloperoxidase (MPO) activity and the level of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor α (TNF-α) were measured. DAI, histological scores and MPO activity of mice treated with a medium or high dose of LC-01 were significantly lower compared to a low-dose of LC-01 and DSS treatment alone (P<0.05). Colon length shortening could be prevented with increasing dose of LC-01. In addition, the levels of IL-1β and TNF-α were suppressed significantly by treatment with a medium and high dose of LC-01. However, no significant difference in the indices mentioned above were observed between a low dose of LC-01 and treatment with DSS alone (P≯0.05). An appropriate dose of LC-01 can prevent intestinal damage in mice with DSS-induced colitis. The expression of inflammatory cytokines related to pathogenesis of DSS-induced colitis decreased following treatment with LC-01. PMID:24889889

  7. Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis.

    PubMed

    Qiu, Xinyun; Zhang, Feng; Yang, Xi; Wu, Na; Jiang, Weiwei; Li, Xia; Li, Xiaoxue; Liu, Yulan

    2015-01-01

    Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS)-colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS-colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-β-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis. PMID:26013555

  8. Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to Citrobacter rodentium-induced colitis.

    PubMed

    Ryz, Natasha R; Lochner, Arion; Bhullar, Kirandeep; Ma, Caixia; Huang, Tina; Bhinder, Ganive; Bosman, Else; Wu, Xiujuan; Innis, Sheila M; Jacobson, Kevan; Vallance, Bruce A

    2015-11-01

    Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver. Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β, IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense. PMID:26336925

  9. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.

    PubMed

    Barrett, Caitlyn W; Reddy, Vishruth K; Short, Sarah P; Motley, Amy K; Lintel, Mary K; Bradley, Amber M; Freeman, Tanner; Vallance, Jefferson; Ning, Wei; Parang, Bobak; Poindexter, Shenika V; Fingleton, Barbara; Chen, Xi; Washington, Mary K; Wilson, Keith T; Shroyer, Noah F; Hill, Kristina E; Burk, Raymond F; Williams, Christopher S

    2015-07-01

    Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions. PMID:26053663

  10. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage

    PubMed Central

    Barrett, Caitlyn W.; Reddy, Vishruth K.; Short, Sarah P.; Motley, Amy K.; Lintel, Mary K.; Bradley, Amber M.; Freeman, Tanner; Vallance, Jefferson; Ning, Wei; Parang, Bobak; Poindexter, Shenika V.; Fingleton, Barbara; Chen, Xi; Washington, Mary K.; Wilson, Keith T.; Shroyer, Noah F.; Hill, Kristina E.; Burk, Raymond F.; Williams, Christopher S.

    2015-01-01

    Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions. PMID:26053663

  11. The noncommensal bacterium Methylococcus capsulatus (Bath) ameliorates dextran sulfate (Sodium Salt)-Induced Ulcerative Colitis by influencing mechanisms essential for maintenance of the colonic barrier function.

    PubMed

    Kleiveland, Charlotte R; Hult, Lene T Olsen; Spetalen, Signe; Kaldhusdal, Magne; Christofferesen, Trine Eker; Bengtsson, Oskar; Romarheim, Odd Helge; Jacobsen, Morten; Lea, Tor

    2013-01-01

    Dietary inclusion of a bacterial meal has recently been shown to efficiently abolish soybean meal-induced enteritis in Atlantic salmon. The objective of this study was to investigate whether inclusion of this bacterial meal in the diet could abrogate disease development in a murine model of epithelial injury and colitis and thus possibly have therapeutic potential in human inflammatory bowel disease. C57BL/6N mice were fed ad libitum a control diet or an experimental diet containing 254 g/kg of body weight BioProtein, a bacterial meal consisting of Methylococcus capsulatus (Bath), together with the heterogenic bacteria Ralstonia sp., Brevibacillus agri, and Aneurinibacillus sp. At day 8, colitis was induced by 3.5% dextran sulfate sodium (DSS) ad libitum in the drinking water for 6 days. Symptoms of DSS treatment were less profound after prophylactic treatment with the diet containing the BioProtein. Colitis-associated parameters such as reduced body weight, colon shortening, and epithelial damage also showed significant improvement. Levels of acute-phase reactants, proteins whose plasma concentrations increase in response to inflammation, and neutrophil infiltration were reduced. On the other, increased epithelial cell proliferation and enhanced mucin 2 (Muc2) transcription indicated improved integrity of the colonic epithelial layer. BioProtein mainly consists of Methylococcus capsulatus (Bath) (88%). The results that we obtained when using a bacterial meal consisting of M. capsulatus (Bath) were similar to those obtained when using BioProtein in the DSS model. Our results show that a bacterial meal of the noncommensal bacterium M. capsulatus (Bath) has the potential to attenuate DSS-induced colitis in mice by enhancing colonic barrier function, as judged by increased epithelial proliferation and increased Muc2 transcription. PMID:23064342

  12. The Noncommensal Bacterium Methylococcus capsulatus (Bath) Ameliorates Dextran Sulfate (Sodium Salt)-Induced Ulcerative Colitis by Influencing Mechanisms Essential for Maintenance of the Colonic Barrier Function

    PubMed Central

    Hult, Lene T. Olsen; Spetalen, Signe; Kaldhusdal, Magne; Christofferesen, Trine Eker; Bengtsson, Oskar; Romarheim, Odd Helge; Jacobsen, Morten; Lea, Tor

    2013-01-01

    Dietary inclusion of a bacterial meal has recently been shown to efficiently abolish soybean meal-induced enteritis in Atlantic salmon. The objective of this study was to investigate whether inclusion of this bacterial meal in the diet could abrogate disease development in a murine model of epithelial injury and colitis and thus possibly have therapeutic potential in human inflammatory bowel disease. C57BL/6N mice were fed ad libitum a control diet or an experimental diet containing 254 g/kg of body weight BioProtein, a bacterial meal consisting of Methylococcus capsulatus (Bath), together with the heterogenic bacteria Ralstonia sp., Brevibacillus agri, and Aneurinibacillus sp. At day 8, colitis was induced by 3.5% dextran sulfate sodium (DSS) ad libitum in the drinking water for 6 days. Symptoms of DSS treatment were less profound after prophylactic treatment with the diet containing the BioProtein. Colitis-associated parameters such as reduced body weight, colon shortening, and epithelial damage also showed significant improvement. Levels of acute-phase reactants, proteins whose plasma concentrations increase in response to inflammation, and neutrophil infiltration were reduced. On the other, increased epithelial cell proliferation and enhanced mucin 2 (Muc2) transcription indicated improved integrity of the colonic epithelial layer. BioProtein mainly consists of Methylococcus capsulatus (Bath) (88%). The results that we obtained when using a bacterial meal consisting of M. capsulatus (Bath) were similar to those obtained when using BioProtein in the DSS model. Our results show that a bacterial meal of the noncommensal bacterium M. capsulatus (Bath) has the potential to attenuate DSS-induced colitis in mice by enhancing colonic barrier function, as judged by increased epithelial proliferation and increased Muc2 transcription. PMID:23064342

  13. Effects of natural raw meal (NRM) on high-fat diet and dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice

    PubMed Central

    Shin, Sung-Ho; Song, Jia-Le; Park, Myoung-Gyu; Park, Mi-Hyun; Hwang, Sung-Joo

    2015-01-01

    BACKGROUND/OBJECTIVES Colitis is a serious health problem, and chronic obesity is associated with the progression of colitis. The aim of this study was to determine the effects of natural raw meal (NRM) on high-fat diet (HFD, 45%) and dextran sulfate sodium (DSS, 2% w/v)-induced colitis in C57BL/6J mice. MATERIALS/METHODS Body weight, colon length, and colon weight-to-length ratio, were measured directly. Serum levels of obesity-related biomarkers, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), insulin, leptin, and adiponectin were determined using commercial kits. Serum levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were detected using a commercial ELISA kit. Histological study was performed using a hematoxylin and eosin (H&E) staining assay. Colonic mRNA expressions of TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were determined by RT-PCR assay. RESULTS Body weight and obesity-related biomarkers (TG, TC, LDL, HDL, insulin, leptin, and adiponectin) were regulated and obesity was prevented in NRM treated mice. NRM significantly suppressed colon shortening and reduced colon weight-to-length ratio in HFD+DSS induced colitis in C57BL/6J mice (P < 0.05). Histological observations suggested that NRM reduced edema, mucosal damage, and the loss of crypts induced by HFD and DSS. In addition, NRM decreased the serum levels of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6 and inhibited the mRNA expressions of these cytokines, and iNOS and COX-2 in colon mucosa (P < 0.05). CONCLUSION The results suggest that NRM has an anti-inflammatory effect against HFD and DSS-induced colitis in mice, and that these effects are due to the amelioration of HFD and/or DSS-induced inflammatory reactions. PMID:26634051

  14. Matrine ameliorates spontaneously developed colitis in interleukin-10-deficient mice.

    PubMed

    Wu, Cong; Xu, Zheng; Gai, Renhua; Huang, Kehe

    2016-07-01

    Interleukin-10 (IL-10)-deficient mice spontaneously develop T cell-mediated colitis. Previous reports have shown that Matrine may reduce the symptoms of acute colitis induced by trinitrobenzene sulfonic acid (TNBS). However, whether Matrine impacts chronic colitis remains unknown. In this study, we investigated whether Matrine could limit the symptoms of spontaneously developed colitis and its potential molecular mechanisms. IL-10 deficient mice were given Matrine or a PBS control by oral gavage daily for 4weeks and were euthanized at week 2 or week 4. We measured body weight, colon length and weight, and histological scores. We also evaluated the spontaneous secretion of IL-12/23p40, IFN-γ and IL-17 in colon explant cultures as well as IFN-γ and IL-17 secretion in unseparated mesenteric lymph node (MLN) cells, and assessed IFN-γ, IL-17, IL-1β and IL-6 mRNA expression in colon tissue. In addition, we analyzed the proportions of CD4-positive and CD8-positive cells in unseparated MLN cells. Our results show that Matrine-treated mice exhibited better body weight recovery than controls and that histological scores and spontaneously secreted IL-12/23p40, IFN-γ and IL-17 in colon tissue were significantly decreased in treated mice compared with controls. The proportion of CD4-positive cells of MLNs in treated mice was significantly smaller than that in controls at week 4. Both cytokine production and mRNA expression of IFN-γ and IL-17 were significantly reduced in treated mice compared with controls. Taken together, our results indicate that Matrine may ameliorate spontaneously developed chronic colitis and could be considered as a therapeutic alternative for chronic colitis. PMID:27179305

  15. DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model.

    PubMed

    Achiwa, Koichi; Ishigami, Masatoshi; Ishizu, Yoji; Kuzuya, Teiji; Honda, Takashi; Hayashi, Kazuhiko; Hirooka, Yoshiki; Katano, Yoshiaki; Goto, Hidemi

    2016-01-29

    Nonalcoholic steatohepatitis (NASH) patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Several lines of evidence indicate that accumulation of lipopolysaccharide (LPS) and disruption of gut microbiota play contributory roles in HCC. Moreover, in a dextran sodium sulfate (DSS)-induced colitis model in mice, a high-fat diet increases portal LPS level and promotes hepatic inflammation and fibrosis. However, this diet-induced NASH model requires at least 50 weeks for carcinogenesis. In this study, we sought to determine whether increased intestinal permeability would aggravate liver inflammation and fibrosis and accelerate tumorigenesis in a diet-induced NASH model. Mice were fed a choline-deficient high-fat (CDHF) diet for 4 or 12 weeks. The DSS group was fed CDHF and intermittently received 1% DSS in the drinking water. Exposure to DSS promoted mucosal changes such as crypt loss and increased the number of inflammatory cells in the colon. In the DSS group, portal LPS levels were elevated at 4 weeks, and the proportions of Clostridium cluster XI in the fecal microbiota were elevated. In addition, levels of serum transaminase, number of lobular inflammatory cells, F4/80 staining-positive area, and levels of inflammatory cytokines were all elevated in the DSS group. Liver histology in the DSS group revealed severe fibrosis at 12 weeks. Liver tumors were detected in the DSS group at 12 weeks, but not in the other groups. Thus, DSS administration promoted liver tumors in a CDHF diet-induced NASH mouse over the short term, suggesting that the induction of intestinal inflammation and gut disruption of microbiota in NASH promote hepatic tumorigenesis. PMID:26682925

  16. Histologic features associated with tritrichomonas foetus-induced colitis in domestic cats.

    PubMed

    Yaeger, M J; Gookin, J L

    2005-11-01

    Tritrichomonas foetus is a venereal pathogen of naturally bred cattle. In domestic cats, T. foetus colonizes the colon, resulting in chronic, large-bowel diarrhea. The infection is prevalent among young, densely housed cats, and there is no effective treatment. To the authors' knowledge, the characteristic microscopic lesions of T. foetus infection in naturally infected cats have not been described. The aim of the study reported here was to characterize the histologic changes in the colon of seven cats with T. foetus infection and chronic diarrhea. All cats were 1 year old or younger (mean, 6.7 +/- 1.7 months), and a diagnosis of T. foetus infection was made on the basis of direct fecal smear examination (five cats), fecal culture in InPouch TF medium (four cats), single-tube nested polymerase chain reaction (PCR) analysis of DNA extracted from feces (two cats), or observation of trichomonads in sections of colon followed by PCR confirmation on DNA extracted from paraffin-embedded tissue (two cats). The presence of colonic trichomonads was the most diagnostic histologic feature. Organisms were identified in all cats, but in only 24 of 43 (56%) sections of colon. Trichomonads were generally present in close proximity to the mucosal surface and less frequently in the lumen of colonic crypts. The presence of colonic trichomonads was consistently associated with mild-to-moderate lymphoplasmacytic and neutrophilic colitis, crypt epithelial cell hypertrophy, hyperplasia and increased mitotic activity, loss of goblet cells, crypt microabscesses, and attenuation of the superficial colonic mucosa. In two of the cats, histologic lesions were more severe and were associated with invasion of trichomonads into the lamina propria and/or deeper layers of the colon. PMID:16301576

  17. Paternal chronic colitis causes epigenetic inheritance of susceptibility to colitis.

    PubMed

    Tschurtschenthaler, Markus; Kachroo, Priyadarshini; Heinsen, Femke-Anouska; Adolph, Timon Erik; Rühlemann, Malte Christoph; Klughammer, Johanna; Offner, Felix Albert; Ammerpohl, Ole; Krueger, Felix; Smallwood, Sébastien; Szymczak, Silke; Kaser, Arthur; Franke, Andre

    2016-01-01

    Inflammatory bowel disease (IBD) arises by unknown environmental triggers in genetically susceptible individuals. Epigenetic regulation of gene expression may integrate internal and external influences and may thereby modulate disease susceptibility. Epigenetic modification may also affect the germ-line and in certain contexts can be inherited to offspring. This study investigates epigenetic alterations consequent to experimental murine colitis induced by dextran sodium sulphate (DSS), and their paternal transmission to offspring. Genome-wide methylome- and transcriptome-profiling of intestinal epithelial cells (IECs) and sperm cells of males of the F0 generation, which received either DSS and consequently developed colitis (F0(DSS)), or non-supplemented tap water (F0(Ctrl)) and hence remained healthy, and of their F1 offspring was performed using reduced representation bisulfite sequencing (RRBS) and RNA-sequencing (RNA-Seq), respectively. Offspring of F0(DSS) males exhibited aberrant methylation and expression patterns of multiple genes, including Igf1r and Nr4a2, which are involved in energy metabolism. Importantly, DSS colitis in F0(DSS) mice was associated with decreased body weight at baseline of their F1 offspring, and these F1 mice exhibited increased susceptibility to DSS-induced colitis compared to offspring from F0(Ctrl) males. This study hence demonstrates epigenetic transmissibility of metabolic and inflammatory traits resulting from experimental colitis. PMID:27538787

  18. Paternal chronic colitis causes epigenetic inheritance of susceptibility to colitis

    PubMed Central

    Tschurtschenthaler, Markus; Kachroo, Priyadarshini; Heinsen, Femke-Anouska; Adolph, Timon Erik; Rühlemann, Malte Christoph; Klughammer, Johanna; Offner, Felix Albert; Ammerpohl, Ole; Krueger, Felix; Smallwood, Sébastien; Szymczak, Silke; Kaser, Arthur; Franke, Andre

    2016-01-01

    Inflammatory bowel disease (IBD) arises by unknown environmental triggers in genetically susceptible individuals. Epigenetic regulation of gene expression may integrate internal and external influences and may thereby modulate disease susceptibility. Epigenetic modification may also affect the germ-line and in certain contexts can be inherited to offspring. This study investigates epigenetic alterations consequent to experimental murine colitis induced by dextran sodium sulphate (DSS), and their paternal transmission to offspring. Genome-wide methylome- and transcriptome-profiling of intestinal epithelial cells (IECs) and sperm cells of males of the F0 generation, which received either DSS and consequently developed colitis (F0DSS), or non-supplemented tap water (F0Ctrl) and hence remained healthy, and of their F1 offspring was performed using reduced representation bisulfite sequencing (RRBS) and RNA-sequencing (RNA-Seq), respectively. Offspring of F0DSS males exhibited aberrant methylation and expression patterns of multiple genes, including Igf1r and Nr4a2, which are involved in energy metabolism. Importantly, DSS colitis in F0DSS mice was associated with decreased body weight at baseline of their F1 offspring, and these F1 mice exhibited increased susceptibility to DSS-induced colitis compared to offspring from F0Ctrl males. This study hence demonstrates epigenetic transmissibility of metabolic and inflammatory traits resulting from experimental colitis. PMID:27538787

  19. Fucoidan Extracts Ameliorate Acute Colitis.

    PubMed

    Lean, Qi Ying; Eri, Rajaraman D; Fitton, J Helen; Patel, Rahul P; Gueven, Nuri

    2015-01-01

    Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent

  20. Fucoidan Extracts Ameliorate Acute Colitis

    PubMed Central

    Lean, Qi Ying; Eri, Rajaraman D.; Fitton, J. Helen; Patel, Rahul P.; Gueven, Nuri

    2015-01-01

    Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore

  1. Oroxyloside prevents dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB pathway through PPARγ activation.

    PubMed

    Wang, Xiaoping; Sun, Yang; Zhao, Yue; Ding, Youxiang; Zhang, Xiaobo; Kong, Lingyi; Li, Zhiyu; Guo, Qinglong; Zhao, Li

    2016-04-15

    Oroxyloside, as a metabolite of oroxylin A, may harbor various beneficial bioactivities which have rarely been reported in the previous studies. Here we established the dextran sulfate sodium (DSS)-induced experimental colitis and evaluated the anti-inflammatory effect of oroxyloside in vivo. As a result, oroxyloside attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. Furthermore, oroxyloside inhibited inflammatory cell infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well. The production of pro-inflammatory cytokines in serum and colon was also significantly reduced by oroxyloside. We unraveled the underlying mechanisms that oroxyloside inhibited NF-κB pathway by activating Peroxisome Proliferator-Activated Receptor γ (PPARγ) to attenuate DSS-induced colitis. Moreover, we investigated the anti-inflammatory effect and mechanisms of oroxyloside in the mouse macrophage cell line RAW264.7 and bone marrow derived macrophages (BMDM). Oroxyloside decreased several LPS-induced inflammatory cytokines, including IL-1β, IL-6 and TNF-α in RAW264.7 and BMDM. We also found that oroxyloside inhibited LPS-induced activation of NF-κB signaling pathway via activating PPARγ in RAW 264.7 and BMDM. Docking study showed that oroxyloside could bind with PPARγ. GW9662, the inhibitor of PPARγ, and PPARγ siRNA transfection blocked the effect of oroxyloside on PPARγ activation. Our study suggested that oroxyloside prevented DSS-induced colitis by inhibiting NF-κB pathway through PPARγ activation. Therefore, oroxyloside may be a promising and effective agent for inflammatory bowel disease (IBD). PMID:26947454

  2. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile

    PubMed Central

    Wang, Yilin; Wang, Zhengting; Pei, Yaofei; Fan, Rong; Liu, Xiqiang; Wang, Lei; Zhou, Jie; Zheng, Sichang; Zhang, Tianyu; Lin, Yun; Zhang, Maochen; Tao, Ran; Zhong, Jie

    2016-01-01

    It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation. PMID:27128484

  3. Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice.

    PubMed

    Xi, Meiyang; Ge, Jun; Wang, Xiaojian; Sun, Chenbin; Liu, Tianqi; Fang, Liang; Xiao, Qiong; Yin, Dali

    2016-07-15

    Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N'-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human. PMID:27255176

  4. TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

    PubMed Central

    Chen, Xin; Nie, Yingjie; Xiao, Haitao; Bian, Zhaoxiang; Scarzello, Anthony J.; Song, Na-Young; Anna, Trivett L.; Yang, De; Oppenheim, Joost J.

    2016-01-01

    There is now compelling evidence that TNFR2 is constitutively expressed on CD4+ Foxp3+ regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4+ Foxp3− effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2−/− mice into Rag 1−/− recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells. PMID:27601345

  5. Alteration of T cell maturation and proliferation in the mouse thymus induced by serum factors from patients with ulcerative colitis.

    PubMed Central

    Watanabe, M; Aiso, S; Hibi, T; Watanabe, N; Iwao, Y; Yoshida, T; Asakura, H; Tsuru, S; Tsuchiya, M

    1987-01-01

    Recently it has been reported that patients with ulcerative colitis (UC) often have thymus abnormalities, although the precise mechanisms which induce those abnormalities remain unclear. We have examined the effect of serum fractions from patients with UC and other colonic diseases on mouse thymus to clarify the possible existence of factors which have thymus growth activity. These fractions were separated from sera of patients with UC by gel filtration and anion exchange high performance liquid chromatography. In mice given UC serum fractions; (i) remarkable increases in weight and total cell number of the thymus were observed from day 4 to day 9; (ii) a significant increase in the number of peanut agglutinin (PNA)+ thymus cells was demonstrated using flow cytometry on day 9; (iii) on quantitative analysis of surface antigens the percentage of Lyt-2+ thymus cells decreased and that of L3T4+ thymus cells increased remarkably on day 13; the number of bright Thy-1.2+ cells and of dull Lyt-1+ cells increased. In contrast, the serum fractions from patients with other colonic diseases and from normal persons caused little change in mouse thymus throughout the study. The results suggest that factors fractionated from the serum of patients with UC disturb intra-thymic T cell maturation and enhance the proliferation of thymus cells. PMID:3498579

  6. TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis.

    PubMed

    Chen, Xin; Nie, Yingjie; Xiao, Haitao; Bian, Zhaoxiang; Scarzello, Anthony J; Song, Na-Young; Anna, Trivett L; Yang, De; Oppenheim, Joost J

    2016-01-01

    There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4(+) Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2(-/-) mice into Rag 1(-/-) recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells. PMID:27601345

  7. Probiotics increase T regulatory cells and reduce severity of experimental colitis in mice

    PubMed Central

    Zhao, Hai-Mei; Huang, Xiao-Ying; Zuo, Zhi-Qin; Pan, Qi-Hong; Ao, Mei-Ying; Zhou, Feng; Liu, Hong-Ning; Liu, Zhi-Yong; Liu, Duan-Yong

    2013-01-01

    AIM: To investigate the effect of probiotics on regulating T regulatory cells and reducing the severity of experimental colitis in mice. METHODS: Forty C57/BL mice were randomly divided into four groups. Colitis was induced in the mice using 2,4,6-trinitrobenzene sulfonic acid (TNBS). After 10-d treatment with Bifico capsules (combined bifidobacterium, lactobacillus and enterococcus), body weight, colonic weight, colonic weight index, length of colon, and histological scores were evaluated. CD4+CD25+Foxp3+T cell in mesenteric lymph nodes were measured by flow cytometry, and cytokines in colonic tissue homogenates were analyzed by a cytometric bead array. RESULTS: The colonic weight index and the colonic weight of colitis mice treated with Bifico were lower than that of TNBS-induced mice without treatment. However, colonic length and percent of body weight amplification were higher than in TNBS-induced mice without treatment. Compared with TNBS-induced mice without treatment, the level of CD4+CD25+Foxp3+T cells in mesenteric lymph nodes, the expression of interleukin (IL)-2, IL-4 and IL-10 in colonic tissues from colitis mice treated with Bifico were upregulated, and tumor necrosis factor-α and interferon-γ were downregulated. CONCLUSION: Probiotics effectively treat experimental colitis by increasing CD4+CD25+Foxp3+T cell and regulating the balance of Th1 and Th2 cytokines in the colonic mucosa. PMID:23430765

  8. Effects of the Sijunzi decoction on the immunological function in rats with dextran sulfate-induced ulcerative colitis

    PubMed Central

    YU, WANGUI; LU, BING; ZHANG, HENGWEN; ZHANG, YANXIANG; YAN, JIN

    2016-01-01

    The present study investigated the effects of the Sijunzi decoction (SJZD) at various dosages on the immunological function of rats with 3% dextran sulfate sodium (DSS; molecular weight 5,000)-induced ulcerative colitis (UC). A total of 40 male Wistar rats were randomly divided into 5 groups: Normal, model, low-dose SJZD, moderate-dose SJZD and high-dose SJZD groups. The 3% DSS was intragastrically administered for 7 consecutive days in order to induce the UC model. The normal group consumed distilled water. Subsequently, SJZD (5.0, 10.0 and 30.0 g/kg) was intragastrically administered, and scores of the disease activity index (DAI) were calculated. After 2 weeks, all the rats were sacrificed. Scores of the colon mucosa damage index (CMDI) were evaluated; and secretory immunoglobulin A (sIgA) and interleukin-2 (IL-2) were measured in intestinal tissue by ELISA assays. The model group rats had ulcers, hyperemia and interstitial edema and infiltrated inflammatory cells. SJZD attenuated the severity of the gross lesions and reduced the histopathological injuries. Compared with the normal group, DAI and CMDI were significantly increased (P<0.01), and levels of determined sIgA in the intestinal mucosa and IL-2 in the intestinal tissue were significantly decreased (P<0.05) in the model group. Compared with the model group, moderate and high doses of SJZD showed a restoration effect on all the aforementioned indexes, and the high dose was the most effective. In conclusion, SJZD can ameliorate inflammation in DSS-induced UC rats. The mechanism is most likely due to enhancing intestinal local immunity. PMID:27347409

  9. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis.

    PubMed

    Kang, Chil-Sung; Ban, Mingi; Choi, Eun-Jeong; Moon, Hyung-Geun; Jeon, Jun-Sung; Kim, Dae-Kyum; Park, Soo-Kyung; Jeon, Seong Gyu; Roh, Tae-Young; Myung, Seung-Jae; Gho, Yong Song; Kim, Jae Gyu; Kim, Yoon-Keun

    2013-01-01

    Gut microbiota play an important part in the pathogenesis of mucosal inflammation, such as inflammatory bowel disease (IBD). However, owing to the complexity of the gut microbiota, our understanding of the roles of commensal and pathogenic bacteria in the maintenance of immune homeostasis in the gut is evolving only slowly. Here, we evaluated the role of gut microbiota and their secreting extracellular vesicles (EV) in the development of mucosal inflammation in the gut. Experimental IBD model was established by oral application of dextran sulfate sodium (DSS) to C57BL/6 mice. The composition of gut microbiota and bacteria-derived EV in stools was evaluated by metagenome sequencing using bacterial common primer of 16S rDNA. Metagenomics in the IBD mouse model showed that the change in stool EV composition was more drastic, compared to the change of bacterial composition. Oral DSS application decreased the composition of EV from Akkermansia muciniphila and Bacteroides acidifaciens in stools, whereas increased EV from TM7 phylum, especially from species DQ777900_s and AJ400239_s. In vitro pretreatment of A. muciniphila-derived EV ameliorated the production of a pro-inflammatory cytokine IL-6 from colon epithelial cells induced by Escherichia coli EV. Additionally, oral application of A. muciniphila EV also protected DSS-induced IBD phenotypes, such as body weight loss, colon length, and inflammatory cell infiltration of colon wall. Our data provides insight into the role of gut microbiota-derived EV in regulation of intestinal immunity and homeostasis, and A. muciniphila-derived EV have protective effects in the development of DSS-induced colitis. PMID:24204633

  10. Salmon cartilage proteoglycan suppresses mouse experimental colitis through induction of Foxp3{sup +} regulatory T cells

    SciTech Connect

    Mitsui, Toshihito; Sashinami, Hiroshi; Sato, Fuyuki; Kijima, Hiroshi; Ishiguro, Yoh; Fukuda, Shinsaku; Yoshihara, Shuichi; Hakamada, Ken-Ichi; Nakane, Akio

    2010-11-12

    Research highlights: {yields} Salmon proteoglycan suppresses IL-10{sup -/-} cell transfer-induced colitis progression. {yields} Salmon proteoglycan suppresses Th1- and Th17-related factors in colitis mice. {yields} Salmon proteoglycan enhances Foxp3 expression. -- Abstract: Proteoglycans (PGs) are complex glycohydrates which are widely distributed in extracellular matrix (ECM). PGs are involved in the construction of ECM, cell proliferation and differentiation. ECM components are involved in transduction of proinflammatory responses, but it is still unknown whether PGs are involved in inflammatory response. In this study, we investigated the effect of PG extracted from salmon cartilage on the progression of experimental colitis-induced in severe combined immunodeficiency mice by cell transfer from interleukin-10 (IL-10){sup -/-} mice. IL-10{sup -/-} cell-transferred mice showed weight loss, colon shortening and histological appearance of mild colitis. Daily oral administration of PG attenuated the clinical progression of colitis in a dose-dependent manner. Colitis-induced mice showed the elevated expression of IFN-{gamma}, IL-12, TNF-{alpha}, IL-21, IL-23p19, IL-6, IL-17A and retinoic acid-related orphan receptor {gamma}t (ROR{gamma}t) in lamina propria mononuclear cells (LPMCs) and oral administration of PG suppressed the expression of these factors. Conversely, expression of Foxp3 that induces CD4{sup +}CD25{sup +} regulatory T cells in LPMCs was enhanced by PG administration. These findings suggested that salmon PG attenuated the progression of colitis due to suppression of inflammatory response by enhancement of regulatory T cell induction.

  11. Beneficial Effects of Maprotiline in a Murine Model of Colitis in Normal and Reserpinised Depressed Rats

    PubMed Central

    Minaiyan, Mohsen; Hajhashemi, Valiollah; Rabbani, Mohammad; Fattahian, Ehsan; Mahzouni, Parvin

    2014-01-01

    Background. Anti-inflammatory and immunomodulatory activities have been reported for maprotiline, a strong norepinephrine reuptake inhibitor. In addition, some other antidepressant drugs have shown beneficial effects in experimental colitis. Methods. All the animals were divided into normal and depressed groups. In normal rats colitis was induced by instillation of 2 mL of 4% acetic acid and after 2 hours, maprotiline (10, 20, and 40 mg/kg, i.p.) was administered. In reserpinised depressed rats, depression was induced by injection of reserpine (6 mg/kg, i.p.), 1 h prior to colitis induction, and then treated with maprotiline (10, 20, and 40 mg/kg). Treatment continued daily for four days. Dexamethasone (1 mg/kg, i.p.) was given as a reference drug. On day five following colitis induction, animals were euthanized and distal colons were assessed macroscopically, histologically, and biochemically (assessment of myeloperoxidase activity). Results. Maprotiline significantly improved macroscopic and histologic scores and diminished myeloperoxidase activity in both normal and depressed rats while reserpine exacerbated the colonic damage. Conclusion. Our data suggests that the salutary effects of maprotiline on acetic acid colitis are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug. PMID:27355055

  12. Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis

    PubMed Central

    EL-SALHY, MAGDY; UMEZAWA, KAZUO

    2016-01-01

    The aim of this study was to determine the effects of two anti-inflammatory agents on the abnormalities in colonic endocrine cells in dextran sodium sulfate (DSS)-induced colitis. Colitis was induced in male Wistar rats (n=45) using DSS; a further 15 rats without colitis were included in a healthy control group. The animals with DSS-induced colitis were randomly divided into 3 treatment groups as follows: i) DSS group, rats were treated with 0.5 ml of 0.5% carboxymethyl cellulose (CMC); ii) DSS-G group, rats were treated with 3-[(dodecyl thiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel activator protein 1 (AP-1) inhibitor, 20 mg/kg in CMC; and iii) DSS-Q group, rats were treated with dehydroxymethylepoxyquinomicin, a nuclear factor κB (NF-κB) inhibitor, 15 mg/kg in CMC. The treatments were administered intraperitoneally, twice daily for 5 days, after which the animals were sacrificed and tissue samples from the colon were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), enteroglucagon, pancreatic polypeptide (PP), somatostatin, leukocytes, B/T lymphocytes, B lymphocytes, T lymphocytes, macrophages/monocytes and mast cells. The densities of these endocrine and immune cells were quantified by computer-aided image analysis. The densities of CgA-, serotonin-, PYY- and enteroglucagon-producing cells were significantly higher, and those of PP- and somatostatin-producing cells were significantly lower in the DSS-G, DSS-Q and control groups than in the DSS group. The densities of all the immune cells were lower in the DSS-G, DSS-Q and control groups than in the DSS group. The densities of all endocrine cell types and immune cells in both the DSS groups treated with anti-inflammatory agents were restored to control levels. In conclusion, our data demonstrate that there is an interaction between endocrine and immune cells during inflammation. This interaction with subsequent changes in endocrine cells is responsible for the clinical manifestation of

  13. Effects of Antioxidant Therapy on Leukocyte Myeloperoxidase and Cu/Zn-Superoxide Dismutase and Plasma Malondialdehyde Levels in Experimental Colitis

    PubMed Central

    Belge Kurutas, Ergul; Cetinkaya, Ali; Bulbuloglu, Ertan; Kantarceken, Bulent

    2005-01-01

    The aim of the present study was to evaluate the effects of N-acetylcysteine (NAC) and L-carnitine (LCAR) supplementations on polymorphonuclear leukocytes myeloperoxidase (MPO) and Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and plasma malondialdehyde (MDA) in acetic acid (AA)-induced ulcerative colitis model. The mean polymorphonuclear leukocyte MPO and Cu/Zn-SOD activity was significantly higher in the colitis group than in the control group. Both NAC and LCAR pretreatment markedly decreased MPO and Cu/Zn-SOD activity compared to colitis group. AA administration significantly increased the levels of plasma MDA in comparison with controls. However, NAC and LCAR administration to the AA-treated rats significantly reduced the MDA levels compared to colitis group. In conclusion NAC and LCAR could be beneficial agents in restoring the circulating proinflammatory mediators. PMID:16489261

  14. Nod2 Activates NF-kB in CD4+ T Cells but Its Expression Is Dispensable for T Cell-Induced Colitis

    PubMed Central

    Zanello, Galliano; Goethel, Ashleigh; Forster, Katharina; Geddes, Kaoru; Philpott, Dana J.; Croitoru, Kenneth

    2013-01-01

    Although the etiology of Crohn's disease (CD) remains elusive this disease is characterized by T cell activation that leads to chronic inflammation and mucosal damage. A potential role for maladaptation between the intestinal microbiota and the mucosal immune response is suggested by the fact that mutations in the pattern recognition receptor Nod2 are associated with higher risks for developing CD. Although Nod2 deletion in CD4+ T cells has been shown to impair the induction of colitis in the murine T cell transfer model, the analysis of T cell intrinsic Nod2 function in T cell differentiation and T cell-mediated immunity is inconsistent between several studies. In addition, the role of T cell intrinsic Nod2 in regulatory T cell (Treg) development and function during colitis remain to be analyzed. In this study, we show that Nod2 expression is higher in activated/memory CD4+ T cells and its expression was inducible after T cell receptor (TCR) ligation. Nod2 stimulation with muramyl dipeptide (MDP) led to a nuclear accumulation of c-Rel NF-kB subunit. Although functionally active in CD4+ T cells, the deletion of Nod2 did not impair the induction and the prevention of colitis in the T cell transfer model. Moreover, Nod2 deletion did not affect the development of Foxp3+ Treg cells in the spleen of recipient mice and Nod2 deficient CD4 T cells expressing the OVA specific transgenic TCR were able to differentiate in Foxp3+ Treg cells after OVA feeding. In vitro, CD25+ Nod2 deficient T cells suppressed T cell proliferation as well as wild type counter parts and T cell stimulation with MDP did not affect the proliferation and the cytokine secretion of T cells. In conclusion, our data indicate that Nod2 is functional in murine CD4+ T cells but its expression is dispensable for the T cell regulation of colitis. PMID:24324812

  15. Microscopic colitis: A review of etiology, treatment and refractory disease.

    PubMed

    Park, Tina; Cave, David; Marshall, Christopher

    2015-08-01

    Microscopic colitis is a common cause of chronic, nonbloody diarrhea. Microscopic colitis is more common in women than men and usually affects patients in their sixth and seventh decade. This article reviews the etiology and medical management of microscopic colitis. The etiology of microscopic colitis is unknown, but it is associated with autoimmune disorders, such as celiac disease, polyarthritis, and thyroid disorders. Smoking has been identified as a risk factor of microscopic colitis. Exposure to medications, such as non-steroidal anti-inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors, is suspected to play a role in microscopic colitis, although their direct causal relationship has not been proven. Multiple medications, including corticosteroids, anti-diarrheals, cholestyramine, bismuth, 5-aminosalicylates, and immunomodulators, have been used to treat microscopic colitis with variable response rates. Budesonide is effective in inducing and maintaining clinical remission but relapse rate is as high as 82% when budesonide is discontinued. There is limited data on management of steroid-dependent microscopic colitis or refractory microscopic colitis. Immunomodulators seem to have low response rate 0%-56% for patients with refractory microscopic colitis. Response rate 66%-100% was observed for use of anti-tumor necrosis factor (TNF) therapy for refractory microscopic colitis. Anti-TNF and diverting ileostomy may be an option in severe or refractory microscopic colitis. PMID:26269669

  16. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats.

    PubMed

    El-Salhy, Magdy; Umezawa, Kazuo

    2016-06-01

    The aim of the present study was to elucidate the anti-inflammatory effects of the two novel anti-inflammatory substances, 3-[(dodecylthiocarbonyl)‑methyl]-glutarimide (DTCM-G) and dehydroxymethylepoxyquinomicin (DHMEQ), on DSS-induced colitis in rats. For this purpose, rats with dextran sulfate sodium (DSS)-induced colitis were randomly divided into 3 groups with 10 animals in each group as follows: i) the control group, which received 0.5 ml of 0.5% carboxymethyl cellulose (CMC; vehicle), ii) rats that received DTCM-G (20 mg/kg body weight in 0.5% CMC; the DTCM-G group), and iii) rats that received DHMEQ (15 mg/kg body weight in 0.5% CMC; the DHMEQ group). The animals were sacrificed after the 5-day treatment period, and tissue samples were taken from their colons and sectioned for histological evaluation. The tissue sections were stained with hematoxylin and eosin, and immunostained for leukocytes, lymphocytes, macrophages/monocytes and mast cells. The disease activity index (DAI), histological grading of colitis, and densities of several types of submucosal immune cells were compared between the controls, and the DTCM-G and DHMEQ groups. The DAI values were significantly lower in both the DTCM-G and DHMEQ groups than in the control group. The total scores for the histological grading of colitis were also significantly lower in the DTCM-G and DHMEQ groups than in the control group. The submucosal densities of leucocytes, lymphocytes, macrophages/monocytes and mast cells were significantly lower in the DTCM-G and DHMEQ groups than in the control group. Our findings indicate that the anti-inflammatory and anticancer effects of DTCM-G and DHMEQ, and the absence of any associated toxicity render them excellent therapeutic candidates for clinical use in the treatment of colitis. PMID:27082818

  17. Altered response to hydrogen sulphide during experimental colitis in rats.

    PubMed

    Steidle, J; Würner, L; Diener, M

    2012-09-10

    Hydrogen sulphide (H(2) S) is produced in the intestine by sulphate-reducing bacteria and during metabolism of L-cysteine within the mucosa. This gasotransmitter induces anion secretion by stimulating enteric neurons and by a direct effect on epithelial cells. As H(2) S is discussed to exert both pro- and anti-inflammatory actions, we aimed to investigate the role of H(2) S during experimental colitis by comparing the effects of blockade of H(2) S-forming endogenous enzymes with the effect of a S-reduced diet to diminish microbial production of H(2) S. Rectal application of trinitrobenzenesulfonic acid (TNBS) was used to induce chronic colitis. The level of inflammation was assessed macroscopically and histologically. In Ussing chamber experiments, colonic specimens from TNBS-treated animals exhibited a higher tissue conductance, that is, a higher epithelial permeability, and a slightly reduced basal short-circuit current (a measure of net ion transport) in relation to non-inflamed control tissue. Analgetic treatment with flupirtine, a central antinociceptive analgetic, did not interfere with the induction of the inflammatory response so that all animals were treated with flupirtine to reduce pain and distress during the development of colitis. The secretory response evoked by an exogenous H(2) S donor, NaHS, was significantly decreased after induction of colitis, whereas the response to Ca(2+) - or cAMP-dependent secretagogues was unaltered. This downregulation was not observed in the colitis group fed on a S-reduced diet. The decreased NaHS response indicates a desensitization of the tissue by inflammation, which might be explained by an upregulation of colonic H(2) S production as described in some models of inflammation. PMID:22963333

  18. Comparison of prophylactic and therapeutic use of short‐chain fatty acid enemas in diversion colitis: a study in Wistar rats

    PubMed Central

    de Oliveira, Ariano José Freitas; Júnior, Francisco Edilson Leite Pinto; Formiga, Maria Célia Carvalho; da Costa Melo, Syomara Pereira; Brandão‐Neto, José; de Oliveira Ramos, Ana Maria

    2010-01-01

    OBJECTIVES: To study the effect of short‐chain fatty‐acids on atrophy and inflammation of excluded colonic segments before and after the development of diversion colitis. INTRODUCTION: Diversion colitis is a chronic inflammatory process affecting the dysfunctional colon, possibly evolving with mucous and blood discharge. The most favored hypotheses to explain its development is short‐chain fatty‐acid deficiency in the colon lumen. METHODS: Wistar rats were submitted to colostomy with distal colon exclusion. Two control groups (A1 and B1) received rectally administered physiological saline, whereas two experimental groups (A2 and B2) received rectally administered short‐chain fatty‐acids. The A groups were prophylactically treated (5th to 40th days postoperatively), whereas the B groups were therapeutically treated (after post‐operative day 40). The mucosal thickness of the excluded colon was measured histologically. The inflammatory reaction of the mucosal lamina propria and the lymphoid tissue response were quantified through established scores. RESULTS: There was a significant thickness recovery of the colonic mucosa in group B2 animals (p  =  0.0001), which also exhibited a significant reduction in the number of eosinophilic polymorphonuclear cells in the lamina propria (p  =  0.0126) and in the intestinal lumen (p  =  0.0256). Group A2 showed no mucosal thickness recovery and significant increases in the numbers of lymphocytes (p  =  0.0006) and eosinophilic polymorphonuclear cells in the lamina propria of the mucosa (p  =  0.0022). CONCLUSION: Therapeutic use of short‐chain fatty‐acids significantly reduced eosinophilic polymorphonuclear cell numbers in the intestinal wall and in the colonic lumen; it also reversed the atrophy of the colonic mucosa. Prophylactic use did not impede the development of mucosal atrophy. PMID:21340226

  19. Eosinophilic colitis.

    PubMed

    Dionísio de Sousa, Isabel José; Bonito, Nuno; Pais, Ana; Gervásio, Helena

    2016-01-01

    A 57-year-old man, diagnosed with colon cancer stage III in July/2010, underwent surgery and received adjuvant chemotherapy with FOLFOX 4 (5-fluorouracil; calcium folinate and oxaliplatin), which ended in March/2011 after 12-cycles. It was then decided to maintain periodical surveillance. About 1 year later, the patient developed several episodes of diarrhoea, mainly during the night, and presented persistent peripheral eosinophilia in the blood count (range 585-1300 eosinophils/µL). Colonoscopy was performed, with the histological result showing eosinophilic infiltration of the colon, compatible with eosinophilic colitis. The patient was treated with a short course of budesonide, achieving resolution of symptoms, and has remained asymptomatic. PMID:26957036

  20. A lipidomics investigation into the intervention of celastrol in experimental colitis.

    PubMed

    Wang, Renping; Gu, Xueqin; Dai, Weiquan; Ye, Jun; Lu, Feng; Chai, Yifeng; Fan, Guorong; Gonzalez, Frank J; Duan, Gengli; Qi, Yunpeng

    2016-04-26

    Celastrol is well known for its anti-inflammatory and anti-cancer effects. In this study, the efficacy of celastrol against dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mice was established and the mechanism was investigated using lipidomics. Celastrol treatment significantly alleviated DSS-induced colitis in mice, as revealed by the body weight, colon length, scores of rectal bleeding and diarrhea, serum TNF-α level, and histological analysis results. Lipidomics analysis based on UPLC/MS revealed characteristic changes in the metabolic profiles of the colitis mice, with altered levels of lipid markers associated with IBD, including LPC18 : 0, LPC18 : 1, LPC18 : 2, sphingomyelin (SM), and increased LPC18 : 0/LPC18 : 1 and LPC18 : 0/LPC18 : 2 ratios. For the celastrol-treated colitis mice, however, levels of the above lipid markers were restored, together with recovered saturated LPC/unsaturated LPC ratios. Accordingly, using GC-MS analysis, increased stearic acid (C18 : 0)/oleic acid (C18 : 1) and stearic acid (C18 : 0)/linoleic acid (C18 : 2) ratios were observed in colitis mice, which were later recovered after celastrol treatment. Quantitative real-time PCR analysis revealed that the liver expression of stearoyl-coenzyme A desaturase 1 (SCD1), the key enzyme controlling the desaturation of saturated fatty acid, was dramatically inhibited in IBD mice, and was obviously recovered after celastrol treatment. These results suggest that the increased saturated LPC/unsaturated LPC (and saturated fatty acid/unsaturated fatty acid) ratios associated with SCD1 down-regulation could be regarded as biomarkers of colitis, and celastrol alleviates DSS-induced colitis partially via up-regulation of SCD1, restoring the altered balance between stearic acid- and oleic acid-derived lipid species, which plays an important role in alleviating colitis. In all, this study provided the scientific basis for further

  1. Peroxisome proliferator-activated receptor-γ is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia

    PubMed Central

    DOU, XIAOTAN; XIAO, JUNHUA; JIN, ZILIANG; ZHENG, PING

    2015-01-01

    The aim of the present study was to evaluate the expression of peroxisome proliferator-activated receptor (PPAR)-γ in inflammatory bowel disease (IBD), and to also identify the association between PPAR-γ and the clinical features of patients with IBD. An azoxymethane (AOM)/dextran sodium sulfate (DSS) animal model of colitis-associated neoplasia was established to investigate the protective effect of 5-aminosalicylic acid (5-ASA) and to explore the changes in the expression of PPAR-γ during this process. A total of 66 specimens of colorectal tissue obtained from biopsy performed on IBD patients and 30 healthy control individuals were immunohistochemically stained for PPAR-γ. An AOM/DSS animal model of colitis-associated neoplasia was then established. Reverse transcription quantitative polymerase chain reaction was conducted and it was found that, compared with the control group and patients with Crohn's disease (CD), the expression of PPAR-γ in the intestinal tissue of patients with ulcerative colitis (UC) was significantly decreased (P=0.027 and 0.046, respectively). The expression of PPAR-γ was found to be negatively associated with the disease activity of UC and was not associated with the severity of disease, site of lesions or CD characteristics. Administration of 5-ASA decreased the colitis and tumor burden of colons. The expression level of PPAR-γ in the intestinal tissue was also increased in the AOM/DSS/5-ASA group compared with AOM/DSS group (P<0.001). PPAR-γ is an important factor in the pathogenesis of UC and colitis-associated cancer. The present study found that 5-ASA significantly alleviates the colitis and tumor burden in a mouse model of AOM/DSS-induced colitis-associated neoplasia, and promotes the expression of PPAR-γ in the intestinal tract. PMID:26622660

  2. B-vitamin deficiency is protective against DSS-induced colitis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met) and its increase in IBD patients indicates a disruption of Met metabolism, yet the role of Hcys and Met metabolism in IBD is not well und...

  3. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig.

    PubMed

    Hons, Ian M; Burda, Joshua E; Grider, John R; Mawe, Gary M; Sharkey, Keith A

    2009-04-01

    Inflammatory bowel diseases (IBD) can involve widespread gastrointestinal dysfunction, even in cases in which inflammation is localized to a single site. The underlying pathophysiology of dysfunction in noninflamed regions is unclear. We examined whether colitis is associated with altered electrogenic ion transport in the ileal mucosa and/or changes in the properties of ileal submucosal neurons. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS), and the uninflamed ileum from animals was examined 3, 7, and 28 days later. Electrogenic ion transport was assessed in Ussing chambers. Intracellular microelectrode recordings were used to examine the neurophysiology of the submucosal plexus of the ileum in animals with colitis. Noncholinergic secretion was reduced by 33% in the ileum from animals 7 days after the induction of colitis. The epithelial response to vasoactive intestinal peptide (VIP) was unaltered in animals with colitis, but the response to carbachol was enhanced. Slow excitatory synaptic transmission was dramatically reduced in VIP-expressing, noncholinergic secretomotor neurons. This change was detected as early as 3 days following TNBS treatment. No changes to fast synaptic transmission or the number of VIP neurons were observed. In addition, cholinergic secretomotor neurons fired more action potentials during a given stimulus, and intrinsic primary afferent neurons had broader action potentials in animals with colitis. These findings implicate changes to enteric neural circuits as contributing factors in inflammation-induced secretory dysfunction at sites proximal to a localized inflammatory insult. PMID:19221017

  4. Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis

    PubMed Central

    Yuan, Bosi; Zhou, Shuping; Lu, Youke; Liu, Jiong; Jin, Xinxin; Wan, Haijun; Wang, Fangyu

    2015-01-01

    Background/Aims This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Methods Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. Results The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. Conclusions There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability. PMID:25717051

  5. Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

    PubMed Central

    Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

    2015-01-01

    AIM: To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. METHODS: The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is

  6. Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice.

    PubMed

    Pandurangan, Ashok Kumar; Ismail, Salmiah; Saadatdoust, Zeinab; Esa, Norhaizan Mohd

    2015-01-01

    The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P < 0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3(Y705) pathways. PMID:26075036

  7. Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice

    PubMed Central

    Ismail, Salmiah; Saadatdoust, Zeinab; Esa, Norhaizan Mohd.

    2015-01-01

    The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P < 0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3Y705 pathways. PMID:26075036

  8. Examination of the Anti-Inflammatory, Antioxidant, and Xenobiotic-Inducing Potential of Broccoli Extract and Various Essential Oils during a Mild DSS-Induced Colitis in Rats.

    PubMed

    Mueller, Kristin; Blum, Nicole Michaela; Mueller, Andreas Stefan

    2013-01-01

    Phytogenic compounds with antioxidant and anti-inflammatory properties are currently discussed as promising complementary agents in prevention and treatment of inflammatory bowel disease (IBD). Our study aimed to evaluate possible protective and curative effects of broccoli extract (BE) and of the essential oils of turmeric (Cuo), thyme (To), and rosemary (Ro) in a rat model with a mild dextran sulphate sodium- (DSS-) induced colitis. Therefore Wistar rats were fed a diet without an additive (Con) or diets with the addition of BE, Cuo, To, and Ro during the whole experiment. Pretreatment with Ro, Cuo, and To increased the expression of the tight junction protein Cldn3. All additives reduced mRNA of VCAM-1 which plays a crucial role in the first state of inflammatory response. Only Ro pretreatment affected the expression of the antioxidant enzymes HO1, GPx2, and of glutathione-S-transferases. All additives counteracted the DSS-induced rise in COX2 and VCAM-1 expression. Colonic IL-10 was increased by Cuo, To, and Ro. During the recovery phase DSS pretreatment increased NF κ B, VCAM-1, and MCP-1: This response was counter-regulated by all additives. We conclude that the phytogenic additives tested have a promising anti-inflammatory potential in vivo and a particular role in the prevention of IBD. PMID:23533793

  9. Examination of the Anti-Inflammatory, Antioxidant, and Xenobiotic-Inducing Potential of Broccoli Extract and Various Essential Oils during a Mild DSS-Induced Colitis in Rats

    PubMed Central

    Blum, Nicole Michaela; Mueller, Andreas Stefan

    2013-01-01

    Phytogenic compounds with antioxidant and anti-inflammatory properties are currently discussed as promising complementary agents in prevention and treatment of inflammatory bowel disease (IBD). Our study aimed to evaluate possible protective and curative effects of broccoli extract (BE) and of the essential oils of turmeric (Cuo), thyme (To), and rosemary (Ro) in a rat model with a mild dextran sulphate sodium- (DSS-) induced colitis. Therefore Wistar rats were fed a diet without an additive (Con) or diets with the addition of BE, Cuo, To, and Ro during the whole experiment. Pretreatment with Ro, Cuo, and To increased the expression of the tight junction protein Cldn3. All additives reduced mRNA of VCAM-1 which plays a crucial role in the first state of inflammatory response. Only Ro pretreatment affected the expression of the antioxidant enzymes HO1, GPx2, and of glutathione-S-transferases. All additives counteracted the DSS-induced rise in COX2 and VCAM-1 expression. Colonic IL-10 was increased by Cuo, To, and Ro. During the recovery phase DSS pretreatment increased NFκB, VCAM-1, and MCP-1: This response was counter-regulated by all additives. We conclude that the phytogenic additives tested have a promising anti-inflammatory potential in vivo and a particular role in the prevention of IBD. PMID:23533793

  10. The effect of methylsulfonylmethane on the experimental colitis in the rat.

    PubMed

    Amirshahrokhi, K; Bohlooli, S; Chinifroush, M M

    2011-06-15

    Methylsulfonylmethane (MSM), naturally occurring in green plants, fruits and vegetables, has been shown to exert anti-inflammatory and antioxidant effects. MSM is an organosulfur compound and a normal oxidative metabolite of dimethyl sulfoxide. This study was carried out to investigate the effect of MSM in a rat model of experimental colitis. Colitis was induced by intracolonic instillation of 1 ml of 5% of acetic acid. Rats were treated with MSM (400 mg/kg/day, orally) for 4 days. Animals were euthanized and distal colon evaluated histologically and biochemically. Tissue samples were used to measurement of malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), glutathione (GSH) and proinflammatory cytokine (TNF-α and IL-1β) levels. Results showed that MSM decreased macroscopic and microscopic colonic damage scores caused by administration of acetic acid. MSM treatment also significantly reduced colonic levels of MDA, MPO and IL-1β, while increased the levels of GSH and CAT compared with acetic acid-induced colitis group. It seems that MSM as a natural product may have a protective effect in an experimental ulcerative colitis. PMID:21463646

  11. Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon

    PubMed Central

    Mawe, Gary M.

    2015-01-01

    Effective colonic motility involves an intricate pattern of excitatory and inhibitory neuromuscular signals that arise from the enteric neural circuitry of the colon. Recent investigations have demonstrated that inflammation leads to a variety of changes in the physiological properties of the neurons in this circuitry, including hyperexcitability of neurons at the afferent end of the peristaltic reflex, synaptic facilitation, and attenuated inhibitory neuromuscular transmission. Furthermore, links have been established between these changes and disrupted motor activity in the colon, and we now know that some of these changes persist long after recovery from inflammation. It is highly likely that inflammation-induced neuroplasticity, which is not detectable by clinical diagnostics, contributes to disrupted motility in active and quiescent inflammatory bowel disease and in functional gastrointestinal disorders. PMID:25729851

  12. Substance P modulates colitis-associated fibrosis.

    PubMed

    Koon, Hon Wai; Shih, David; Karagiannides, Iordanes; Zhao, Dezheng; Fazelbhoy, Zafeer; Hing, Tressia; Xu, Hua; Lu, Bao; Gerard, Norma; Pothoulakis, Charalabos

    2010-11-01

    Substance P (SP) and the neurokinin-1 receptor (NK-1R) are involved in the development of colitis and mucosal healing after colonic inflammation. We studied whether SP modulates colonic fibrosis by using a chronic model of trinitrobenzenesulfonic acid (TNBS)-induced colitis in wild-type (WT) and NK-1R-deficient (NK-1R KD) mice. We found increased mRNA expression levels of collagen, vimentin, and the fibrogenic factors transforming growth factor β1 and insulin-like growth factor 1 in the chronically inflamed colons of WT mice treated with repeated intracolonic TNBS administrations. Fibrosis in TNBS-treated mice was also evident immunohistochemically by collagen deposition in the colon. Treatment of TNBS-exposed WT mice with the NK-1R antagonist CJ-12255 reduced colonic inflammation, colonic fibrosis, fibroblast accumulation, and expression levels of the fibrogenic factors. NK-1R knockout mice chronically exposed to TNBS had similar colonic inflammation compared with WT, but reduced colonic fibrosis, fibroblast accumulation, and expression levels of fibrogenic factors. Immunohistochemical staining also showed co-localization of NK-1R with fibroblasts in inflamed colons of mice and in colonic mucosa of patients with Crohn's disease. Exposure of human colonic CCD-18Co fibroblasts to SP (10 nmol/L) increased cell migration. SP stimulated collagen synthesis in CCD-18Co fibroblasts in the presence of transforming growth factor β1 and insulin-like growth factor 1, and this effect was reduced by Akt inhibition. Thus, SP, via NK-1R, promotes intestinal fibrogenesis after chronic colitis by stimulating fibrotic responses in fibroblasts. PMID:20889569

  13. Metabolomics Reveals that Hepatic Stearoyl-CoA Desaturase 1 Downregulation Exacerbates Inflammation and Acute Colitis

    PubMed Central

    Chen, Chi; Shah, Yatrik M.; Morimura, Keiichirou; Krausz, Kristopher W.; Miyazaki, Makoto; Richardson, Terrilyn A.; Morgan, Edward T.; Ntambi, James M.; Idle, Jeffrey R.; Gonzalez, Frank J.

    2008-01-01

    SUMMARY To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases. PMID:18249173

  14. [Microscopic colitis: update 2014].

    PubMed

    Burgmann, Konstantin; Fraga, Montserrat; Schoepfer, Alain M; Yun, Pu

    2014-09-01

    Microscopic colitis, which includes lymphocytic colitis and collagenous colitis, represents a frequent cause of chronic watery diarrhea especially in the elderly population. Several medications, such as nonsteroidal antiinflammatory drugs, proton pump inhibitors or antidepressants, as well as cigarette smoking have been recognized as risk factors for microscopic colitis. The diagnosis of microscopic colitis is based on a macroscopically normal ileo-colonoscopy and several biopsies from the entire colon, which demonstrate the pathognomonic histopathologic findings. Therapy is mainly based on the use of budesonide. Other medications, such as mesalazine, cholestyramine and bismuth, have been evaluated as well but the evidence is less solid. PMID:25276996

  15. Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis

    PubMed Central

    Zheng, Zengjie; Jiang, Hailong; Huang, Yan; Wang, Jie; Qiu, Lei; Hu, Zhenlin; Ma, Xingyuan; Lu, Yiming

    2016-01-01

    Snake has been used for centuries as a traditional Chinese medicine, especially for therapeutic treatment for inflammatory diseases; however, its mechanisms of action and active constituents remain controversial. In our study, a tumor necrosis factor receptor 1 (TNFR1) selective binding peptide, Hydrostatin-SN1 (H-SN1), which was screened from a Hydrophis cyanocinctus venom gland T7 phage display library, was shown to exhibit significant anti-inflammatory activity in vitro and in vivo. As a TNFR1 antagonist, it reduced cytotoxicity mediated by TNF-α in L929 fibroblasts and effectively inhibited the combination between TNF-α with TNFR1 in surface plasmon resonance analysis. H-SN1 was also shown to suppress TNFR1–associated signaling pathways as it minimized TNF-α-induced NF-кB and MAPK activation in HEK293 embryonic kidney and HT29 adenocarcinoma cell lines. We next determined the effect of H-SN1 in vivo using a murine model of acute colitis induced by dextran sodium sulfate, demonstrating that H-SN1 lowered the clinical parameters of acute colitis including the disease activity index and histologic scores. H-SN1 also inhibited TNF/TNFR1 downstream targets at both mRNA and protein levels. These results indicate that H-SN1 might represent a suitable candidate for use in the treatment of TNF-α-associated inflammatory diseases such as inflammatory bowel diseases. PMID:27158082

  16. Neuroprotective Potential of Mesenchymal Stem Cell-Based Therapy in Acute Stages of TNBS-Induced Colitis in Guinea-Pigs

    PubMed Central

    Robinson, Ainsley M.; Miller, Sarah; Payne, Natalie; Boyd, Richard; Sakkal, Samy; Nurgali, Kulmira

    2015-01-01

    Background & Aims The therapeutic benefits of mesenchymal stem cells (MSCs), such as homing ability, multipotent differentiation capacity and secretion of soluble bioactive factors which exert neuroprotective, anti-inflammatory and immunomodulatory properties, have been attributed to attenuation of autoimmune, inflammatory and neurodegenerative disorders. In this study, we aimed to determine the earliest time point at which locally administered MSC-based therapies avert enteric neuronal loss and damage associated with intestinal inflammation in the guinea-pig model of colitis. Methods At 3 hours after induction of colitis by 2,4,6-trinitrobenzene-sulfonate (TNBS), guinea-pigs received either human bone marrow-derived MSCs, conditioned medium (CM), or unconditioned medium by enema into the colon. Colon tissues were collected 6, 24 and 72 hours after administration of TNBS. Effects on body weight, gross morphological damage, immune cell infiltration and myenteric neurons were evaluated. RT-PCR, flow cytometry and antibody array kit were used to identify neurotrophic and neuroprotective factors released by MSCs. Results MSC and CM treatments prevented body weight loss, reduced infiltration of leukocytes into the colon wall and the myenteric plexus, facilitated repair of damaged tissue and nerve fibers, averted myenteric neuronal loss, as well as changes in neuronal subpopulations. The neuroprotective effects of MSC and CM treatments were observed as early as 24 hours after induction of inflammation even though the inflammatory reaction at the level of the myenteric ganglia had not completely subsided. Substantial number of neurotrophic and neuroprotective factors released by MSCs was identified in their secretome. Conclusion MSC-based therapies applied at the acute stages of TNBS-induced colitis start exerting their neuroprotective effects towards enteric neurons by 24 hours post treatment. The neuroprotective efficacy of MSC-based therapies can be exerted

  17. Fumigaclavine C, an fungal metabolite, improves experimental colitis in mice via downregulating Th1 cytokine production and matrix metalloproteinase activity.

    PubMed

    Wu, Xue-Feng; Fei, Ming-Jian; Shu, Ren-Geng; Tan, Ren-Xiang; Xu, Qiang

    2005-09-01

    In the present paper, the effect of Fumigaclavine C, a fungal metabolite, on experimental colitis was examined. Fumigaclavine C, when administered intraperitoneally once a day, significantly reduced the weight loss and mortality rate of mice with experimental colitis induced by intrarectally injection of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). This compound also markedly alleviated the macroscopic and microscopic appearances of colitis. Furthermore, Fumigaclavine C, given both in vivo and in vitro, showed a marked inhibition on the expression of several inflammatory cytokines, including IL-1beta, IL-2, IL-12alpha, IFN-gamma, TNF-alpha as well as MMP-9 in sacral lymph node cells, colonic patch lymphocytes and colitis tissues from the TNBS colitis mice. Meanwhile, the compound caused a dose-dependent reduction in IL-2 and IFN-gamma from the lymphocytes at the protein level and MMP-9 activity. These results suggest that Fumigaclavine C may alleviate experimental colitis mainly via down-regulating the production of Th1 cytokines and the activity of matrix metalloproteinase. PMID:16023606

  18. Antioxidants as novel therapy in a murine model of colitis.

    PubMed

    Oz, Helieh S; Chen, Theresa S; McClain, Craig J; de Villiers, Willem J S

    2005-05-01

    Reactive oxygen species (ROS) are increased in inflammatory bowel disease (IBD) and have been implicated as mediators of intestinal inflammation. We investigated the hypothesis that antioxidants with diverse properties attenuate disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model. These antioxidants were (A) S-adenosylmethionine, a glutathione (GSH) precursor; (B) green tea polyphenols, a well-known antioxidant; and (C) 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA), a cysteine prodrug, involved in GSH biosynthesis. BALB/c mice were divided into four groups and provided with the above mentioned antioxidants or the vehicle incorporated into chow. The animals were further divided into two subgroups and given normal drinking water (control) or water supplemented with DSS (to induce colitis), and the progression of the disease was studied. DSS-treated mice developed severe colitis as shown by bloody diarrhea, weight loss and pathological involvement (P<.001). However, all the antioxidants significantly improved diarrhea and colon lesions (P<.01), and increased body weights (P<.05). Hematocrits were significantly less affected in DSS-treated animals receiving antioxidants (P<.01). Colon lengths were significantly decreased due to mucosal inflammation in DSS-treated animals, but antioxidant therapy normalized this pathological finding (P<.001). The blood level of reduced GSH was decreased in DSS-treated mice (P<.05) and returned to normal when treated with antioxidants. Serum amyloid A (acute phase protein; P=.0015) and tumor necrosis factor-alpha (TNF-alpha; pro-inflammatory cytokine; P<.01) were significantly increased in DSS-treated animals (161+/-40 pg/ml) and improved with antioxidant treatment (P<.01). Finally, actin cytoskeleton was distorted and fragmented in the mucosa of DSS-treated mice and improved with antioxidant therapy. In conclusion, three structurally dissimilar antioxidants provided protection against DSS-induced

  19. Antiinflammatory Effect of Phytosterols in Experimental Murine Colitis Model: Prevention, Induction, Remission Study

    PubMed Central

    Aldini, Rita; Micucci, Matteo; Cevenini, Monica; Fato, Romana; Bergamini, Christian; Nanni, Cristina; Cont, Massimiliano; Camborata, Cecilia; Spinozzi, Silvia; Montagnani, Marco; Roda, Giulia; D'Errico-Grigioni, Antonia; Rosini, Francesca; Roda, Aldo; Mazzella, Giuseppe; Chiarini, Alberto; Budriesi, Roberta

    2014-01-01

    Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects. PMID:25268769

  20. Ethanol Extract of Antrodia camphorata Grown on Germinated Brown Rice Suppresses Inflammatory Responses in Mice with Acute DSS-Induced Colitis

    PubMed Central

    Park, Dong Ki; Park, Hye-Jin

    2013-01-01

    The anti-inflammatory activity of Antrodia camphorata (AC) grown on germinated brown rice (CBR) extract was evaluated in vitro and in vivo. CBR suppressed the release of nitric oxide (NO) and prostaglandin (PG) E2 from lipopolysaccharide-(LPS-)stimulated RAW264.7 cells. CBR inhibited the level of inducible nitric oxide synthase (iNOS) and cyclooxygenase-(COX-)2 proteins, and it activated p38-MAPK, extracellular signal-related kinases (ERK), and NF-κB in LPS-stimulated RAW264.7 macrophages. LPS-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA expression was reduced in CBR-treated RAW264.7 cells. In concert with in vitro data, CBR suppressed the levels of dextran-sulfate-sodium-(DSS-)induced iNOS and COX-2 proteins in the colon tissue. CBR treatment inhibited activated p38-MAPK, ERK, and NF-κB proteins in the colon tissue of DSS-induced mice. TNF-α and IL-6 mRNA expression was reduced in DSS+CBR-treated mice. The disease activity index and histological scores were significantly lower in CBR-treated mice (500 mg/kg/day) than in DSS-treated mice (P < 0.05 versus DSS). This is the first report of anti-inflammatory activity of CBR in DSS-induced acute colitis. These results suggest that CBR is a promising, potential agent for preventing acute colitis through the inhibition of NF-κB signaling and its upstream signaling molecules, including MAPKs. PMID:23818935

  1. Baicalin down regulates the expression of TLR4 and NFkB-p65 in colon tissue in mice with colitis induced by dextran sulfate sodium

    PubMed Central

    Feng, Jinshan; Guo, Cancan; Zhu, Yuzhen; Pang, Liping; Yang, Zheng; Zou, Ying; Zheng, Xuebao

    2014-01-01

    Background: Baicalin is one of flavonoid extracts from Scutellaria baicalensis, which has several functions including anti-inflammation, anti-bacteria, antitumor and et al. However, the mechanisms of anti-inflammatory of baicalin in ulcerative colitis is not clear. Methods: Mice colitis models were established by dextran sodium sulfate, Mice administrated with baicalin (100 mg/kg) and mesalazine (100 mg/kg) twice daily by intragastric injection for 7 days after colitis induced were defined as treated group. Then the mice were sacrificed and the colon samples were collected. Toll-like receptor-2, 4, 9 were detected by immunohistochemistry. Signaling proteins such as TLR4, MyD88, and NF-κB p65 were analyzed by western blotting. Cytokine’s mRNA include TNF-α, IL-6 IL-10 and IL-13 were measured by reverse transcription polymerase chain reaction. Modified disease activity index were used to analyse the severity of the disease by assessed of diarrhea, stool (occult) blood and body weight loss of the mice. Results: Compared with control and model groups, modified disease activity index in baicalin and mesalazine treated, mice decreased gradually. Immunohistochemistry analysis showed the expression of TLR4, but not TLR2 and TLR9, in the mucosa of mice colon were decreased. Western blot analysis showed that in colitis model, the expression of NF-κB p65 and TLR4 decreased (P < 0.05), while the expression of MyD88 increased significantly compared to control group, and MyD88 expression can not be repressed by baicalin (P < 0.05). Baicalin and mesalazine treatment suppressed the expression of TNF-α, IL-6 and IL-13 mRNA (P < 0.05), yet up-regulated the expression of IL-10 mRNA (P < 0.05), compared to the DDS and control groups. Conclusions: Baicalin administration by intragastric injection ameliorates the severity of colon inflammation. The possible mechanism of anti-inflammatory response by baicalin may involve in the blocking of the TLR4/NF-κB-p65/IL-6 signaling pathway

  2. The anti-ulcerative colitis effects of Annona squamosa Linn. leaf aqueous extract in experimental animal model.

    PubMed

    Ibrahim, Rasha Ym; Hassan, Amal I; Al-Adham, Eithar K

    2015-01-01

    This study aimed to evaluate the anti-inflammatory effects of Annona squamosa (A. squamosa) leaf aqueous extract against acetic acid induced colitis in rats with a trial to explore its use for the treatment of colon inflammation. Sprague Dawley rats weighing 180-200 g were used in this study. Treatment with A. squamosa extract at dose 300 mg/kg for 4 weeks counteracted acetic acid induced ulcerative colitis by a significant decrease (P<0.05) of colonic tissue of malondialdehyde (MDA) and significant increases of catalase (CAT), glutathione (GSH) and glutathione peroxidase (Gpx) compared to ulcerative colitis control group. Furthermore, induction of oxidative stress was observed in the colonic tissue through the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) which significant increase in colonic tissue DNA by acetic acid. Moreover AA induced significant increase in serum interleukin-10 (IL10), tumor necrosis factor-α (TNF-α), transforming growth factor (TGF 1β), and C reactive protein (CRP) as compared to the control group. On the contrary, our results showed AA induced significant decrease of vascular endothelial growth factor (VEGF) and thyroid hormones triiodothyronin and thyroxin (T3 & T4) in installed group with AA as compared to control which significantly improved after treatment with A. squamosa leaf extract. Histopathological observation in our study confirmed the biochemical study. Thus, therapeutic method offer a sign to analyze further the effectiveness of A. squamosa as a unique agent for alleviating colitis. PMID:26885156

  3. The anti-ulcerative colitis effects of Annona squamosa Linn. leaf aqueous extract in experimental animal model

    PubMed Central

    Ibrahim, Rasha YM; Hassan, Amal I; AL-Adham, Eithar K

    2015-01-01

    This study aimed to evaluate the anti-inflammatory effects of Annona squamosa (A. squamosa) leaf aqueous extract against acetic acid induced colitis in rats with a trial to explore its use for the treatment of colon inflammation. Sprague Dawley rats weighing 180-200 g were used in this study. Treatment with A. squamosa extract at dose 300 mg/kg for 4 weeks counteracted acetic acid induced ulcerative colitis by a significant decrease (P<0.05) of colonic tissue of malondialdehyde (MDA) and significant increases of catalase (CAT), glutathione (GSH) and glutathione peroxidase (Gpx) compared to ulcerative colitis control group. Furthermore, induction of oxidative stress was observed in the colonic tissue through the levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG) which significant increase in colonic tissue DNA by acetic acid. Moreover AA induced significant increase in serum interleukin-10 (IL10), tumor necrosis factor-α (TNF-α), transforming growth factor (TGF 1β), and C reactive protein (CRP) as compared to the control group. On the contrary, our results showed AA induced significant decrease of vascular endothelial growth factor (VEGF) and thyroid hormones triiodothyronin and thyroxin (T3 & T4) in installed group with AA as compared to control which significantly improved after treatment with A. squamosa leaf extract. Histopathological observation in our study confirmed the biochemical study. Thus, therapeutic method offer a sign to analyze further the effectiveness of A. squamosa as a unique agent for alleviating colitis. PMID:26885156

  4. Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate-induced colitis: differential regulation of tumour necrosis factor-α and interleukin-18 in BALB/c and severe combined immunodeficiency mice

    PubMed Central

    Hudcovic, T; Kolinska, J; Klepetar, J; Stepankova, R; Rezanka, T; Srutkova, D; Schwarzer, M; Erban, V; Du, Z; Wells, J M; Hrncir, T; Tlaskalova-Hogenova, H; Kozakova, H

    2012-01-01

    One of the promising approaches in the therapy of ulcerative colitis is administration of butyrate, an energy source for colonocytes, into the lumen of the colon. This study investigates the effect of butyrate producing bacterium Clostridium tyrobutyricum on dextran sodium sulphate (DSS)-induced colitis in mice. Immunocompetent BALB/c and immunodeficient severe combined immunodeficiency (SCID) mice reared in specific-pathogen-free (SPF) conditions were treated intrarectally with C. tyrobutyricum 1 week prior to the induction of DSS colitis and during oral DSS treatment. Administration of DSS without C. tyrobutyricum treatment led to an appearance of clinical symptoms – bleeding, rectal prolapses and colitis-induced increase in the antigen CD11b, a marker of infiltrating inflammatory cells in the lamina propria. The severity of colitis was similar in BALB/c and SCID mice as judged by the histological damage score and colon shortening after 7 days of DSS treatment. Both strains of mice also showed a similar reduction in tight junction (TJ) protein zonula occludens (ZO)-1 expression and of MUC-2 mucin depression. Highly elevated levels of cytokine tumour necrosis factor (TNF)-α in the colon of SCID mice and of interleukin (IL)-18 in BALB/c mice were observed. Intrarectal administration of C. tyrobutyricum prevented appearance of clinical symptoms of DSS-colitis, restored normal MUC-2 production, unaltered expression of TJ protein ZO-1 and decreased levels of TNF-α and IL-18 in the descending colon of SCID and BALB/c mice, respectively. Some of these features can be ascribed to the increased production of butyrate in the lumen of the colon and its role in protection of barrier functions and regulation of IL-18 expression. PMID:22236013

  5. Conjugated Linoleic Acid Ameliorates Inflammation-Induced Colorectal Cancer in Mice through Activation of PPARγ1–3

    PubMed Central

    Evans, Nicholas P.; Misyak, Sarah A.; Schmelz, Eva M.; Guri, Amir J.; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-01-01

    Conjugated linoleic acid (CLA) exerts a protective effect on experimental inflammatory bowel disease and shows promise as a chemopreventive agent against colorectal cancer (CRC) in mice, although the mechanisms by which it exerts its beneficial effects against malignancies in the gut are not completely understood. Mice lacking PPARγ in immune and epithelial cells and PPARγ-expressing littermates were fed either control or CLA-supplemented (1 g CLA/100 g) diets to determine the role of PPARγ in inflammation-induced CRC. To induce tumor formation and colitis, mice were treated with azoxymethane and then challenged with 2% dextran sodium sulfate, respectively. Dietary CLA ameliorated disease activity, decreased colitis, and prevented adenocarcinoma formation in the PPARγ-expressing floxed mice but not in the tissue-specific PPARγ-null mice. Dietary CLA supplementation significantly decreased the percentages of macrophages in the mesenteric lymph nodes (MLN) regardless of the genotype and increased regulatory T cell numbers in MLN of PPARγ-expressing, but not in the tissue-specific, PPARγ-null mice. Colonic tumor necrosis factor-α mRNA expression was significantly suppressed in CLA-fed, PPARγ-expressing mice. This study suggests CLA ameliorates colitis and prevents tumor formation in part through a PPARγ-dependent mechanism. PMID:20089779

  6. Crucial role of macrophage selenoproteins in experimental colitis

    PubMed Central

    Kaushal, Naveen; Kudva, Avinash K.; Patterson, Andrew D.; Chiaro, Christopher; Kennett, Mary J.; Desai, Dhimant; Amin, Shantu; Carlson, Bradley A.; Cantorna, Margherita T.; Prabhu, K. Sandeep

    2014-01-01

    Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between selenium (Se) status and IBD-induced inflammation, our objective was to demonstrate that selenoproteins in macrophages were essential to suppress pro-inflammatory mediators, in part, by the modulation of arachidonic acid metabolism. Acute colitis was induced using 4% DSS in wild type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.1 ppm; sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite) diets. Transfer RNASec (tRNA[sec]) knockout mice (Trspfl/flLysMCre) were used to examine the role of selenoproteins in macrophages on disease progression and severity using histopathological evaluation, expression of pro-inflammatory and anti-inflammatory genes, and modulation of prostaglandin (PG) metabolites in urine and plasma. While Se-deficient and Se-adequate mice showed increased colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased colitis-associated inflammation with an up-regulation of expression of pro-inflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of 15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH, lack of selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific selenoproteins and upregulation of 15-PGDH expression were key for Se-dependent anti-inflammatory and pro-resolving effects. Selenoproteins in macrophages protect mice from DSS-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate inflammation, suggesting a therapeutic role for Se in IBD. PMID:25187657

  7. Ulcerative Colitis: An Overview

    PubMed Central

    Archambault, Andre

    1990-01-01

    Idiopathic ulcerative colitis primarily affects young adults. Colonic symptoms are the most annoying. In severe colitis, systemic and extraintestinal inflammatory manifestations can be disabling. Proximal extension of colitis is demonstrated by double-contrast barium enema and total colonoscopy. Bacterial and parasitic colitis must be excluded by appropriate microbiological studies. Colonoscopy is recommended to screen for high-grade dysplasia or neoplasia in cases of chronic diffuse colitis (after seven years). Severe colitis can benefit from hospitalization, parenteral nutritional support, and high doses of corticosteroids that are progressively tapered. Mild or moderate cases or severe cases in remission respond well to rest, low-irritant diets, mild symptomatic medication, oral sulfasalazine, or more recent 5-acetylsalicylic derivatives. Long-term maintenance with reduced dosages will control more than 80% of cases. PMID:21234051

  8. Therapeutic efficacy of a mutant of keratinocyte growth factor-2 on trinitrobenzene sulfonic acid-induced rat model of Crohn’s disease

    PubMed Central

    Wang, Jinfeng; Chen, Huihua; Wang, Yuanyuan; Cai, Xin; Zou, Minji; Xu, Tao; Wang, Min; Wang, Jiaxi; Xu, Donggang

    2016-01-01

    Background: Keratinocyte growth factor-2 (KGF-2) has been testified to be a multifunctional growth factor, which can stimulate the regeneration and reconstruction of epidermis, corium and mucosa. Its effect on Crohn’s disease has hitherto not been evaluated. Here, we investigated the preventive and therapeutic actions of STEA, a mutant of human KGF-2 with high activity, on trinitrobenzene sulfonic acid (TNBS)-induced rat model of Crohn’s disease. Methods: Rats with TNBS-induced colitis were treated with STEA and clinical scores were evaluated. Body weight, mortality, macroscopic and microscopic damage of the colonic tissue were examined. The levels of inflammatory cytokines in serum were detected by ELISA, the T cell subpopulations and the cell cycle of intestinal epithelial cells were analyzed by flow cytometry. Results: Both preventive and therapeutic administration of STEA significantly ameliorated body weight loss, diarrhea, and intestinal inflammation, reduced the high mortality and histopathologic damage of rats with TNBS-induced colitis. The serum level of inflammatory cytokines, such as TNF-α, IL-1β, IFN-γ and IL-6 were markedly decreased in colitis rats treated with STEA. The CD4+ and CD8+ T lymphocytes in peripheral blood were reduced with STEA administration at early stage of colitis. In addition, STEA treatment could promote the growth of intestinal epithelial cells by increasing the cell proportion in S phase of cell cycle and inhibiting cell apoptosis. Conclusions: Both preventive and therapeutic administration of STEA could ameliorate the colonic damages in rats with TNBS-induced colitis. STEA might be a promising option for the treatment of Crohn’s disease. PMID:27158345

  9. Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis.

    PubMed

    Scarminio, Viviane; Fruet, Andrea C; Witaicenis, Aline; Rall, Vera L M; Di Stasi, Luiz C

    2012-03-01

    Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, combination of this dietary supplementation with prednisolone presents synergistic effects. For this, we used the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Our results revealed that the protective effect produced by a combination of 10% green dwarf banana flour with prednisolone was more pronounced than those promoted by a single administration of prednisolone or a diet containing 10% or 20% banana flour. This beneficial effect was associated with an improvement in the colonic oxidative status because the banana flour diet prevented the glutathione depletion and inhibited myeloperoxidase activity and lipid peroxidation. In addition, the intestinal anti-inflammatory activity was associated with an inhibition of alkaline phosphatase activity, a reduction in macroscopic and microscopic scores, and an extension of the lesions. In conclusion, the dietary use of the green dwarf banana flour constitutes an important dietary supplement and complementary medicine product to prevention and treatment of human inflammatory bowel disease. PMID:22464807

  10. Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis.

    PubMed

    Ohkusa, Toshifumi; Yoshida, Tsutomu; Sato, Nobuhiro; Watanabe, Sumio; Tajiri, Hisao; Okayasu, Isao

    2009-05-01

    Interleukin 2 (IL-2)- and IL-10-knockout mice develop spontaneous colitis under conventional but not germ-free conditions, suggesting that commensal bacteria play an important role in the pathogenesis of colitis. However, interactions between commensal bacteria and colonic epithelial cells have not been fully investigated. We therefore assessed the ability of various commensal bacteria and probiotics to adhere to and invade colonic epithelial cells. Effects of the bacteria on production of proinflammatory cytokines were also measured. Commensal bacteria, including mucosal organisms isolated from ulcerative colitis (UC) patients, such as Fusobacterium varium, reported as a possible pathogen in UC, Bacteroides vulgatus, Escherichia coli and Clostridium clostridioforme, as well as their type strains and probiotics, were assessed for their ability to adhere to and invade colonic epithelial cells using two cell lines, SW-480 and HT-29. Our experiments employed co-incubation, a combination of scanning and transmission electron microscopy and recovery of bacteria from infected-cell lysates. F. varium and several other commensal bacteria, but not probiotics, adhered to colonic epithelial cells and invaded their cytoplasm. ELISA and real-time PCR revealed that the host cells, particularly those invaded by F. varium, showed significant increases in IL-8 and TNF-alpha concentrations in supernatants, with elevation of IL-8, TNF-alpha, MCP-1 and IL-6 mRNAs. Furthermore, IL-8 and TNF-alpha expression and nuclear phosphorylated NF-kappaB p65 expression could be immunohistochemically confirmed in inflamed epithelium with cryptitis or crypt abscess in UC patients. Certain commensal bacteria can invade colonic epithelial cells, activating early intracellular signalling systems to trigger host inflammatory reactions. PMID:19369513

  11. Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates DSS-induced colitis

    PubMed Central

    Luther, Jay; Owyang, Stephanie Y.; Takeuchi, Tomomi; Cole, Tyler; Zhang, Min; Liu, Maochang; Erb-Downward, John; Rubenstein, Joel H.; Kao, John Y.

    2012-01-01

    Background & Aims Recently there has been emerging epidemiological data to suggest Helicobacter pylori (H. pylori) may protect against certain chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, the mechanism for the observed inverse association between H. pylori and IBD has not been described. Methods The frequency of immunoregulatory (IRS) to immunostimulatory (ISS) sequences within the genome of various bacteria was calculated using MacVector software. The induction of type I IFN and IL-12 responses by DNA-pulsed murine bone marrow–derived dendritic cells (BMDC) and human plasmacytoid dendritic cells (pDC) was analyzed by cytokine production. The effect of H. pylori DNA on E. coli DNA production of type I IFN and IL-12 was assessed. The in vivo significance of H. pylori DNA suppression was assessed in a DSS-model of colitis. The systemic levels of type I IFN were assessed in H. pylori-colonized and non-colonized patients. Results We showed that H. pylori DNA has a significantly elevated IRS:ISS ratio. In vitro experiments revealed the inability of H. pylori DNA to stimulate type I IFN or IL-12 production from mouse BMDCs or human pDCs. Additionally, H. pylori DNA was able to suppress E. coli-DNA production of type I IFN and IL-12. Administration of H. pylori DNA prior to the induction of DSS colitis significantly ameliorated the severity of colitis as compared to E. coli DNA or vehicle control in both an acute and chronic model. Finally, the systemic levels of type I IFN were found to be lower in H. pylori-colonized patients versus non-colonized controls. Conclusions Overall, our study indicates that H pylori DNA has the ability to down-regulate pro-inflammatory responses from DCs and this may in part explain the inverse association between H. pylori and IBD. PMID:21471567

  12. Collagenous Colitis and Spondylarthropathy

    PubMed Central

    Ben Abdelghani, Kaouther; Sahli, Hana; Souabni, Leila; Chekili, Selma; Belhadj, Salwa; Kassab, Selma; Laatar, Ahmed; Zakraoui, Leith

    2012-01-01

    Collagenous colitis is a recent cause of chronic diarrhea. Cooccurrence with spondylarthropathy is rare. We describe two cases: one man and one woman of 33 and 20 years old were suffering from spondylarthropathy. They then developed collagenous colitis, 4 and 14 years after the onset of spondylarthropathy. The diagnosis was based on histological features. A sicca syndrome and vitiligo were observed with the female case. The presence of colitis leads to therapeutic problems. This association suggests a systemic kind of rheumatic disease of collagenous colitis. PMID:22701491

  13. β-Arrestin-1 deficiency protects mice from experimental colitis.

    PubMed

    Lee, Taehyung; Lee, Eunhee; Irwin, Regina; Lucas, Peter C; McCabe, Laura R; Parameswaran, Narayanan

    2013-04-01

    β-Arrestins are intracellular scaffolding proteins that modulate specific cell signaling pathways. Recent studies, in both cell culture and in vivo models, have demonstrated an important role for β-arrestin-1 in inflammation. However, the role of β-arrestin-1 in the pathogenesis of inflammatory bowel disease (IBD) is not known. Our goal was to investigate the role of β-arrestin-1 in IBD using mouse models of colitis. To this end, we subjected wild-type (WT) and β-arrestin-1 knockout (β-arr-1(-/-)) mice to colitis induced by trinitrobenzenesulfonic acid or dextran sulfate sodium and examined the clinical signs, gross pathology, and histopathology of the colon, as well as inflammatory components. The β-arr-1(-/-) mice displayed significantly attenuated colitis, compared with WT mice, in both models. Consistent with the phenotypic observations, histological examination of the colon revealed attenuated disease pathology in the β-arr-1(-/-) mice. Our results further demonstrate that β-arr-1(-/-) mice are deficient in IL-6 expression in the colon, but have higher expression of the anti-inflammatory IL-10 family of cytokines. Our results also demonstrate diminished ERK and NFκB pathways in the colons of β-arr-1(-/-) mice, compared with WT mice. Taken together, our results demonstrate that decreased IL-6 production and enhanced IL-10 and IL-22 production in β-arrestin-1-deficient mice likely lead to attenuated gut inflammation. PMID:23395087

  14. Preventive and Therapeutic Euphol Treatment Attenuates Experimental Colitis in Mice

    PubMed Central

    Bento, Allisson F.; Marcon, Rodrigo; Schmidt, Éder C.; Bouzon, Zenilda L.; Pianowski, Luiz F.; Calixto, João B.

    2011-01-01

    Background The tetracyclic triterpene euphol is the main constituent found in the sap of Euphorbia tirucalli. This plant is widely known in Brazilian traditional medicine for its use in the treatment of several kinds of cancer, including leukaemia, prostate and breast cancers. Here, we investigated the effect of euphol on experimental models of colitis and the underlying mechanisms involved in its action. Methodology/Principal Findings Colitis was induced in mice either with dextran sulfate sodium (DSS) or with 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the effect of euphol (3, 10 and 30 mg/kg) on colonic injury was assessed. Pro-inflammatory mediators and cytokines were measured by immunohistochemistry, enzyme-Linked immunoabsorbent assay (ELISA), real time-polymerase chain reaction (RT-PCR) and flow cytometry. Preventive and therapeutic oral administration of euphol attenuated both DSS- and TNBS-induced acute colitis as observed by a significant reduction of the disease activity index (DAI), histological/microscopic damage score and myeloperoxidase (MPO) activity in colonic tissue. Likewise, euphol treatment also inhibited colon tissue levels and expression of IL-1β, CXCL1/KC, MCP-1, MIP-2, TNF-α and IL-6, while reducing NOS2, VEGF and Ki67 expression in colonic tissue. This action seems to be likely associated with inhibition of activation of nuclear factor-κB (NF-κB). In addition, euphol decreased LPS-induced MCP-1, TNF-α, IL-6 and IFN-γ, but increased IL-10 secretion from bone marrow-derived macrophages in vitro. Of note, euphol, at the same schedule of treatment, markedly inhibited both selectin (P- and E-selectin) and integrin (ICAM-1, VCAM-1 and LFA-1) expression in colonic tissue. Conclusions/Significance Together, these results clearly demonstrated that orally-administered euphol, both preventive or therapeutic treatment were effective in reducing the severity of colitis in two models of chemically-induced mouse colitis and suggest this plant

  15. Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis

    PubMed Central

    Shi, Xuan-Zheng; Winston, John H.

    2011-01-01

    Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Gαq protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the α1C1b subunit of Cav1.2b channels, CPI-17 and Gαq. TNBS inflammation increased IGF-1 and TGF-β time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-β induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of

  16. A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents

    PubMed Central

    Randhawa, Puneet Kaur; Singh, Kavinder; Singh, Nirmal

    2014-01-01

    Ulcerative colitis and Crohn's disease are a set of chronic, idiopathic, immunological and relapsing inflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, development of various animal models provides new insights to unveil the onset and the progression of IBD. Various chemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closely mimic morphological, histopathological and symptomatical features of human IBD. Among the chemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazolone induced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBS elicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response of Th-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. The present review discusses the methodology and rationale of using various chemical-induced colitis models for evaluating the pathogenesis of IBD. PMID:25177159

  17. Cytomegalovirus-induced Hemorrhagic Colitis in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy.

    PubMed

    Yassin, Mohamed A; Nashwan, Abdulqadir J; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afra; AlBattah, Afaf; Mohamed, Shehab F; Mudawi, Deena S; Elkourashy, Sarah; Asaari, Deena-Raiza; Gutierrez, Hope-Love G; Almusharaf, Mohamed; Hussein, Radwa M; Moustafa, Abbas H; Derhoubi, Hatim El; Boukhris, Sarra; Kohla, Samah; AlDewik, Nader

    2015-01-01

    Dasatinib is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase and accelerated (myeloid or lymphoid blast) phase, and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia1 The most common adverse reactions (≥15%) in patients with newly diagnosed chronic-phase (CP) CML include myelosuppression, fluid retention, and diarrhea, whereas in patients with resistance or intolerance to prior imatinib therapy, side effects include myelosuppression, fluid retention, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. We report a 39-year-old Ethiopian female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for two months, which progressed to hemorrhagic colitis due to cytomegalovirus (CMV) infection of the colon. To our knowledge, this is the first case of CMV colitis in a patient receiving dasatinib as upfront therapy. PMID:26379451

  18. Cytomegalovirus-induced Hemorrhagic Colitis in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy

    PubMed Central

    Yassin, Mohamed A; Nashwan, Abdulqadir J; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afra; AlBattah, Afaf; Mohamed, Shehab F; Mudawi, Deena S; Elkourashy, Sarah; Asaari, Deena-Raiza; Gutierrez, Hope-Love G; Almusharaf, Mohamed; Hussein, Radwa M; Moustafa, Abbas H; Derhoubi, Hatim El; Boukhris, Sarra; Kohla, Samah; AlDewik, Nader

    2015-01-01

    Dasatinib is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase and accelerated (myeloid or lymphoid blast) phase, and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia1 The most common adverse reactions (≥15%) in patients with newly diagnosed chronic-phase (CP) CML include myelosuppression, fluid retention, and diarrhea, whereas in patients with resistance or intolerance to prior imatinib therapy, side effects include myelosuppression, fluid retention, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. We report a 39-year-old Ethiopian female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for two months, which progressed to hemorrhagic colitis due to cytomegalovirus (CMV) infection of the colon. To our knowledge, this is the first case of CMV colitis in a patient receiving dasatinib as upfront therapy. PMID:26379451

  19. A budesonide prodrug accelerates treatment of colitis in rats.

    PubMed Central

    Cui, N; Friend, D R; Fedorak, R N

    1994-01-01

    Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-beta-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hours with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colonic fluid absorption. Adrenal suppression was determined by measuring plasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-treated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion. Treatment with oral budesonide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatment with budesonide-beta-D-glucuronide did not result in adrenal suppression whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing with limited adrenal suppression. Development of an orally administered colon-specific steroid delivery system represents a novel approach to inflammatory bowel disease treatment. PMID:7959202

  20. Novel pH-sensitive hydrogels for 5-aminosalicylic acid colon targeting delivery: in vivo study with ulcerative colitis targeting therapy in mice.

    PubMed

    Bai, Xia Yan; Yan, Yan; Wang, Lin; Zhao, Lan Gui; Wang, Ke

    2016-07-01

    Current guidelines recommend patients with active and mild-to-moderate ulcerative colitis (UC), who have received initial therapy with 5-aminosalicylic acid (5-ASA). In this study, a novel drug delivery vehicle achieved by pH-sensitive hydrogels was applied to 5-ASA. In our previous work, a novel P(CE-MAA-MEG) pH-sensitive hydrogel was successfully synthesized by the heat-initiated free radical polymerization method. The aim of this study is to investigate its site-specific delivering of drugs to the colon and evaluate its colon-targeting characteristic in vivo. 5-ASA was chosen as a model drug and successfully loaded in the hydrogel. In vitro investigations were carried out to evaluate its release process. Above all, animal treatment results reveal an obvious effect on the UC healing. Therefore, all results suggested that the developed 5-ASA-P(CE-MAA-MEG) hydrogel (5-ASA-GEL) as a colon-targeting vector might have a great potential application in the UC therapy. PMID:25693641

  1. Experimental Colitis Is Attenuated by Cardioprotective Diet Supplementation That Reduces Oxidative Stress, Inflammation, and Mucosal Damage

    PubMed Central

    Vargas Robles, Hilda; Citalán Madrid, Alí Francisco; García Ponce, Alexander; Silva Olivares, Angelica; Shibayama, Mineko; Betanzos, Abigail; Del Valle Mondragón, Leonardo; Nava, Porfirio; Schnoor, Michael

    2016-01-01

    Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are multifactorial, relapsing disorders of the gastrointestinal tract. However, the etiology is still poorly understood but involves altered immune responses, epithelial dysfunction, environmental factors, and nutrition. Recently, we have shown that the diet supplement corabion has cardioprotective effects due to reduction of oxidative stress and inflammation. Since oxidative stress and inflammation are also prominent risk factors in IBD, we speculated that corabion also has beneficial effects on experimental colitis. Colitis was induced in male mice by administration of 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 3 or 7 days with or without daily gavage feeding of corabion consisting of vitamin C, vitamin E, L-arginine, and eicosapentaenoic and docosahexaenoic acid. We found that corabion administration attenuated DSS-induced colon shortening, tissue damage, and disease activity index during the onset of colitis. Mechanistically, these effects could be explained by reduced neutrophil recruitment, oxidative stress, production of proinflammatory cytokines, and internalization of the junctional proteins ZO-1 and E-cadherin leading to less edema formation. Thus, corabion may be a useful diet supplement for the management of chronic inflammatory intestinal disorders such as IBD. PMID:26881044

  2. IL-22 Restrains Tapeworm-Mediated Protection against Experimental Colitis via Regulation of IL-25 Expression

    PubMed Central

    Reyes, José L.; Fernando, Maria R.; Lopes, Fernando; Leung, Gabriella; Mancini, Nicole L.; Matisz, Chelsea E.; Wang, Arthur; McKay, Derek M.

    2016-01-01

    Interleukin (IL)-22, an immune cell-derived cytokine whose receptor expression is restricted to non-immune cells (e.g. epithelial cells), can be anti-inflammatory and pro-inflammatory. Mice infected with the tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Here we assessed expulsion of H. diminuta, the concomitant immune response and the outcome of DNBS-induced colitis in wild-type (WT) and IL-22 deficient mice (IL-22-/-) ± infection. Interleukin-22-/- mice had a mildly impaired ability to expel the worm and this correlated with reduced or delayed induction of TH2 immunity as measured by splenic and mesenteric lymph node production of IL-4, IL-5 and IL-13 and intestinal Muc-2 mRNA and goblet cell hyperplasia; in contrast, IL-25 increased in the small intestine of IL-22-/- mice 8 and 12 days post-infection compared to WT mice. In vitro experiments revealed that H. diminuta directly evoked epithelial production of IL-25 that was inhibited by recombinant IL-22. Also, IL-10 and markers of regulatory T cells were increased in IL-22-/- mice that displayed less DNBS (3 mg, ir. 72h)-induced colitis. Wild-type mice infected with H. diminuta were protected from colitis, as were infected IL-22-/- mice and the latter to a degree that they were almost indistinguishable from control, non-DNBS treated mice. Finally, treatment with anti-IL-25 antibodies exaggerated DNBS-induced colitis in IL-22-/- mice and blocked the anti-colitic effect of infection with H. diminuta. Thus, IL-22 is identified as an endogenous brake on helminth-elicited TH2 immunity, reducing the efficacy of expulsion of H. diminuta and limiting the effectiveness of the anti-colitic events mobilized following infection with H. diminuta in a non-permissive host. PMID:27055194

  3. IL-22 Restrains Tapeworm-Mediated Protection against Experimental Colitis via Regulation of IL-25 Expression.

    PubMed

    Reyes, José L; Fernando, Maria R; Lopes, Fernando; Leung, Gabriella; Mancini, Nicole L; Matisz, Chelsea E; Wang, Arthur; McKay, Derek M

    2016-04-01

    Interleukin (IL)-22, an immune cell-derived cytokine whose receptor expression is restricted to non-immune cells (e.g. epithelial cells), can be anti-inflammatory and pro-inflammatory. Mice infected with the tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Here we assessed expulsion of H. diminuta, the concomitant immune response and the outcome of DNBS-induced colitis in wild-type (WT) and IL-22 deficient mice (IL-22-/-) ± infection. Interleukin-22-/- mice had a mildly impaired ability to expel the worm and this correlated with reduced or delayed induction of TH2 immunity as measured by splenic and mesenteric lymph node production of IL-4, IL-5 and IL-13 and intestinal Muc-2 mRNA and goblet cell hyperplasia; in contrast, IL-25 increased in the small intestine of IL-22-/- mice 8 and 12 days post-infection compared to WT mice. In vitro experiments revealed that H. diminuta directly evoked epithelial production of IL-25 that was inhibited by recombinant IL-22. Also, IL-10 and markers of regulatory T cells were increased in IL-22-/- mice that displayed less DNBS (3 mg, ir. 72h)-induced colitis. Wild-type mice infected with H. diminuta were protected from colitis, as were infected IL-22-/- mice and the latter to a degree that they were almost indistinguishable from control, non-DNBS treated mice. Finally, treatment with anti-IL-25 antibodies exaggerated DNBS-induced colitis in IL-22-/- mice and blocked the anti-colitic effect of infection with H. diminuta. Thus, IL-22 is identified as an endogenous brake on helminth-elicited TH2 immunity, reducing the efficacy of expulsion of H. diminuta and limiting the effectiveness of the anti-colitic events mobilized following infection with H. diminuta in a non-permissive host. PMID:27055194

  4. Antagonism of protease-activated receptor 2 protects against experimental colitis.

    PubMed

    Lohman, Rink-Jan; Cotterell, Adam J; Suen, Jacky; Liu, Ligong; Do, Anh T; Vesey, David A; Fairlie, David P

    2012-02-01

    Many trypsin-like serine proteases such as β-tryptase are involved in the pathogenesis of colitis and inflammatory bowel diseases. Inhibitors of individual proteases show limited efficacy in treating such conditions, but also probably disrupt digestive and defensive functions of proteases. Here, we investigate whether masking their common target, protease-activated receptor 2 (PAR2), is an effective therapeutic strategy for treating acute and chronic experimental colitis in rats. A novel PAR2 antagonist (5-isoxazoyl-Cha-Ile-spiro[indene-1,4'-piperidine]; GB88) was evaluated for the blockade of intracellular calcium release in colonocytes and anti-inflammatory activity in acute (PAR2 agonist-induced) versus chronic [2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced] models of colitis in Wistar rats. Disease progression (disease activity index, weight loss, and mortality) and postmortem colonic histopathology (inflammation, bowel wall thickness, and myeloperoxidase) were measured. PAR2 and tryptase colocalization were investigated by using immunohistochemistry. GB88 was a more potent antagonist of PAR2 activation in colonocytes than another reported compound, N¹-3-methylbutyryl-N⁴-6-aminohexanoyl-piperazine (ENMD-1068) (IC₅₀ 8 μM versus 5 mM). Acute colonic inflammation induced in rats by the PAR2 agonist SLIGRL-NH₂ was inhibited by oral administration of GB88 (10 mg/kg) with markedly reduced edema, mucin depletion, PAR2 receptor internalization, and mastocytosis. Chronic TNBS-induced colitis in rats was ameliorated by GB88 (10 mg/kg/day p.o.), which reduced mortality and pathology (including colon obstruction, ulceration, wall thickness, and myeloperoxidase release) more effectively than the clinically used drug sulfasalazine (100 mg/kg/day p.o.). These disease-modifying properties for the PAR2 antagonist in both acute and chronic experimental colitis strongly support a pathogenic role for PAR2 and PAR2-activating proteases and therapeutic potential for

  5. Effectiveness of a hydroxynaphthoquinone fraction from Arnebia euchroma in rats with experimental colitis

    PubMed Central

    Fan, Hua-Ying; Zhang, Zi-Liang; Liu, Ke; Yang, Ming-Yan; Lv, Wei-Hong; Che, Xin; Xu, Hui; Song, Wei-Wei

    2013-01-01

    AIM: To evaluate the potential effectiveness of hydroxynaphthoquinone mixture (HM) in rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: Colitis was induced by intracolonic administration of TNBS (80 mg/kg, dissolved in 50% ethanol). Rats were treated daily for 7 d with HM (2.5, 5, 10 mg/kg) and mesalazine 100 mg/kg 24 h after TNBS instillation. Disease progression was monitored daily by observation of clinical signs and body weight change. At the end of the experiment, macroscopic and histopathologic lesions of rats were scored, and myeloperoxidase (MPO) activity was determined. We also determined inflammatory cytokine tumor necrosis factor (TNF)-α level by ELISA, Western blotting and immunochemistry to explore the potential mechanisms of HM. RESULTS: After intracolonic instillation of TNBS, animals developed colitis associated with soft stool, diarrhea and marked colonic destruction. Administration of HM significantly attenuated clinical and histopathologic severity of TNBS-induced colitis in a dose-dependent manner. It abrogated body weight loss, diarrhea and inflammation, decreased macroscopic damage score, and improved histological signs, with a significant reduction of inflammatory infiltration, ulcer size and the severity of goblet cell depletion (all P < 0.05 vs TNBS alone group). HM could reduce MPO activity. In addition, it also decreased serum TNF-α level and down-regulated TNF-α expression in colonic tissue. This reduction was statistically significant when the dose of HM was 10 mg/kg (P < 0.05 vs TNBS alone group), and the effect was comparable to that of mesalazine and showed no apparent adverse effect. The underlying mechanism may be associated with TNF-α inhibition. CONCLUSION: These findings suggest that HM possesses favourable therapeutic action in TNBS-induced colitis, which provides direct pharmacological evidence for its clinical application. PMID:24409058

  6. Bile acids in radiation-induced diarrhea

    SciTech Connect

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-10-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style.

  7. PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

    PubMed Central

    Zhou, Xueyan; Cao, Lijuan; Jiang, Changtao; Xie, Yang; Cheng, Xuefang; Krausz, Kristopher W.; Qi, Yunpeng; Sun, Lu; Shah, Yatrik M.; Gonzalez, Frank J.; Wang, Guangji; Hao, Haiping

    2014-01-01

    Bile acids play a pivotal role in the pathological development of inflammatory bowel disease (IBD). However, the mechanism of bile acid dysregulation in IBD remains unanswered. Here we show that intestinal peroxisome proliferator-activated receptor α (PPARα)-UDP-glucuronosyltransferases (UGTs) signalling is an important determinant of bile acid homeostasis. Dextran sulphate sodium (DSS)-induced colitis leads to accumulation of bile acids in inflamed colon tissues via activation of the intestinal peroxisome PPARα-UGTs pathway. UGTs accelerate the metabolic elimination of bile acids, and thereby decrease their intracellular levels in the small intestine. Reduced intracellular bile acids results in repressed farnesoid X receptor (FXR)-FGF15 signalling, leading to upregulation of hepatic CYP7A1, thus promoting the de novo bile acid synthesis. Both knockout of PPARα and treatment with recombinant FGF19 markedly attenuate DSS-induced colitis. Thus, we propose that intestinal PPARα-UGTs and downstream FXR-FGF15 signalling play vital roles in control of bile acid homeostasis and the pathological development of colitis. PMID:25183423

  8. A new therapeutic association to manage relapsing experimental colitis: Doxycycline plus Saccharomyces boulardii.

    PubMed

    Garrido-Mesa, José; Algieri, Francesca; Rodriguez-Nogales, Alba; Utrilla, Maria Pilar; Rodriguez-Cabezas, Maria Elena; Zarzuelo, Antonio; Ocete, Maria Angeles; Garrido-Mesa, Natividad; Galvez, Julio

    2015-07-01

    Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti-inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25 mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses. PMID:25917208

  9. Melatonin improves experimental colitis with sleep deprivation

    PubMed Central

    PARK, YOUNG-SOOK; CHUNG, SOOK-HEE; LEE, SEONG-KYU; KIM, JA-HYUN; KIM, JUN-BONG; KIM, TAE-KYUN; KIM, DONG-SHIN; BAIK, HAING-WOON

    2015-01-01

    Sleep deprivation (SD) is an epidemic phenomenon in modern countries, and its harmful effects are well known. SD acts as an aggravating factor in inflammatory bowel disease. Melatonin is a sleep-related neurohormone, also known to have antioxidant and anti-inflammatory effects in the gastrointestinal tract; however, the effects of melatonin on colitis have been poorly characterized. Thus, in this study, we assessed the measurable effects of SD on experimental colitis and the protective effects of melatonin. For this purpose, male imprinting control region (ICR) mice (n=24) were used; the mice were divided into 4 experimental groups as follows: the control, colitis, colitis with SD and colitis with SD and melatonin groups. Colitis was induced by the administration of 5% dextran sulfate sodium (DSS) in the drinking water for 6 days. The mice were sleep-deprived for 3 days. Changes in body weight, histological analyses of colon tissues and the expression levels of pro-inflammatory cytokines and genes were evaluated. SD aggravated inflammation and these effects were reversed by melatonin in the mice with colitis. In addition, weight loss in the mice with colitis with SD was significantly reduced by the injection of melatonin. Treatment with melatonin led to high survival rates in the mice, in spite of colitis with SD. The levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-17, interferon-γ and tumor necrosis factor-α, in the serum of mice were significantly increased by SD and reduced by melatonin treatment. The melatonin-treated group showed a histological improvement of inflammation. Upon gene analysis, the expression of the inflammatory genes, protein kinase Cζ (PKCζ) and calmodulin 3 (CALM3), was increased by SD, and the levels decreased following treatment with melatonin. The expression levels of the apoptosis-related inducible nitric oxide synthase (iNOS) and wingless-type MMTV integration site family, member 5A (Wnt5a) genes was

  10. Ethanol extract of Cordyceps militaris grown on germinated soybeans attenuates dextran-sodium-sulfate- (DSS-) induced colitis by suppressing the expression of matrix metalloproteinases and inflammatory mediators.

    PubMed

    Park, Dong Ki; Park, Hye-Jin

    2013-01-01

    The effect of Cordyceps militaris (CM) grown on germinated soybeans (GSC) in the inflammatory bowel disease (IBD) model was studied. To demonstrate the preventive effect of GSC extract in a dextran-sodium-sulfate- (DSS-) induced acute colitis mouse model, GSC was administered 2 days before DSS coadministration. GSC significantly suppressed DSS-induced disease activity index (DAI) as well as histopathological scores, compared to control or CM-treated group. To elucidate the anti-IBD activity of GSC, we checked the level of matrix metalloproteinases (MMPs) and inflammatory mediators. GSC extract decreased the level of MMP-3 and -9 mRNAs and p53 proteins. The level and activity of LPS-induced MMP-9 were reduced in GSC-treated RAW264.7 cells. It also attenuated the level of inducible nitric oxide synthase (iNOS) and tumor necrosis factor- (TNF-) α mRNAs both in colon tissue and in macrophage cells. These results suggest that GSC can be applied as a protective agent against IBDs. PMID:23841050

  11. Qingchang Wenzhong Decoction Ameliorates Dextran Sulphate Sodium-Induced Ulcerative Colitis in Rats by Downregulating the IP10/CXCR3 Axis-Mediated Inflammatory Response

    PubMed Central

    Mao, Tang-you; Shi, Rui; Zhao, Wei-han; Guo, Yi; Gao, Kang-li; Chen, Chen; Xie, Tian-hong; Li, Jun-xiang

    2016-01-01

    Qingchang Wenzhong Decoction (QCWZD) is an effective traditional Chinese medicine prescription. Our previous studies have shown that QCWZD has significant efficacy in patients with mild-to-moderate ulcerative colitis (UC) and in colonic mucosa repair in UC rat models. However, the exact underlying mechanism remains unknown. Thus, this study was conducted to determine QCWZD's efficacy and mechanism in dextran sulphate sodium- (DSS-) induced UC rat models, which were established by 7-day administration of 4.5% DSS solution. QCWZD was administered daily for 7 days, after which the rats were euthanized. Disease activity index (DAI), histological score (HS), and myeloperoxidase (MPO) level were determined to evaluate UC severity. Serum interferon gamma-induced protein 10 (IP10) levels were determined using ELISA kits. Western blotting and real-time polymerase chain reaction were, respectively, used to determine colonic protein and gene expression of IP10, chemokine (cys-x-cys motif) receptor (CXCR)3, and nuclear factor- (NF-) κB p65. Intragastric QCWZD administration ameliorated DSS-induced UC, as evidenced by decreased DAI, HS, and MPO levels. Furthermore, QCWZD decreased the protein and gene expression of IP10, CXCR3, and NF-κB p65. Overall, these results suggest that QCWZD ameliorates DSS-induced UC in rats by downregulating the IP10/CXCR3 axis-mediated inflammatory response and may be a novel UC therapy. PMID:27413386

  12. Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility.

    PubMed

    Ward, Marc A; Pierre, Joseph F; Leal, Raquel F; Huang, Yong; Shogan, Benjamin; Dalal, Sushila R; Weber, Christopher R; Leone, Vanessa A; Musch, Mark W; An, Gary C; Rao, Mrinalini C; Rubin, David T; Raffals, Laura E; Antonopoulos, Dionysios A; Sogin, Mitch L; Hyman, Neil H; Alverdy, John C; Chang, Eugene B

    2016-06-01

    Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SEL remain empty. In WT mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions. PMID:27079612

  13. Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer

    PubMed Central

    Lo Sasso, Giuseppe; Ryu, Dongryeol; Mouchiroud, Laurent; Fernando, Samodha C.; Anderson, Christopher L.; Katsyuba, Elena; Piersigilli, Alessandra; Hottiger, Michael O.; Schoonjans, Kristina; Auwerx, Johan

    2014-01-01

    Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int−/−) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC. PMID:25013930

  14. CYTOKINE-INDUCED ALTERATIONS OF α7 NICOTINIC RECEPTOR IN COLONIC CD4 T CELLS MEDIATE DICHOTOMOUS RESPONSE TO NICOTINE IN MURINE MODELS OF Th1/Th17 VS. Th2-MEDIATED COLITIS

    PubMed Central

    Galitovskiy, Valentin; Qian, Jing; Chernyavsky, Alexander I.; Marchenko, Steve; Gindi, Vivian; Edwards, Robert A.; Grando, Sergei A.

    2014-01-01

    Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease. CD4 T cells play a central role in the pathogenesis of both diseases. Smoking affects both UC and CD but with opposite effects, ameliorating UC and worsening CD. We hypothesized that the severity of gut inflammation could be modulated through T-cell nicotinic acetylcholine receptors (nAChRs) and that the exact clinical outcome would depend on the repertoire of nAChRs on CD4 T cells mediating each form of colitis. We measured clinical and immunologic outcomes of treating BALB/c mice with oxazolone- and TNBS-induced colitides by nicotine. Nicotine attenuated oxazolone colitis, which was associated with increased percentage of colonic Tregs and a reduction of Th17 cells. TCR stimulation of naïve CD4+CD62L+ T cells in the presence of nicotine upregulated expression of Foxp3. In marked contrast, nicotine worsened TNBS colitis, and this was associated with increased Th17 cells among colonic CD4 T cells. Nicotine upregulated IL-10 and inhibited IL-17 production, which could be abolished by exogenous IL-12 that also abolished the nicotine-dependent upregulation of Tregs. The dichotomous action of nicotine resulted from the up- and downregulation of anti-inflammatory α7 nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu in oxazolone (IL-4), and TNBS (IL-12) colitis, respectively. These findings help explain the dichotomous effect of smoking in patients with UC and CD, and underscore the potential for nicotinergic drugs in regulating colonic inflammation. PMID:21784975

  15. Enhanced excitability of guinea pig inferior mesenteric ganglion neurons during and following recovery from chemical colitis.

    PubMed

    Linden, David R

    2012-11-01

    Postganglionic sympathetic neurons in the prevertebral ganglia (PVG) provide ongoing inhibitory tone to the gastrointestinal tract and receive innervation from mechanosensory intestinofugal afferent neurons primarily located in the colon and rectum. This study tests the hypothesis that colitis alters the excitability of PVG neurons. Intracellular recording techniques were used to evaluate changes in the electrical properties of inferior mesenteric ganglion (IMG) neurons in the trinitrobenzene sulfonic acid (TNBS) and acetic acid models of guinea pig colitis. Visceromotor IMG neurons were hyperexcitable 12 and 24 h, but not 6 h, post-TNBS during "acute" inflammation. Hyperexcitability persisted at 6 days post-TNBS during "chronic" inflammation, as well as at 56 days post-TNBS when colitis had resolved. In contrast, there was only a modest decrease in the current required to elicit an action potential at 24 h after acetic acid administration. Vasomotor neurons from inflamed preparations exhibited normal excitability. The excitatory effects of XE-991, a blocker of the channel that contributes to the M-type potassium current, and heteropodatoxin-2, a blocker of the channel that contributes to the A-type potassium current, were unchanged in TNBS-inflamed preparations, suggesting that these currents did not contribute to hyperexcitability. Riluzole, an inhibitor of persistent sodium currents, caused tonic visceromotor neurons to accommodate to sustained current pulses, regardless of the inflammatory state of the preparation, and restored a normal rheobase in neurons from TNBS-inflamed preparations but did not alter the rheobase of control preparations, suggesting that enhanced activity of voltage-gated sodium channels may contribute to colitis-induced hyperexcitability. Collectively, these data indicate that enhanced sympathetic drive as a result of hyperexcitable visceromotor neurons may contribute to small bowel dysfunction during colitis. PMID:22961805

  16. GL-V9, a new synthetic flavonoid derivative, ameliorates DSS-induced colitis against oxidative stress by up-regulating Trx-1 expression via activation of AMPK/FOXO3a pathway

    PubMed Central

    Ding, Youxiang; Wang, Xiaoping; Zhou, Yuxin; Li, Wenjun; Huang, Shaoliang; Li, Zhiyu; Kong, Lingyi; Guo, Qinglong; Lu, Na

    2015-01-01

    GL-V9, a new synthesized flavonoid derivative, has been reported to possess anti-cancer properties in our previous studies. Uncontrolled overproduction of reactive oxygen species (ROS) has been implicated in oxidative damage of inflammatory bowel disease (IBD). In this study, we aimed to investigate the protective effect of GL-V9 against dextran sulfate sodium (DSS)-induced colitis. GL-V9 attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. GL-V9 also inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. Moreover, GL-V9 inhibited ROS and malondialdehyde (MDA) generation, but enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity. GL-V9 reduced pro-inflammatory cytokines production in serum and colon as well. Mechanically, GL-V9 could increase Trx-1 via activation of AMPK/FOXO3a to suppress DSS-induced colonic oxidative stress. Furthermore, GL-V9 decreased pro-inflammatory cytokines and ROS production and increased the antioxidant defenses in the mouse macrophage cells RAW264.7 by promoting Trx-1 expression. In conclusion, our study demonstrated that GL-V9 attenuated DSS-induced colitis against oxidative stress by up-regulating Trx-1 via activation of AMPK/FOXO3a pathway, suggesting that GL-V9 might be a potential effective drug for colitis. PMID:26327408

  17. Monotropein isolated from the roots of Morinda officinalis ameliorates proinflammatory mediators in RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis via NF-κB inactivation.

    PubMed

    Shin, Ji-Sun; Yun, Kyung-Jin; Chung, Kyung-Sook; Seo, Kyeong-Hwa; Park, Hee-Juhn; Cho, Young-Wuk; Baek, Nam-In; Jang, Daesik; Lee, Kyung-Tae

    2013-03-01

    We previously demonstrated that monotropein isolated from the roots of Morinda officinalis (Rubiaceae) has anti-inflammatory effects in vivo. In the present study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA in LPS-induced RAW 264.7 macrophages. Treatment with monotropein decreased the DNA binding activity of nuclear factor-κB (NF-κB). Consistent with these findings, monotropein also suppressed phosphorylation and degradation of inhibitory κB-α (IκB-α), and consequently the translocations of NF-κB. In the DSS-induced colitis model, monotropein reduced disease activity index (DAI), myeloperoxidase (MPO) activity, and inflammation-related protein expressions by suppressing NF-κB activation in colon mucosa. Taken together, these findings suggest that the anti-inflammatory effects of monotropein are mainly related to the inhibition of the expressions of inflammatory mediators via NF-κB inactivation, and support its possible therapeutic role in colitis. PMID:23261679

  18. GL-V9, a new synthetic flavonoid derivative, ameliorates DSS-induced colitis against oxidative stress by up-regulating Trx-1 expression via activation of AMPK/FOXO3a pathway.

    PubMed

    Zhao, Yue; Sun, Yang; Ding, Youxiang; Wang, Xiaoping; Zhou, Yuxin; Li, Wenjun; Huang, Shaoliang; Li, Zhiyu; Kong, Lingyi; Guo, Qinglong; Lu, Na

    2015-09-22

    GL-V9, a new synthesized flavonoid derivative, has been reported to possess anti-cancer properties in our previous studies. Uncontrolled overproduction of reactive oxygen species (ROS) has been implicated in oxidative damage of inflammatory bowel disease (IBD). In this study, we aimed to investigate the protective effect of GL-V9 against dextran sulfate sodium (DSS)-induced colitis. GL-V9 attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. GL-V9 also inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. Moreover, GL-V9 inhibited ROS and malondialdehyde (MDA) generation, but enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity. GL-V9 reduced pro-inflammatory cytokines production in serum and colon as well. Mechanically, GL-V9 could increase Trx-1 via activation of AMPK/FOXO3a to suppress DSS-induced colonic oxidative stress. Furthermore, GL-V9 decreased pro-inflammatory cytokines and ROS production and increased the antioxidant defenses in the mouse macrophage cells RAW264.7 by promoting Trx-1 expression. In conclusion, our study demonstrated that GL-V9 attenuated DSS-induced colitis against oxidative stress by up-regulating Trx-1 via activation of AMPK/FOXO3a pathway, suggesting that GL-V9 might be a potential effective drug for colitis. PMID:26327408

  19. Lactobacillus GG-fermented milk prevents DSS-induced colitis and regulates intestinal epithelial homeostasis through activation of epidermal growth factor receptor

    PubMed Central

    Yoda, Kazutoyo; Miyazawa, Kenji; Hosoda, Masataka; Hiramatsu, Masaru; Yan, Fang; He, Fang

    2014-01-01

    Background Fermented milk is considered one of the best sources for efficient consumption of probiotic strains by hosts to promote good health. The purpose of this study was to investigate the effects of orally administering LGG-fermented milk (LGG milk) on intestinal inflammation and injury and to study the mechanisms of LGG milk's action. Methods LGG milk and non-LGG-fermented milk (non-LGG milk) were administered through gavage to mice before and during dextran sodium sulfate (DSS)-induced intestinal injury and colitis. Inflammatory/injury score and colon length were assessed. Intestinal epithelial cells were treated with the soluble fraction of LGG milk to detect its effects on the epidermal growth factor receptor (EGFR) and its down stream target, Akt activation, cytokine-induced apoptosis, and hydrogen peroxide (H2O2)-induced disruption of tight junctions. Results LGG milk treatment significantly reduced DSS-induced colonic inflammation and injury, and colon shortening in mice, compared to that in non-LGG milk-treated and untreated mice. The soluble fraction of LGG milk, but not non-LGG milk, stimulated activation of EGFR and Akt in a concentration-dependent manner, suppressed cytokine-induced apoptosis, and attenuated H2O2-induced disruption of tight junction complex in the intestinal epithelial cells. These effects of LGG milk were blocked by the EGFR kinase inhibitor. LGG milk, but not non-LGG milk, contained two soluble proteins, p40 and p75, which have been reported to promote survival and growth of intestinal epithelial cells through activation of EGFR. Depletion of p40 and p75 from LGG milk abolished the effects of LGG milk on prevention of cytokine-induced apoptosis and H2O2-induced disruption of tight junctions. Conclusions These results suggest that LGG milk may regulate intestinal epithelial homeostasis and potentially prevent intestinal inflammatory diseases through activation of EGFR by LGG-derived proteins.