Uhrf1-Mediated Tnf-α Gene Methylation Controls Pro-Inflammatory Macrophages in Experimental Colitis Resembling IBD

AbstractThe aim of this study was to evaluate the preventive and/or protective action of Mimosa caesalpiniifolia (M. caesalpiniifolia) following experimental colitis in rats. The rats were randomized into ten groups (n=10 per group), as follows: G1 – Sham group:; G2 – TNBS group; G3, G4 –colitis and treated with hydroalcoholic extract of M. caesalpiniifolia 250 mg/kg/day after and before/after inducing colitis, respectively; G5, G6 – colitis and treated with hydroalcoholic extract of M. caesalpiniifolia at 125 mg/kg/day after and before/after inducing colitis respectively; G7,G8 – colitis and treated with ethylacetate fraction of M. caesalpiniifolia at 50 mg/kg/day after and before/after inducing colitis, respectively; G9,G10 – colitis and treated with ethylacetate fraction of M. caesalpiniifolia at 50 mg/kg/day after and before/after inducing colitis, respectively. Rats treated with hydroalcoholic extract of M. caesalpiniifolia for both doses showed lower tissue damage in the distal colon. Ethylacetate fraction was effective at the highest dose only when administrated after inducing colitis. A downregulation of COX-2 was detected to rats suffering colitis and treated with M. caesalpiniifolia at high dose. On the other hand, TNF-alpha immunoexpression decreased in groups treated with M. caesalpiniifolia at low dose after inducing colitis. In summary, our results suggest that M. caesalpiniifolia attenuated the lesions of the colon, reduced inflammation, and modulates the expression of COX-2 and TNF-α during chronic colitis induced by TNBS when using for therapeutic purposes on a dose-dependent manner.

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Anticolitic Effect of Berberine in Rat Experimental Model: Impact of PGE2/p38 MAPK Pathways

Mediators of Inflammation ◽

10.1155/2020/9419085 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Li Jia ◽

Kuijin Xue ◽

Junheng Liu ◽

Ola A. Habotta ◽

Lianhai Hu ◽

...

Keyword(s):

Mrna Expression ◽

P38 Mapk ◽

Experimental Colitis ◽

Mucosal Damage ◽

Isoquinoline Alkaloid ◽

Protective Mechanism ◽

Colon Mucosa ◽

Tnf Α ◽

Anti Inflammatory ◽

High Doses

Berberine (BER), a natural isoquinoline alkaloid, has been demonstrated to have appreciable anticolitis effects. Nevertheless, the protective mechanism of BER in ulcerative colitis (UC) is barely understood. The present study was aimed at exploring the therapeutic efficacy of BER on UC in experimental colitis rat model. Rats were orally administered with BER for seven days at low and high doses (25 and 50 mg/kg/day) before AcOH intracolonic instillation. BER significantly retrieved colon inflammation and mucosal damage indicated by inhibition of macroscopic score and lessened the levels of inflammatory biomarkers (IL-1β, IL-6, TNF-α, MPO, and PGE2). Notable downregulation of mRNA expression of p38 MAPK and increased protein expression of TGF-β were achieved by BER treatment. The anti-inflammatory potential of BER was supported by the histopathological screening of colon mucosa. In addition, BER restored colonic antioxidant capacity through elevation of GSH level and antioxidant enzymatic activities (SOD, CAT, GPx, and GR) together with reductions of both MDA and NO levels. Marked downregulation of Nos2 mRNA expression is accompanied by increased Nrf2 and Hmox-1 expressions in colon specimens treated by BER. Furthermore, BER exhibited noticeable antiapoptotic activities through decreasing proapoptotic proteins (Bax and caspase-3) and lessening antiapoptotic Bcl-2 protein in the colon mucosa. Based on these findings, BER may improve colitis markedly which may be mediated by its striking antioxidant, anti-inflammatory, and antiapoptotic properties.

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Intracellular NAD+ levels are associated with LPS-induced TNF-α release in pro-inflammatory macrophages

Bioscience Reports ◽

10.1042/bsr20150247 ◽

2016 ◽

Vol 36 (1) ◽

Cited By ~ 18

Author(s):

Abbas Jawad Al-Shabany ◽

Alan John Moody ◽

Andrew David Foey ◽

Richard Andrew Billington

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Inflammatory Cytokine ◽

Bacterial Lipopolysaccharide ◽

Tumour Necrosis Factor Α ◽

Tnf Α ◽

Factor Α ◽

Inflammatory Macrophages ◽

Inflammatory Macrophage ◽

Necrosis Factor

Bacterial lipopolysaccharide induces changes in intracellular NAD+ levels in a pro-inflammatory, but not an anti-inflammatory, macrophage model that are correlated with the release of the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α).

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Dynamics of enterocyte tight junctions: effect of experimental colitis and two different anti-TNF strategies

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00469.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. G938-G947 ◽

Cited By ~ 37

Author(s):

Walter Fries ◽

Carmelo Muja ◽

Carmela Crisafulli ◽

Salvatore Cuzzocrea ◽

Emanuela Mazzon

Keyword(s):

Intestinal Barrier ◽

Experimental Colitis ◽

Intestinal Barrier Function ◽

Cell Contact ◽

Rapid Loss ◽

Zonula Occludens ◽

Tnf Α ◽

Zonula Occludens 1 ◽

Early Effects ◽

Present Setting

An alteration of the intestinal barrier is considered to represent an early step in pathogenesis of Crohn's disease. The integrity of intestinal barrier function is guaranteed among other factors by enterocyte tight junction (TJ) proteins. Clinical and experimental data indicate the TNF-α to be the major responsible factor for these defects. In the present study we investigated the very early effects of DNBS-ethanol colitis on ileal enterocyte TJ proteins [occludin, zonula occludens-1 (ZO-1), claudin-2] in controls, mice treated with infliximab (IFX) or with etanercept (ETC), and in knockout mice for the TNF-α receptor 1 (TNFR-1−/−). Circulating TNF-α levels were effectively reduced by IFX and ETC ( P < 0.01, both) at 3 and at 6 h. DNBS colitis induced disappearance of occludin and ZO-1 from enterocyte cell-cell contact, whereas claudin-2, absent under control conditions, appeared in the ileal epithelium. These alterations were prevented equally by both treatments, IFX and ETC, and in TNFR-1−/− animals. DNBS colitis induced a very rapid loss of occludin and ZO-1 from ileal TJ together with an upregulation of claudin-2. Our data are consistent with the hypothesis that TNF-α is involved in early TJ rearrangement and that its effects are mediated through TNFR-1. Despite clinical differences, both anti-TNF treatments were equally effective in the present setting.

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Effect of Forced Physical Activity on the Severity of Experimental Colitis in Normal Weight and Obese Mice. Involvement of Oxidative Stress and Proinflammatory Biomarkers

Nutrients ◽

10.3390/nu11051127 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1127 ◽

Cited By ~ 5

Author(s):

Jan Bilski ◽

Agnieszka Mazur-Bialy ◽

Dagmara Wojcik ◽

Marcin Magierowski ◽

Marcin Surmiak ◽

...

Keyword(s):

Oxidative Stress ◽

Treadmill Exercise ◽

Experimental Colitis ◽

Treadmill Running ◽

Adaptation Period ◽

Obese Mice ◽

Trinitrobenzenesulfonic Acid ◽

Sod Activity ◽

Tnf Α ◽

Colonic Blood Flow

Inflammatory bowel diseases are a heterogeneous group of disorders represented by two major phenotypic forms, Crohn’s disease and ulcerative colitis. Cross talk between adipokines and myokines, as well as changes in intestinal microcirculation, was proposed in pathogenesis of these disorders. C57BL/6 male mice were fed ad libitum for 12 weeks a standard (SD) or high-fat diet (HFD). After the adaptation period, two groups of animals fed SD or HFD were subjected to 6 weeks of the forced treadmill exercise and the experimental colitis was induced in both groups of sedentary and exercising mice fed SD and HFD by intra-colonic administration of 2,4,6-trinitrobenzenesulfonic acid. The disease activity index (DAI), colonic blood flow (CBF), the weight of animals, caloric intake, the mesenteric fad pad, the colonic oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) activity and intestinal expression and protein content of proinflammatory markers were evaluated. Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF and exacerbated in those fed a HFD. The contents of MDA, GSH, and SOD activity were significantly increased in both SD and HFD fed mice with treadmill exercise as compared with sedentary mice. In sedentary HFD mice a significant increase in the intestinal oxidative stress parameters and mucosal expression of IL-1β, TNF-α, IL-17, IFNγ, IL-6, and IL-10 protein were observed and these effects were aggravated in mice subjected to forced treadmill exercise. The mucosal expression of mRNA for TNF-α, IL-1β, iNOS, COX-2, SOD-1, SOD-2, GPx mRNAs, and the hypoxia inducible factor (HIF)-1α protein expression were upregulated in colonic mucosa of treadmill exercising HFD mice with colitis compared with those without exercise. We conclude that forced treadmill running exacerbates the severity of colonic damage in obese mice due to a fall in colonic microcirculation, an increase in oxidative stress, and the rise in expression and activity of proinflammatory biomarkers.

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Protective effect of low molecular weight heparin on experimental colitis: role of neutrophil recruitment and TNF-α production

Inflammation Research ◽

10.1007/pl00000290 ◽

2002 ◽

Vol 51 (4) ◽

pp. 182-187 ◽

Cited By ~ 13

Author(s):

M. X. Wan ◽

Q. Liu ◽

Y. Wang ◽

H. Thorlacius

Keyword(s):

Molecular Weight ◽

Protective Effect ◽

Low Molecular Weight Heparin ◽

Experimental Colitis ◽

Neutrophil Recruitment ◽

Low Molecular Weight ◽

Tnf Α

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Effect of Astragalus polysaccharides on expression of TNF-α, IL-1β and NFATc4 in a rat model of experimental colitis

Cytokine ◽

10.1016/j.cyto.2014.07.250 ◽

2014 ◽

Vol 70 (2) ◽

pp. 81-86 ◽

Cited By ~ 48

Author(s):

Min Yang ◽

Huan-Bing Lin ◽

Sitang Gong ◽

Pei-Yu Chen ◽

Lan-Lan Geng ◽

...

Keyword(s):

Rat Model ◽

Experimental Colitis ◽

Astragalus Polysaccharides ◽

Tnf Α

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T Cell–mediated Pathology in Two Models of Experimental Colitis Depends Predominantly on the Interleukin 12/Signal Transducer and Activator of Transcription (Stat)-4 Pathway, but Is Not Conditional on Interferon γ Expression by T Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.8.1225 ◽

1998 ◽

Vol 187 (8) ◽

pp. 1225-1234 ◽

Cited By ~ 207

Author(s):

Stephen J. Simpson ◽

Samir Shah ◽

Martina Comiskey ◽

Ype P. de Jong ◽

Baoping Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Experimental Colitis ◽

Interferon Γ ◽

Adoptive Cell Transfer ◽

Interleukin 12 ◽

Signal Transducer ◽

Immunodeficient Mice ◽

Tnf Α ◽

Ifn Γ

The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell–specific interferon (IFN)-γ expression in the development of T helper cell (Th)1–type pathology were examined in two different models of experimental colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a wasting syndrome and inflammation of the colon, induced by IFN-γ and tumor necrosis factor (TNF)-α–producing T cells. We show here that treatment with anti–IL-12 antibodies in one of the models, or reconstitution with T cells from Stat-4–deficient (Stat-4null) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-γ–producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from the attenuation of IFN-γ expression by T cells. To test whether the development of pathogenic T cells in the two colitis models was directly dependent on T cell–specific IFN-γ expression, IFN-γnull donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-γnull–reconstituted mice developed wasting and colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed TNF-α, demonstrating that they had retained the ability to produce another proinflammatory cytokine. Taken together, these results demonstrate that in some forms of chronic experimental colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by IL-12 via the actions of Stat-4 proteins. Furthermore, our data suggest that in the models of colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-γ gene expression in T lymphocytes.

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Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice

Pharmacology ◽

10.1159/000471808 ◽

2017 ◽

Vol 101 (1-2) ◽

pp. 35-42 ◽

Cited By ~ 2

Author(s):

Vanessa Mateus ◽

João Rocha ◽

Paula Alves ◽

Hélder Mota-Filipe ◽

Bruno Sepodes ◽

...

Keyword(s):

Glycogen Synthase ◽

Experimental Colitis ◽

Trinitrobenzene Sulfonic Acid ◽

Protective Actions ◽

Tnf Α ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Gsk 3Β ◽

Necrosis Factor

Thiadiazolidinone-8 (TDZD-8) is an effective thiadiazolidinone derivate that is able to suppress the expression of inflammatory cytokines; it also presents tissue protective actions by glycogen synthase kinase (GSK)-3β inhibition, promoting thus an anti-inflammatory effect. Since inflammatory bowel disease is a chronic disease with reduced quality of life, where currently available therapies are only able to induce or maintain the patient in remission, it is crucial to investigate new pharmacological approaches. The main objective of this study was to evaluate the effect of TDZD-8 in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Male CD-1 mice with TNBS-induced colitis were treated with a daily dose of TDZD-8 5 mg/kg/day IP during 4 days. The anti-inflammatory properties of TDZD-8 in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and myeloperoxidase, as well as by the significant increase of the anti-inflammatory cytokine, IL-10. These treated mice also presented a reduction in fecal hemoglobin and alkaline phosphatase, suggesting a beneficial effect of TDZD-8. Furthermore, renal and hepatic biomarkers remained stabilized after treatment. In conclusion, TDZD-8 reduces the inflammatory response associated with TNBS-induced colitis in mice, and modulation of GSK-3β seems to be an interesting pharmacological target in colitis.

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