INT177875

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Context Info
Confidence 0.66
First Reported 2004
Last Reported 2010
Negated 0
Speculated 0
Reported most in Body
Documents 18
Total Number 19
Disease Relevance 9.40
Pain Relevance 0.40

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

cytosol (NFE2L2) plasma membrane (NFE2L2) nucleus (NFE2L2)
DNA binding (NFE2L2) cytoplasm (NFE2L2)
Anatomy Link Frequency
epithelial cells 2
NFE2L2 (Homo sapiens)
Pain Link Frequency Relevance Heat
Inflammation 68 99.70 Very High Very High Very High
Glutamate 12 71.08 Quite High
metalloproteinase 3 68.24 Quite High
Pain 3 60.96 Quite High
Osteoarthritis 1 60.48 Quite High
Inflammatory response 6 20.08 Low Low
psoriasis 44 5.00 Very Low Very Low Very Low
cytokine 18 5.00 Very Low Very Low Very Low
chemokine 14 5.00 Very Low Very Low Very Low
palliative 8 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Cancer 901 99.92 Very High Very High Very High
INFLAMMATION 65 99.70 Very High Very High Very High
Non-small-cell Lung Cancer 192 96.68 Very High Very High Very High
Apoptosis 156 94.24 High High
Toxicity 108 93.60 High High
Malignant Neoplastic Disease 32 90.32 High High
Targeted Disruption 11 89.36 High High
Stress 114 88.56 High High
Lung Cancer 446 88.16 High High
Wound Healing 2 87.56 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.


Positive_regulation (induced) of Positive_regulation (accumulation) of NRF2 associated with cancer
1) Confidence 0.66 Published 2006 Journal PLoS Medicine Section Abstract Doc Link PMC1584412 Disease Relevance 1.01 Pain Relevance 0
If future experiments verify that enhanced activation of NRF2 is a key cause of chemoresistance and poor prognosis, one could envision development of specific siRNA or small molecule inhibitors of NRF2 for treatment of patients with tumors resistant to chemotherapy.


Positive_regulation (enhanced) of Positive_regulation (activation) of NRF2 associated with cancer
2) Confidence 0.66 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.84 Pain Relevance 0
In the absence of functional KEAP1 activity, cancer cells demonstrated an increased nuclear accumulation of NRF2 as well as an increase in total NRF2.
Positive_regulation (increased) of Positive_regulation (accumulation) of NRF2 associated with cancer
3) Confidence 0.66 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.14 Pain Relevance 0
Total NRF2 level was also higher in cancer cells, suggesting that there was increased stabilization of NRF2 in the absence of functional KEAP1.
Positive_regulation (increased) of Positive_regulation (stabilization) of NRF2 associated with cancer
4) Confidence 0.66 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.93 Pain Relevance 0
Previously, it has been demonstrated that Nrf2 activators, including tBHQ, induce the Nrf2 signaling pathway primarily through stabilization of the Nrf2 protein, rather than up-regulation of its mRNA (Nguyen et al. 2003).
Positive_regulation (induce) of Positive_regulation (stabilization) of Nrf2 protein
5) Confidence 0.50 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.21 Pain Relevance 0
This finding suggests that loss of both functional KEAP1 alleles is essential for constitutive activation of NRF2-mediated gene expression.
Positive_regulation (essential) of Positive_regulation (activation) of NRF2
6) Confidence 0.48 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 1.09 Pain Relevance 0
Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response.
Positive_regulation (leading) of Positive_regulation (activation) of Nrf2
7) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Abstract Doc Link PMC2535615 Disease Relevance 0.25 Pain Relevance 0
Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response.
Positive_regulation (leading) of Positive_regulation (accumulation) of Nrf2 protein
8) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Abstract Doc Link PMC2535615 Disease Relevance 0.25 Pain Relevance 0
Taken together, these results indicate that oridonin activates the Nrf2 pathway by inhibiting ubiquitination and degradation of Nrf2, leading to an increase in Nrf2 protein level and activation of the Nrf2-dependent response.


Positive_regulation (leading) of Positive_regulation (activation) of Nrf2
9) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.17 Pain Relevance 0
Taken together, these results indicate that oridonin activates the Nrf2 pathway by inhibiting ubiquitination and degradation of Nrf2, leading to an increase in Nrf2 protein level and activation of the Nrf2-dependent response.


Positive_regulation (increase) of Positive_regulation (activation) of Nrf2
10) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.17 Pain Relevance 0
Upon induction, Nrf2 is stabilized because of impaired Keap1-E3 ubiquitin ligase activity, which results in activation of the Nrf2 signaling pathway (Cullinan et al. 2004; Furukawa and Xiong 2005; Kobayashi et al. 2004; Sun et al. 2007; Zhang et al. 2004b).
Positive_regulation (results) of Positive_regulation (activation) of Nrf2
11) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0 Pain Relevance 0
Taken together, these results indicate that oridonin activates the Nrf2 pathway by inhibiting ubiquitination and degradation of Nrf2, leading to an increase in Nrf2 protein level and activation of the Nrf2-dependent response.


Positive_regulation (leading) of Positive_regulation (increase) of Nrf2 protein
12) Confidence 0.47 Published 2008 Journal Environ Health Perspect Section Body Doc Link PMC2535615 Disease Relevance 0.16 Pain Relevance 0
Phosphorylation of NRF2 by protein kinase(s) associated with the MAPK/ERK signaling cascade increases stabilization of NRF2 and has been proposed as an important mechanism leading to increased expression of ARE-dependent genes [11].
Positive_regulation (increases) of Positive_regulation (stabilization) of NRF2
13) Confidence 0.44 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.42 Pain Relevance 0.07
Increased NRF2 staining and NRF2-dependent enzyme activities in tumor samples with wild-type KEAP1 suggests that there are other possible mechanisms operating in tumor cells that contribute to increased stabilization and activation of NRF2 [11,36].
Positive_regulation (increased) of Positive_regulation (activation) of NRF2 associated with cancer
14) Confidence 0.39 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.67 Pain Relevance 0
Increased NRF2 staining and NRF2-dependent enzyme activities in tumor samples with wild-type KEAP1 suggests that there are other possible mechanisms operating in tumor cells that contribute to increased stabilization and activation of NRF2 [11,36].
Positive_regulation (increased) of Positive_regulation (stabilization) of NRF2 associated with cancer
15) Confidence 0.39 Published 2006 Journal PLoS Medicine Section Body Doc Link PMC1584412 Disease Relevance 0.67 Pain Relevance 0
Under conditions of Nrf2 activation, the elevated expression of SQSTM1 may enable the targeting of Keap1 for degradation via autophagy, which in turn may (i) further contribute to the activation of Nrf2 and/or (ii) represent a means by which modified/inactivated Keap1 is removed/recycled to restore homeostasis in the pathway (Fig. 5).
Positive_regulation (contribute) of Positive_regulation (activation) of Nrf2
16) Confidence 0.25 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878012 Disease Relevance 0.41 Pain Relevance 0.09
The transcriptional activation of Nrf2-dependent genes can be induced by various chemicals, including redox-active compounds such as quinones, isothiocyanates, peroxides, mercaptans, transition metals, trivalent arsenicals, and also by chemopreventive antioxidants such as dietary polyphenols [11].
Positive_regulation (induced) of Positive_regulation (activation) of Nrf2
17) Confidence 0.22 Published 2010 Journal Mediators of Inflammation Section Body Doc Link PMC2929514 Disease Relevance 0.33 Pain Relevance 0.11
By contrast, chemopreventive polyphenols may oppose inflammation and cancer by enhancing cellular antioxidant and detoxifying enzymes via activation of Nrf2.
Positive_regulation (enhancing) of Positive_regulation (activation) of Nrf2 associated with inflammation and cancer
18) Confidence 0.20 Published 2010 Journal Mediators of Inflammation Section Body Doc Link PMC2929514 Disease Relevance 0.42 Pain Relevance 0.14
Curcumin exposure resulted in an increase in nuclear Nrf2 content in bronchial epithelial cells [60] and in increased expression of Nrf2 in renal epithelial cells [61].
Positive_regulation (resulted) of Positive_regulation (increase) of Nrf2 in epithelial cells
19) Confidence 0.14 Published 2004 Journal J Carcinog Section Body Doc Link PMC421747 Disease Relevance 0.26 Pain Relevance 0

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