Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis

Filho, Nélson Alexandre Kretzmann; Fillmann, Henrique Sarubbi; Mauriz, José L.; Marroni, Cláudio Augusto; Marroni, Norma Possa; González‐Gallego, Javier; Tuñón, María J.

doi:10.1002/ibd.20543

Cited by 110 publications

(107 citation statements)

References 63 publications

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“…Indeed, activation of these pathways has been described in conjunction with dextran sulfate sodium-induced colitis in mice and TNBS-induced colitis in rodents (Bai et al, 2007;Kretzmann et al, 2008;Youn et al, 2009;Fitzpatrick et al, 2011b). Moreover, we have reported that Vido inhibits activation of these intracellular signaling pathways in the mouse colon and murine splenocytes (Fitzpatrick et al, 2011b).…”

Section: Discussionmentioning

confidence: 78%

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Fitzpatrick

Small

Doblhofer

et al. 2012

J Pharmacol Exp Ther

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Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation. Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and the parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. To further delineate the mechanism of action for Vido, rats were dosed concomitantly with uridine (Uri). Young Wistar rats received a 150-l enema of either phosphate-buffered saline (PBS) or TNBS on study day 1. The ex vivo effects of Vido on 24-h colonic IL-17 secretion were determined by using colonic strips from PBS-or TNBStreated rats. Some rats were dosed with vehicle, Vido, or Vido ϩ Uri for 6 days. On day 6, the parameters of colitis were determined from colonic tissue. These parameters included macroscopic, histological, and transcription factor measurements, IL-17 production, and numbers of CD3 ϩ T cells. Ex vivo Vido completely blocked IL-23 ϩ IL-1␤-stimulated secretion of IL-17 by colonic strips. In vivo Vido treatment alone most effectively reduced macroscopic and histological pathology and the numbers of CD3 ϩ T cells. In contrast, similarly reduced nuclear signal transducer and activator of transcription 3 (STAT3) binding and IL-17 levels were observed from animals treated with Vido alone and Vido ϩ Uri. Vido improves TNBS-induced colonic inflammation by a unique dual mode of action: 1) inhibiting expansion of colonic T lymphocytes, and 2) suppressing colonic IL-17 production, which is independent from the control of T-lymphocyte proliferation, by inhibition of STAT3 and nuclear factor-B activation.

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Section: Discussionmentioning

confidence: 78%

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Fitzpatrick

Small

Doblhofer

et al. 2012

J Pharmacol Exp Ther

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“…35,46 The action of glutamine on cytokine production is mediated by different signaling pathways (Fig. 2), including nuclear factor kappa B (NF-jB), 16,46,47,50,51 signal transducer and activator of transcription (STAT), 37,47 Jun N-terminal kinase (JNK), 48 or peroxisome proliferator-activated receptor-c (PPARc). 49 During IBD, oxidative stress is increased in intestinal mucosa and antioxidative defenses, especially glutathione, are reduced.…”

Section: Glutaminementioning

confidence: 99%

Potential for amino acids supplementation during inflammatory bowel diseases

Coëffier

Marion‐Letellier

Déchelotte

2010

Inflammatory Bowel Diseases

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The pathophysiology of inflammatory bowel diseases (IBDs) is multifactorial and involves interactions of gut luminal content with mucosal barrier and especially immune cells. Malnutrition is a frequent issue during IBD flares, especially in Crohn's disease (CD) patients, and nutritional support is frequently used to treat malnutrition but also in an attempt to modulate intestinal inflammation. The use of oral or enteral nutrition intervention in IBDs may be effective, alone or in combination with drugs, to achieve and maintain remission. However, standard diets are less effective than new-generation biotherapies and could be improved by supplementation with specific immunomodulatory amino acids. Experimental studies evaluating glutamine, the preferential substrate for enterocytes, are promising. Some clinical studies with oral glutamine in CD are until now disappointing, but new formulations and targeting could enhance glutamine efficacy at the site of mucosal lesions. The role of arginine, involved in nitric oxide and polyamines synthesis, still remains debated. However, the effects of these amino acids in IBD have been poorly documented in humans. Other candidates like glycine, cysteine, histidine, or taurine should also be evaluated in the future.

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“…After washing with Trisbuffered saline containing 0.05% Tween 20, the membranes were incubated for 1 hour at room temperature with secondary horseradish peroxidaseconjugated antibody (1:5000; Dako, Glostrup, Denmark), and visualized using enhanced chemiluminescence (ECL) detection kit (Amersham Pharmacia, Uppsala, Sweden). 27 The density of the specific bands was quantified with an imaging densitometer (Scion Image J Software 1.46a, Bethesda, Maryland).…”

Section: Real-time Reverse Transcription-polymerase Chainmentioning

confidence: 99%

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo

San‐Miguel

Fernández

et al. 2015

Translational Research

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We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl 4 ). Mice in treatment groups received CCl 4 5 mL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl 4 administration. Treatment with CCl 4 resulted in fibrosis evidenced by the staining of Van Gieson and a-smooth muscle actin (a-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl 4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-b, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of a-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-b, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl 4 -induced liver fibrosis. (Translational Research 2015;165:346-357) Abbreviations: a-SMA ¼ a-smooth muscle actin; CCl 4 ¼ carbon tetrachloride; CTGF ¼ connective tissue growth factor; HSC ¼ hepatic stellate cell; MMP-9 ¼ matrix metalloproteinase 9; Nrf2 ¼ nuclear factor erythroid 2-related factor 2; PDGF ¼ platelet-derived growth factor; TGF-b ¼ transforming growth factor b; TIMP-1 ¼ tissue inhibitor of metalloproteinase 1 H epatic fibrosis is a reversible wound-healing response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by an excessive deposition of extracellular matrix (ECM) resulting in liver dysfunction and irreversible cirrhosis. During liver fibrogenesis, hepatic stellate cells (HSCs) undergo activation to a a-smooth muscle actin (SMA)-positive myofibroblastic phenotype and synthesize excess ECM components, particularly collagen. 1 Among the numerous From the

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Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis

Cited by 110 publications

References 63 publications

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Potential for amino acids supplementation during inflammatory bowel diseases

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

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