Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

Merga, J. Yvette; O’Hara, Adrian; Burkitt, Michael D.; Duckworth, Carrie A.; Probert, Chris; Campbell, Barry J.; Pritchard, D. Mark

doi:10.1152/ajpgi.00026.2016

Cited by 51 publications

(42 citation statements)

References 83 publications

(88 reference statements)

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“…Studies revealed that proinflammatory cytokines such as IL‐1β, IL‐6, TNF‐α, and IL‐17 are key mediators and initiators in the inflammation of colon in UC (Bamias & Cominelli, ; Catana et al, ; Chen & Sundrud, ; Fantini & Pallone, ). And transcriptions of these proinflammatory cytokines are dependent on the activation of NF‐κB pathway (Atreya, Atreya, & Neurath, ; Merga et al, ). Typical NF‐κB complex consists of two subunits, p65 and p50.…”

Section: Introductionmentioning

confidence: 99%

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Yin

et al. 2018

Phytotherapy Research

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Casticin, a compound purified from the Chinese herb Viticis Fructus, has been proven effective in preventing tumor progression in previous studies. Ulcerative colitis (UC) is a common inflammatory bowel disease that affects millions of people worldwide, but no effective and safe drugs are available. In this study, we aimed to study how did casticin affect UC by evaluating its effects on dextran sulfate sodium (DSS)-induced colitis in mice. Our data suggested that casticin attenuated body weight loss, colon length shortening, and pathological damage in the colon of DSS-treated mice. Casticin decreased reactive oxygen species level and chemocytokines (IL-1β, IL-6, TNF-α) productions in colon tissue. The decreased reactive oxygen species level and suppressed proinflammatory cytokines productions were also confirmed in casticin-treated LPS-stimulated RAW264.7 cells and hydrogen peroxide-treated CACO-2 cells in vitro. Mechanistically, casticin treatment prevented the profound activation of AKT signaling caused by DSS administration. And casticin inhibited the productions of proinflammatory chemocytokines through downregulating AKT/NF-κB pathway in macrophages. Meanwhile, data revealed that casticin increased expressions of endogenous antioxidants peroxiredoxin 3 and MnSOD were through activation in FOXO3α signaling by downregulating AKT signaling in colon epithelium cells. Our findings demonstrated that casticin alleviated DSS-induced UC by increasing the antioxidant enzyme peroxiredoxin 3 and MnSOD expressions, and decreasing the production of proinflammatory chemocytokines through inhibition of AKT signaling.

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Section: Introductionmentioning

confidence: 99%

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Yin

et al. 2018

Phytotherapy Research

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“…Genistein is known to inhibit the growth of H. pylori 51 and the activation of the nuclear factor-kappaB (NF-κB) signaling pathway. The classical activation pathway of NF-κB signaling has been identified in regulating inflammation-associated gastrointestinal tract malignancies 52–54 . Genistein also reduced the growth and proliferation of gastric cancer cells by cell cycle arrest and the Akt signaling pathway, which increased apoptosis and inhibited angiogenesis 55–57 .…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of Soy Consumption and Gastrointestinal Cancer Risk

Chi

et al. 2017

Sci Rep

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Soy consumption has received considerable attention for its potential role in reducing cancer incidence and mortality. However, its effects on gastrointestinal (GI) cancer are controversial. Therefore, we performed a meta-analysis to evaluate the association between soy consumption and gastrointestinal cancer risk by searching for prospective studies in PubMed, Web of Science, EMBASE and the reference lists of the included articles. The study-specific odds ratio (OR), relative risk (RR) or hazard ratio (HR) estimates and 95% confidence intervals (CIs) were pooled using either a fixed-effect or random-effect model. Twenty-two independent prospective studies were eligible for our meta-analysis, including 21 cohort studies and one nested case-control study. Soy product consumption was inversely associated with the incidence of overall GI cancer (0.857; 95% CI: 0.766, 0.959) and the gastric cancer subgroup (0.847; 95% CI: 0.722, 0.994) but not the colorectal cancer subgroup. After stratifying the results according to gender, an inverse association was observed between soy product intake and the incidence of GI cancer for females (0.711; 95% CI: 0.506, 0.999) but not for males.

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“…In addition to changes in the inflammatory milieu, this network also affects several other processes which are dysregulated during chronic gastrointestinal inflammation including cell turnover, DNA damage responses and cell senescence (8). Several studies have associated aberrant NF-κB signalling with IBD (reviewed in refs (9–11)).…”

Section: Introductionmentioning

confidence: 99%

Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease

Lloyd¹,

Παπουτσοπουλου

Smith

et al. 2019

Preprint

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ObjectiveInflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.DesignThe SysmedIBD consortium established a novel drug-repurposing pipeline based on a combination of in-silico drug discovery and biological assays targeted at demonstrating an impact on NF-kappaB signalling, and a murine model of IBD.ResultsThe drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic Clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions.Clarithromycin’s effects were validated in several experiments: it influenced NF-κB mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids.ConclusionsThese findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.

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Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

Cited by 51 publications

References 83 publications

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Meta-analysis of Soy Consumption and Gastrointestinal Cancer Risk

Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease

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