Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation

Yang, Yang; Cai, Xueting; Yang, Jie; Sun, Xiaomei; Hu, Chunping; Yan, Zhanpeng; Xu, Xiaojun; Lü, Wei; Wang, Xiaoning; Cao, Peng

doi:10.1186/1476-4598-13-48

Cited by 82 publications

(51 citation statements)

References 55 publications

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“…Nrf2 plays a critical role in protecting against inflammation-associated CRC, supporting and extending a published report showing that Nrf2 knockout increases the susceptibility to inflammation-associated aberrant crypt foci [75]. Activation of Nrf2 signaling resulted in suppression of colitisassociated CRC [76][77][78][79]. We showed that 10% cocoa activates Nrf2 (Figs.…”

Section: Discussionsupporting

confidence: 89%

Dietary cocoa protects against colitis‐associated cancer by activating the Nrf2/Keap1 pathway

et al. 2014

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Colorectal cancer (CRC) is the third most common malignancy in males and the second most common cancer worldwide. Chronic colonic inflammation is a known risk factor for CRC. Cocoa contains many polyphenolic compounds that have beneficial effects in humans. The objective of this study is to explore the antioxidant properties of cocoa in the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, focusing on the activation of Nrf2 signaling. Mice were treated with AOM/DSS and randomized to receive either a control diet or a 5 and 10% cocoa diet during the study period. On day 62 of the experiment, the entire colon was processed for biochemical and histopathological examination and further evaluations. Increased levels of malondialdehyde (MDA) were observed in AOM/DSS-induced mice; however, subsequent administration of cocoa decreased the MDA. Enzymatic and nonenzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were decreased in the AOM/DSS mice. Cocoa treatment increases the activities/levels of enzymatic and nonenzymatic antioxidants. Inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were elevated during AOM/DSS-induction, and treatment with 5 and 10% cocoa effectively decreases the expression of iNOS and COX-2. The NF-E2-related factor 2 and its downstream targets, such as NQO1 and UDP-GT, were increased by cocoa treatment. The results of our study suggest that cocoa may merit further clinical investigation as a chemopreventive agent that helps prevent CAC.

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Section: Discussionsupporting

confidence: 89%

Dietary cocoa protects against colitis‐associated cancer by activating the Nrf2/Keap1 pathway

et al. 2014

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“…In order to confirm that the mechanism of enzyme-II induction is via ARE activation [38], we evaluated the Nrf2 nuclear translocation ability, using the 1,2,5-oxadiazole (3) as the model compound. Therefore, to further investigate effects of (3) on the Nrf2/ARE activation, we examined the subcellular location of Nrf2 in Hepa-1c1c7 cells after 1,2,5-oxadiazole treatment.…”

Section: Resultsmentioning

confidence: 99%

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

et al. 2015

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The increased activity of phase-II-detoxification enzymes, such as quinone reductase (QR) and glutation S-transferase (GST), correlates with protection against chemically induced carcinogenesis. Herein we studied 11 different chemotypes, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiazole, 1,3,4-oxathiazole, thienyl hydrazone, α,β-unsaturated-oxime, α,β-unsaturated-N-oxide, coumarin and α,β-unsaturated-carbonyl, as phase-II enzymes inducers in order to identify new pharmacophores with chemopreventive activity. Fifty-four compounds were analyzed on wild-type mouse-hepatoma Hepa-1c1c7 and on the aryl-hydrocarbon-nuclear-translocator (Arnt)-defective mutant BpRc1 cells. New monofunctional inducers of QR and GST were identified, the 1,2,5-oxadiazol-2-oxide (3), the 1,2,4-triazine-4-oxides (23) and (32) and the tetrahydropyrimidinones (28) and (49). It was confirmed that Nrf2 nuclear translocation is the operative molecular mechanism that allows compound (3) to exert protective effects via expression of downstream phase-II enzymes.

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“…The Nrf2 signaling pathway is also activated during inflammation and negatively regulates inflammatory responses. Inflammation can induce the expression of Nrf2 downstream genes (9), and the Nrf2 pathway cross talks with NF-B and other inflammatory signaling pathways to repress the inflammatory response (10).…”

mentioning

confidence: 99%

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Yin

Cao

2015

Molecular and Cellular Biology

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Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.

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Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation

Cited by 82 publications

References 55 publications

Dietary cocoa protects against colitis‐associated cancer by activating the Nrf2/Keap1 pathway

Dietary cocoa protects against colitis‐associated cancer by activating the Nrf2/Keap1 pathway

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

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