3,3′-Diindolylmethane but not indole-3-carbinol activates Nrf2 and induces Nrf2 target gene expression in cultured murine fibroblasts

Ernst, Insa M. A.; Schuemann, C.; Wagner, Anika E.; Rimbach, Gerald

doi:10.3109/10715762.2011.571683

Cited by 18 publications

(14 citation statements)

References 38 publications

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“…Diehn et al reported that enhanced ROS scavenger results in low ROS levels, and tumor radio-resistance (45). GCLC, HO-1 and NQO1 are Nrf2-regulated genes and protect against oxidative and xenobiotic stress by mopping up ROS (46)(47)(48)(49). In our study, inhibition of Nrf2 significantly attenuated IR-induced Nrf2 nuclear translocation and decreased GCLC, HO-1 and NQO1 expression after irradiation.…”

Section: Discussionsupporting

confidence: 64%

Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells

Zhao

Mao

Yan

et al. 2015

International Journal of Oncology

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The nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial regulator of the cellular antioxidant system. Nrf2 is often constitutively activated in non-small cell lung cancer (NSCLC) cell lines, which promotes cytoprotection against oxidative stress and xenobiotics. Notch1 signaling is critically implicated in cell fate determination. It has been reported that Nf2 strongly regulates Notch1 activity. However, the role of Nrf2 mediated Notch1 signaling in response to ionizing radiation (IR) remains elusive. We report that knockdown of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch1 signaling in NSCLC cells. IR activated Nrf2 in a dose-dependent manner and the expression of Nrf2 was significantly elevated at 4 h after exposure. RNAi-mediated reduction of Nrf2 significantly increased endogenous ROS levels, and decreased the expression of glutamate cysteine ligase catalytic subunit (GCLC), heme oxygenase-1 (HO-1) and NAD (P) H quinine oxidoreductase-1 (NQO1) in irradiated cells. Furthermore, decrease in Nrf2 expression significantly dampened Notch1 expression following ionizing radiation exposure, and potentiated IR-induced cellular apoptosis. These results demonstrated that Nrf2 could be activated by ionizing radiation, knockdown of Nrf2 could promote radiation induced apoptosis and Nrf2-mediated Notch signaling is an important determinant in radioresistance of lung cancer cells.

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Section: Discussionsupporting

confidence: 64%

Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells

Zhao

Mao

Yan

et al. 2015

International Journal of Oncology

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“…Resent studies shown that DIM induces the transactivation of Nrf2 in cultured murine fibroblasts [19], while AMPKα2 regulates expression of estrogen-related receptor-alpha (ERRα, a transcriptional factor often affects mitochondrial antioxidants and energy metabolism) [20]. Thus, we detect the myocardial oxidative stress markers and expression of NRF2 and ERRα etc after DIM-treated in both wild type and AMPKα2 KO mice.…”

Section: Resultsmentioning

confidence: 86%

“…Recent research has suggested DIM induced Nrf2 transactivation [19], which is a protective regulator that prevents the maladaptive cardiac remodeling and heart failure associated with a sustained pathological hemodynamic stress via at least partly the suppressing of oxidative stress [32]. Loss of Nrf2 sensitizes cardiomyocytes and cardiac fibroblasts to oxidative stress-mediated cell death [34].…”

Section: Discussionmentioning

confidence: 99%

3,3′-Diindolylmethane Protects against Cardiac Hypertrophy via 5′-Adenosine Monophosphate-Activated Protein Kinase-α2

et al. 2013

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Purpose3,3′-Diindolylmethane (DIM) is a natural component of cruciferous plants. It has strong antioxidant and anti-angiogenic effects and promotes the apoptosis of a variety of tumor cells. However, little is known about the critical role of DIM on cardiac hypertrophy. In the present study, we investigated the effects of DIM on cardiac hypertrophy.MethodsMultiple molecular techniques such as Western blot analysis, real-time PCR to determine RNA expression levels of hypertrophic, fibrotic and oxidative stress markers, and histological analysis including H&E for histopathology, PSR for collagen deposition, WGA for myocyte cross-sectional area, and immunohistochemical staining for protein expression were used.ResultsIn pre-treatment and reverse experiments, C57/BL6 mouse chow containing 0.05% DIM (dose 100 mg/kg/d DIM) was administered one week prior to surgery or one week after surgery, respectively, and continued for 8 weeks after surgery. In both experiments, DIM reduced to cardiac hypertrophy and fibrosis induced by aortic banding through the activation of 5′-adenosine monophosphate-activated protein kinase-α2 (AMPKα2) and inhibition of mammalian target of the rapamycin (mTOR) signaling pathway. Furthermore, DIM protected against cardiac oxidative stress by regulating expression of estrogen-related receptor-alpha (ERRα) and NRF2 etc. The cardioprotective effects of DIM were ablated in mice lacking functional AMPKα2.ConclusionDIM significantly improves left ventricular function via the activation of AMPKα2 in a murine model of cardiac hypertrophy.

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“…Natural Nrf2 activators are also found in the brassica plants. One of these compounds which increases the activity of Nrf2 and not causes toxic effects on NIH3T3 cells is 3,3-diindolylometan which is derived from indol-3-carbinol fermentation [ 20 ]. Walnut sprouts extracts also contain natural Nrf2 activators that cause an increase in cells resistance to oxidative stress and increase survival up to 50 % in the case of fibroblast cells exposed to UVB [ 13 ].…”

Section: Nrf2 Activators In Fibroblastsmentioning

confidence: 99%

The role of transcription factor Nrf2 in skin cells metabolism

2015

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Skin, which is a protective layer of the body, is in constant contact with physical and chemical environmental factors. Exposure of the skin to highly adverse conditions often leads to oxidative stress. Moreover, it has been observed that skin cells are also exposed to reactive oxygen species generated during cell metabolism particularly in relation to the synthesis of melanin or the metabolism in immune system cells. However, skin cells have special features that protect them against oxidative modifications including transcription factor Nrf2, which is responsible for the transcription of the antioxidant protein genes such as antioxidant enzymes, small molecular antioxidant proteins or interleukins, and multidrug response protein. In the present study, the mechanisms of Nrf2 activation have been compared in the cells forming the various layers of the skin: keratinocytes, melanocytes, and fibroblasts. The primary mechanism of control of Nrf2 activity is its binding by cytoplasmic inhibitor Keap1, while cells have also other controlling mechanisms, such as phosphorylation of Nrf2 and modifications of its activators (e.g., Maf, IKKβ) or inhibitors (e.g., Bach1, caveolae, TGF-β). Moreover, there are a number of drugs (e.g., ketoconazole) used in the pharmacotherapy of skin diseases based on the activation of Nrf2, but they may also induce oxidative stress. Therefore, it is important to look for compounds that cause a selective activation of Nrf2 particularly natural substances such as curcumin, sulforaphane, or extracts from the broccoli leaves without side effects. These findings could be helpful in the searching for new drugs for people with vitiligo or even melanoma.

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3,3′-Diindolylmethane but not indole-3-carbinol activates Nrf2 and induces Nrf2 target gene expression in cultured murine fibroblasts

Cited by 18 publications

References 38 publications

Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells

Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells

3,3′-Diindolylmethane Protects against Cardiac Hypertrophy via 5′-Adenosine Monophosphate-Activated Protein Kinase-α2

The role of transcription factor Nrf2 in skin cells metabolism

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