Modulation of nuclear factor E2-related factor 2–mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin

Shen, Guoxiang; Xu, Changjiang; Hu, Rong; Jain, Mohit Raja; Gopalkrishnan, Avantika; Nair, Sreejayan; Huang, Mou‐Tuan; Chan, Julia Y.; Kong, Ah‐Ng Tony

doi:10.1158/1535-7163.mct-05-0293

Cited by 161 publications

(92 citation statements)

References 38 publications

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“…Several common clusters of genes such as that for ubiquitin/proteasome, cell adhesion, transcription factors were observed in this study that were also observed in previous studies with Nrf2 activators [9,33,[42][43][44] which validates our studies from a functional standpoint. In addition, three clusters of genes -calcium homeostasis, ER/Golgi transport & ER/Golgi biosynthesis/ metabolism genes, and glucose homeostasis genes -were uniquely observed as modulated via Nrf2 in response to TM-mediated ER stress that were not discernible in previous studies with Nrf2 activators.…”

Section: Discussionsupporting

confidence: 90%

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

Nair

Shen

et al. 2007

Toxicology Letters

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This objective of this study was to investigate the toxicogenomics and the spatial regulation of global gene expression profiles elicited by Endoplasmic Reticulum (ER) stress inducer Tunicamycin (TM) in mouse small intestine and liver as well as to identify TM-modulated Nuclear Factor-E2-related factor 2 (Nrf2)-dependent genes. Gene expression profiles were analyzed using 45,000 Affymetrix mouse genome 430 2.0 array and GeneSpring 7.2 software. Microarray results were validated by quantitative real-time reverse transcription-PCR analyses. Clusters of genes that were either induced or suppressed more than two fold by TM treatment compared with vehicle in C57BL/6J/Nrf2(−/−; knockout)and C57BL/6J Nrf2 (+/+; wildtype) mice genotypes were identified. Amongst these, in small intestine and liver, 1291 and 750 genes respectively were identified as Nrf2-dependent and upregulated, and 1370 and 943 genes respectively as Nrf2-dependent and downregulated. Based on their biological functions, these genes can be categorized into molecular chaperones and heat shock proteins, ubiquitination/proteolysis, apoptosis/cell cycle, electron transport, detoxification, cell growth/differentiation, signaling molecules/interacting partners, kinases and phosphatases, transport, biosynthesis/metabolism, nuclear assembly and processing, and genes related to calcium and glucose homeostasis. Phase II detoxification/antioxidant genes as well as putative interacting partners of Nrf2 such as nuclear corepressors and coactivators, were also identified as Nrf2-dependent genes. The identification of TM-regulated and Nrf2-dependent genes in the unfolded protein response to ER stress not only provides potential novel insights into the gestalt biological effects of TM on the toxicogenomics and spatial regulation of global gene expression profiles in cancer pharmacology and toxicology, but also points to the pivotal role of Nrf2 in these biological processes.

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Section: Discussionsupporting

confidence: 90%

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

Nair

Shen

et al. 2007

Toxicology Letters

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“…This hypothesis is supported by the beneficial effect of curcumin on CCl 4 -mediated liver fibrosis, 30 which may Nrf2 in liver fibrosis W Xu et al be at least in part mediated through activation of Nrf2 by this polyphenolic antioxidant. 39 In the future, some of these agents may potentially be used as supportive medication to reduce or even prevent toxin-induced liver fibrosis and possibly also to slow down its progression. Future studies will experimentally address this possibility.…”

Section: Discussionmentioning

confidence: 99%

The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis

Hellerbrand

Köhler

et al. 2008

Laboratory Investigation

182

116

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The liver is frequently exposed to insults, including toxic chemicals and alcohol, viral infection or metabolic overload. Although it can fully regenerate after acute injury, chronic liver damage causes liver fibrosis and cirrhosis, which can result in complete liver failure. In this study, we demonstrate that the NF-E2-related factor 2 (Nrf2) transcription factor protects the liver from acute and chronic toxin-mediated damage. Repair of the liver injury that occurs after a single treatment with the hepatotoxin carbon tetrachloride (CCl 4 ) was severely delayed in Nrf2-deficient mice. The defect in repair was accompanied by an enhanced and prolonged inflammatory and profibrotic response. After long-term CCl 4 treatment, liver fibrosis was strongly aggravated in the Nrf2 knockout mice and inflammation was enhanced. We demonstrate that these abnormalities are at least in part due to the reduced expression of known and novel Nrf2 target genes in hepatocytes, which encode enzymes involved in the detoxification of CCl 4 and its metabolites. These results suggest that activation of Nrf2 may be a novel strategy to prevent or ameliorate toxin-induced liver injury and fibrosis.

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“…Nrf2 activators have few common structural properties, but most or all of them react with thiols of Keap1 (Dinkova-Kostova et al, 2001). Many of these Nrf2 activators have been shown to be effective in experimental carcinogenesis models, and their chemopreventive actions are abolished in Nrf2-deficient mice, indicating that their effects are mediated by Nrf2 (Ramos-Gomez et al, 2001;Shen et al, 2006;Xu et al, 2006a;Yates et al, 2006). Several pharmacological and genetic studies have also demonstrated neuroprotective effects of Nrf2-activating phytochemicals in animal models of AD, PD, HD, and ALS (Burton et al, 2006;Jakel et al, 2007;Kraft et al, 2007;Kanninen et al, 2008Kanninen et al, , 2009Vargas et al, 2008;Chen et al, 2009c;Dumont et al, 2009;Yang et al, 2009b).…”

Section: A Adaptive Stress Responsesmentioning

confidence: 99%

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

et al. 2014

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Modulation of nuclear factor E2-related factor 2–mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin

Cited by 161 publications

References 38 publications

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice

The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

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