Broccoli as a Nrf2 Activator

Eat your broccoli! How many times did you hear that as a kid?

Well, it turns out that perhaps what was initially based on a "housewife's tale" and probably by those who had no idea what Nrf2 actually is were actually right on the mark. Latest scientific research validated the powerful impact that broccoli has as a Nrf2 activator. Below are the latest 15 studies published on Pubmed. Don't forget now, "eat your broccoli".
Evaluation of 2-Thiothiazolidine-4-Carboxylic Acid, a Common Metabolite of Isothiocyanates, as a Potential Biomarker of Cruciferous Vegetable Intake
Palliyaguru DL, Salvatore SR, Schopfer FJ, Cheng X, Zhou J, Kensler TW and Wendell SG
Cruciferous vegetable consumption is associated with favorable health outcomes. Bioactive compounds arising in these, especially isothiocyanates, exert effects that contribute to prevention of disease, in large part through the attenuation of inflammation and oxidative stress. However, much about isothiocyanate metabolites and their role as biomarkers of crucifer intake remain unknown.
Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice
Cho HY, Miller-DeGraff L, Blankenship-Paris T, Wang X, Bell DA, Lih F, Deterding L, Panduri V, Morgan DL, Yamamoto M, Reddy AJ, Talalay P and Kleeberger SR
Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidant-induced acute injury, wild-type (Nrf2) and Nrf2-deficient (Nrf2) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxia-induced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2 mice but not in Nrf2 mice. SFN upregulated a large cluster of basal lung genes that are involved in mitochondrial oxidative phosphorylation, energy metabolism, and cardiovascular protection only in Nrf2 mice. Bioinformatic analysis elucidated ARE-like motifs on these genes. Transcript abundance of the mitochondrial machinery genes remained significantly higher after hyperoxia exposure in SFN-treated Nrf2 mice than in SFN-treated Nrf2 mice. Nuclear factor-κB was suggested to be a central molecule in transcriptome networks affected by SFN. Minor improvement of hyperoxia-caused lung histopathology and neutrophilia by SFN in Nrf2 mice implies Nrf2-independent or alternate effector mechanisms. In conclusion, SFN is suggested to be as a preventive intervention in a preclinical model of acute lung injury by linking mitochondria and Nrf2. Administration of SFN alleviated acute lung injury-like pathogenesis in a Nrf2-dependent manner. Potential AREs in the SFN-inducible transcriptome for mitochondria bioenergetics provided a new insight into the downstream mechanisms of Nrf2-mediated pulmonary protection.
Targeted mass spectrometry to monitor nuclear accumulation of endogenous Nrf2 and its application to SH-SY5Y cells stimulated with food components
Östreicher C, Gensberger-Reigl S and Pischetsrieder M
The Nrf2 signaling pathway is highly significant for redox homeostasis. Hence, nutrients and drugs activating Nrf2 can prevent oxidative stress-mediated medical conditions. After activation, Nrf2 accumulates in the cell nucleus; therefore, stimulation of Nrf2 by food components and drugs is usually monitored by measuring nuclear Nrf2 levels. The present study developed a targeted mass spectrometry method for the highly reliable quantification of nuclear Nrf2 levels. Three Nrf2-specific peptides were detected after enzymatic digestion of the nuclear fraction by the developed protocol for micro-liquid chromatography-tandem mass spectrometry in scheduled multiple reaction monitoring mode (microLC-MS/MS-sMRM). The method also identified nuclear Nrf2 unequivocally and specifically in the SDS-PAGE fraction of 100-150 kDa. Moreover, highly precise and linear relative quantification was achieved (mean relative standard deviation 8.3%; coefficient of determination 0.998). Incubation experiments in SH-SY5Y neuroblastoma cells revealed significantly up to 6-fold elevated nuclear Nrf2 levels after stimulation with 10 μM carnosol (rosemary), 10 μM sulforaphane (broccoli), or 20 μM cinnamaldehyde (cinnamon). Our results were in very good accordance with conventional Nrf2 western blotting and were highly correlated with the food components' effect on the expression levels of NAD(P)H dehydrogenase [quinone] 1 and thioredoxin reductase 1, two major Nrf2-regulated cytoprotective enzymes. The newly developed microLC-MS/MS-sMRM method shows broad applicability and can serve as a highly selective and reliable method to analyze Nrf2 activation. Graphical abstract ᅟ.
Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial
Chartoumpekis DV, Ziros PG, Chen JG, Groopman JD, Kensler TW and Sykiotis GP
Sulforaphane is a redox-active natural product present in cruciferous vegetables like broccoli. Broccoli sprout-derived products are promising agents for the prevention of oxidative stress-related diseases, but some have long been suspected of thyroidal toxicity. Recent findings also raise the possibility that long-term exposure to sulforaphane, or to other natural substances or drugs that modulate the activity of the transcription factor Nrf2 (NFE2-related factor 2) may lead to thyroid dysfunction or thyroid autoimmune disease, questioning the safety of trials with sulforaphane-containing products. Previous studies addressing possible effects of sulforaphane-related compounds from natural product extracts on the thyroid were quite short and/or inconsistent. To investigate whether long-term exposure to a beverage enriched with sulforaphane and its precursor glucoraphanin may affect thyroid function, we analyzed biochemical measures of thyroid function and thyroid autoimmunity in 45 female participants in a randomized clinical trial at baseline and after 84 days of beverage administration. Serum levels of thyroid-stimulating hormone, free thyroxine and thyroglobulin were not affected by the treatment, and neither was the thyroid autoimmunity status of participants. These results provide evidence in favor of the safety of chemoprevention strategies that target the activation of Nrf2 to protect against environmental exposures and other oxidative stress-related pathologies.
Sulforaphane as anticancer agent: A double-edged sword? Tricky balance between effects on tumor cells and immune cells
Liang J, Hänsch GM, Hübner K and Samstag Y
Sulforaphane (SFN) is a naturally occurring isothiocyanate derived from cruciferous vegetables such as broccoli. It has been reported to inhibit the growth of a variety of cancers, such as breast, prostate, colon, skin, lung, gastric or bladder cancer. SFN is supposed to act primarily as an antioxidant due to the activation of the Nrf2-Keap1 signaling pathway. This enhances the activity of phase II detoxifying enzymes and the trapping of free radicals. Finally, SFN induces cell cycle arrest or apoptosis of tumor cells. Here, we discuss effects of SFN on the immune defense system. In contrast to the situation in tumor cells, SFN acts pro-oxidatively in primary human T cells. It increases intracellular ROS levels and decreases GSH, resulting in inhibition of T cell activation and T cell effector functions. Regarding the use of SFN as an "anticancer agent" we conclude that SFN could act as a double-edged sword. On the one hand it reduces carcinogenesis, on the other hand it blocks the T cell-mediated immune response, the latter being important for immune surveillance of tumors. Thus, SFN could also interfere with the successful application of immunotherapy by immune checkpoint inhibitors (e.g. CTLA-4 antibodies and PD-1/PD-L1 antibodies) or CAR T cells. Therefore, a combination of SFN with T cell-mediated cancer immunotherapies does not seem advisable.
Cruciferous Vegetables as Antioxidative, Chemopreventive and Antineoplasic Functional Foods: Preclinical and Clinical evidences of Sulforaphane Against Prostate Cancers
Pinheiro Ferreira PM, Rosal Lopes LA, de Alencar Carnib LP, de Lima Sousa PV, Nolasco Lugo LM, Fonseca Nunes NM, Nascimento Silva JD, Silva Araújo LD and Gonçalves Frota KM
Sulforaphane (SF, 1-isothiocyanato-4-(methyl-sulfinyl)-butane) is found in broccoli, cabbage and cauliflower.
Sulforaphane Promotes Mitochondrial Protection in SH-SY5Y Cells Exposed to Hydrogen Peroxide by an Nrf2-Dependent Mechanism
de Oliveira MR, de Bittencourt Brasil F and Fürstenau CR
Sulforaphane (SFN; CHNOS) is an isothiocyanate found in cruciferous vegetables, such as broccoli, kale, and radish. SFN exhibits antioxidant, anti-apoptotic, anti-tumor, and anti-inflammatory activities in different cell types. However, it was not previously demonstrated whether and how this natural compound would exert mitochondrial protection experimentally. Therefore, we investigated here the effects of a pretreatment (for 30 min) with SFN at 5 μM on mitochondria obtained from human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide (HO) at 300 μM for 24 h. We found that SFN prevented loss of viability in HO-treated SH-SY5Y cells. Furthermore, SFN decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes of HO-exposed cells. Importantly, SFN enhanced the levels of both cellular and mitochondrial glutathione (GSH). SFN also suppressed the HO-mediated inhibition of mitochondrial components involved in the maintenance of the bioenergetics state, such as aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase, as well as complexes I and V. Consequently, SFN prevented the decline induced by HO on the levels of ATP in SH-SY5Y cells. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by using small interfering RNA (siRNA) abolished the mitochondrial and cellular protection elicited by SFN. Therefore, SFN abrogated the HO-induced mitochondrial impairment by an Nrf2-dependent manner.
Broccoli Sprout Extract Alleviates Alcohol-Induced Oxidative Stress and Endoplasmic Reticulum Stress in C57BL/6 Mice
Lei P, Zhao W, Pang B, Yang X, Li BL, Ren M and Shan YJ
The potential efficacy of sulforaphane in protecting alcohol-induced hepatic injury in vivo and its underlying mechanism were investigated. Male C57BL/6 mice were orally administrated with broccoli sprout extract (BSE) containing sulforaphane [7.6, 25.2, and 50.4 mg/kg of body weight (bw)] once a day for 14 days. At the 13th day, mice were challenged with alcohol (5 g/kg of bw) every 12 h for 3 times, which increased malondialdehyde (MDA) levels (4.44 ± 1.24 nmol/mg of protein, p < 0.01) in the liver. Our results showed that low-, medium-, and high-dose BSE markedly reversed the decrease of antioxidant capacity through enhancing glutathione (GSH) (2.07 ± 0.31 mg/g of protein, p < 0.05; 2.31 ± 0.32 mg/g of protein, p < 0.01; and 2.46 ± 0.21 mg/g of protein, p < 0.01), superoxide dismutase (SOD) (483.20 ± 62.76 units/mg of protein; 500.81 ± 49.82 units/mg of protein, p < 0.05; and 605.00 ± < 64.32 units/mg of protein, p < 0.01), glutathione peroxidase (GSH-Px) (318 ± 60.74 units/mg of protein; 400.67 ± 72.47 units/mg of protein, p < 0.01; and 394.72 ± 62.97 units/mg of protein, p < 0.01), and glutathione S-transferase (GST) (31.84 ± 6.34 units/mg of protein, p < 0.05; 30.34 ± 6.40 units/mg of protein, p < 0.05; and 38.08 ± 7.05 units/mg of protein, p < 0.01) in the liver. The protective actions are also associated activation of phase 2 enzymes via nuclear erythoriod-2-related factor 2 (Nrf2). The endoplasmic reticulum (ER)-stress-specific proteins, such as glucose-regulated protein 78 (GRP78), activating transcription factor 6, and protein kinase RNA (PKR)-like ER kinase (PERK), were also significantly attenuated by BSE. These results indicate that BSE protects the liver against alcohol challenge via upregulating antioxidant capacity and downregulating ER stress.
Comparison of Adaptive Neuroprotective Mechanisms of Sulforaphane and its Interconversion Product Erucin in in Vitro and in Vivo Models of Parkinson's Disease
Morroni F, Sita G, Djemil A, D'Amico M, Pruccoli L, Cantelli-Forti G, Hrelia P and Tarozzi A
Several studies suggest that an increase of glutathione (GSH) through activation of the transcriptional nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the dopaminergic neurons may be a promising neuroprotective strategy in Parkinson's disease (PD). Among Nrf2 activators, isothiocyanate sulforaphane (SFN), derived from precursor glucosinolate present in Brassica vegetables, has gained attention as a potential neuroprotective compound. Bioavailability studies also suggest the contribution of SFN metabolites, including erucin (ERN), to the neuroprotective effects of SFN. Therefore, we compared the in vitro neuroprotective effects of SFN and ERN at the same dose level (5 μM) and oxidative treatment with 6-hydroxydopamine (6-OHDA) in SH-SY5Y cells. The pretreatment of SH-SY5Y cells with SFN recorded a higher (p < 0.05) active nuclear Nrf2 protein (12.0 ± 0.4 vs 8.0 ± 0.2 fold increase), mRNA Nrf2 (2.0 ± 0.3 vs 1.4 ± 0.1 fold increase), total GSH (384.0 ± 9.0 vs 256.0 ± 8.0 μM) levels, and resistance to neuronal apoptosis elicited by 6-OHDA compared to ERN. By contrast, the simultaneous treatment of SH-SY5Y cells with either SFN or ERN and 6-OHDA recorded similar neuroprotective effects with both the isothiocyanates (Nrf2 protein 2.2 ± 0.2 vs 2.1 ± 0.1 and mRNA Nrf2 2.1 ± 0.3 vs 1.9 ± 0.2 fold increase; total GSH 384.0 ± 4.8 vs 352.0 ± 6.4 μM). Finally, in vitro finding was confirmed in a 6-OHDA-PD mouse model. The metabolic oxidation of ERN to SFN could account for their similar neuroprotective effects in vivo, raising the possibility of using vegetables containing a precursor of ERN for systemic antioxidant benefits in a similar manner to SFN.
KEAP1 and Done? Targeting the NRF2 Pathway with Sulforaphane
Dinkova-Kostova AT, Fahey JW, Kostov RV and Kensler TW
Since the re-discovery of sulforaphane in 1992 and the recognition of the bioactivity of this phytochemical, many studies have examined its mode of action in cells, animals and humans. Broccoli, especially as young sprouts, is a rich source of sulforaphane and broccoli-based preparations are now used in clinical studies probing efficacy in health preservation and disease mitigation. Many putative cellular targets are affected by sulforaphane although only one, KEAP1-NRF2 signaling, can be considered a validated target at this time. The transcription factor NRF2 is a master regulator of cell survival responses to endogenous and exogenous stressors.
Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways
Sturm C and Wagner AE
A high consumption of vegetables belonging to the family has been related to a lower incidence of chronic diseases including different kinds of cancer. These beneficial effects of, e.g., broccoli, cabbage or rocket (arugula) intake have been mainly dedicated to the sulfur-containing glucosinolates (GLSs)-secondary plant compounds nearly exclusively present in and in particular to their bioactive breakdown products including isothiocyanates (ITCs). Overall, the current literature indicate that selected -derived ITCs exhibit health-promoting effects in vitro, as well as in laboratory mice in vivo. Some studies suggest anti-carcinogenic and anti-inflammatory properties for ITCs which may be communicated through an activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) that controls the expression of antioxidant and phase II enzymes. Furthermore, it has been shown that ITCs are able to significantly ameliorate a severe inflammatory phenotype in colitic mice in vivo. As there are studies available suggesting an epigenetic mode of action for -derived phytochemicals, the conduction of further studies would be recommendable to investigate if the beneficial effects of these compounds also persist during an irregular consumption pattern.
Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes
Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, Fahey JW, Derry JMJ, Wollheim CB, Wierup N, Haymond MW, Friend SH, Mulder H and Rosengren AH
A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature. Sulforaphane suppressed glucose production from hepatic cells by nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and decreased expression of key enzymes in gluconeogenesis. Moreover, sulforaphane reversed the disease signature in the livers from diabetic animals and attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin. Finally, sulforaphane, provided as concentrated broccoli sprout extract, reduced fasting blood glucose and glycated hemoglobin (HbA1c) in obese patients with dysregulated type 2 diabetes.
Correction: Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial
Wise RA, Holbrook JT, Criner G, Sethi S, Rayapudi S, Sudini KR, Sugar EA, Burke A, Thimmulappa R, Singh A, Talalay P, Fahey JW, Berenson CS, Jacobs MR, Biswal S and
[This corrects the article DOI: 10.1371/journal.pone.0163716.].
Contribution of NRF2 in Gastrointestinal Protection from Oxidative Injury
Yanaka A
The human gastrointestinal tract is exposed to a variety of toxic agents, such as Helicobacter pylori (H.pylori), Nonsteroidal Anti-inflammatory Drugs (NSAIDs), gastric acid, enteric pathogenic bacteria, excessive auto immune reactions, and chronic mental stresses. These stressors generate free radicals within the gastrointestinal tissues, causing chronic inflammatory diseases, ulcers, cancers, and functional disturbances. Recent studies have demonstrated that some natural food compounds upregulate the nuclear factor erythroid 2-related factor 2- mediated antioxidant system, ameliorating or preventing these disorders. We have previously shown that dietary intake of sulforaphane-rich broccoli sprouts, ameliorates gastric inflammation induced by H. pylori, prevents NSAIDs-induced small intestinal injury, and improve functional constipation. There have been many other compounds, which enhance the nuclear factor erythroid 2-related factor 2-mediated antioxidant system, sufficient evidence for their clinical efficacy has not yet been provided. In addition, we have to pay attention to some reports, which have shown that excessive stimulation of nuclear factor erythroid 2-related factor 2 enhance chemoresistance and facilitates growth of cancer cells.
Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance
Xu L, Nagata N and Ota T
Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabolic tissues, which leads to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Particularly, obesity-induced metabolic endotoxemia plays an important role in the pathogenesis of insulin resistance and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Pharmacological stimulation of Nrf2 mitigates obesity and insulin resistance in mice; however, Nrf2 activators are not clinically available due to biosafety concerns. A recent study demonstrated that glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorates obesity by enhancing energy expenditure and browning of white adipose tissue, and attenuates obesity-related inflammation and insulin resistance by polarizing M2 macrophages and reducing metabolic endotoxemia. Thus, this review focuses on the efficiency and safety of glucoraphanin in alleviating obesity, insulin resistance, and NAFLD. Abbreviations: ALT, Alanine aminotransferase; AMPK, AMP-activated protein kinase; ATMs, Adipose tissue macrophages; BAT, Brown adipose tissue; CDDO-Im, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid-imidazolide; CDDO-Me, CDDO-methyl ester; DIO, High-fat-diet-induced obese; FFA, Free fatty acid; FGF, Fibroblast growth factor; GTP, Glutamyl transpeptidase; HFD, High-fat diet; IKKβ, Inhibitor of κB-kinase β; IL, Interleukin; JNK, C-Jun N-terminal kinase; KD, Knockdown; Keap1, Kelch-like ECH-associated protein 1; KO, Knockout; LPS, Lipopolysaccharide; NADPH, Nicotinamide adenine dinucleotide phosphate; NAFLD, Non-alcoholic fatty liver disease; NF-κB, Nuclear factor-κB; Nrf2, Nuclear factor E2-related factor 2; ROS, Reactive oxygen species; T2D, Type 2 diabetes; TLR, Toll-like receptor; TNF, tumor necrosis factor; UCP, Uncoupling protein; WAT, White adipose tissue.

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