A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice

Funakoshi, Tohru; Yamashita, Kazuo; Ichikawa, Nobuki; Fukai, Moto; Suzuki, Tomomi; Goto, Ryoichi; Oura, Tetsu; Kobayashi, Nozomi; Katsurada, Takehiko; Ichihara, Shin; Ozaki, Michitaka; Umezawa, Kazuo; Todo, Satoru

doi:10.1016/j.crohns.2011.08.011

Cited by 58 publications

(46 citation statements)

References 46 publications

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“…One unifying feature for all three cytokines is their transcriptional regulation by nuclear factor kB (NF-kB) (Funakoshi et al, 2012). Dehydroxymethylepoxyquinomicin, a relatively specific inhibitor of NF-kB, inhibits the mRNA expression of IL-b, IL-6, tumor necrosis factor a (TNF-a), IL-12p40, IL-17A, and monocyte chemoattractant protein 1 (MCP-1) and also suppresses both DSS and trinitrobenzene sulfonic acid (TNBS)-induced colitis.…”

Section: Sepiapterin Mitigates Murine Colitis and Colorectal Cancermentioning

confidence: 99%

Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer

Cardnell

Rabender

Ross

et al. 2013

J Pharmacol Exp Ther

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The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca 21 -induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1b (IL-1b), IL-6, and IL-17A. Highperformance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.

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Section: Sepiapterin Mitigates Murine Colitis and Colorectal Cancermentioning

confidence: 99%

Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer

Cardnell

Rabender

Ross

et al. 2013

J Pharmacol Exp Ther

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“…NF-κB is also a pivotal protein involved in proin ammatory signal transduction. e activation of NF-κB has been demonstrated in colonic epithelial cells and macrophages of patients with IBD [22][23]. Numerous and diverse stimuli can induce NF-κB activity.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine improves oxazolone-induced colitis by inhibiting the NF-κB pathway

Lu¹,

Zhu²,

Chen³

et al. 2014

CIM

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Tetramethylpyrazine improves oxazolone-induced colitis by inhibiting the NF-κB pathway Abstract Purpose: Tetramethylpyrazine (TMP) is an e ective Chinese plant-derived medicine for colitis in the clinic, but the underlying molecular mechanisms of its use remain poorly understood. e purpose of this study was to investigate the mechanisms involved in its therapeutic action.Methods: A colitis mouse model was induced by oxazolone enema. TMP was administered at 80 mg/kg/day and sulphasalazine (SASP) was used as positive control and administered at 100 mg/kg/day for the treatment of colitis. On the fourth day a er enema, mice were sacri ced. e in ammatory response was assessed by the disease activity index and histology. Colon mucosa was isolated and biochemically analyzed. In addition, in vitro studies were performed to evaluate the activity of TMP in Caco-2 cells.Results: Our results showed that TMP improved the colonic in ammatory status as evidenced by histological ndings, as well as SASP. ese e ects were associated with a decrease in nucleus translocation of NF-κB. Paired with this inhibitive activity, there was a decrease in downstream signaling, such as C-MYC, iNOS and COX-2. In vitro assays revealed that TMP inhibited NF-κB translocation and its downstream production of inammatory factors, such as TNF-α, IL-6 and IL-8, and that ROS production that was induced by LPS in Caco-2 cells.Conclusion: TMP improved the colitis induced by oxazoline, and its activity was associated with inhibition of NF-κB translocation, and subsequent inhibition of proin ammatory factor production and oxidative stress.

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“…Administration of an NFKB decoy oligonucleotide in rats limited the expression of proinflammatory pathways and showed increased survival rate on inducing DSS-induced colitis 131. Another NFKB inhibitor, dehydroxymethylepoxyquinomicin, blocks the nuclear translocation of NFKB and ameliorated experimental TNBS-induced and DSS-induced colitis in mice 132. Finally, the natural NFKB inhibitor curcumin has shown positive effects on the treatment of IBD in phase I, II and III trials 133…”

Section: Dres As Therapeutic Targetsmentioning

confidence: 99%

Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Meddens

List

Nieuwenhuis

et al. 2019

Gut

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Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.

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A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice

Abstract: DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD.

Cited by 58 publications

References 46 publications

Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer

Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer

Tetramethylpyrazine improves oxazolone-induced colitis by inhibiting the NF-κB pathway

Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

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