In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.
Abstract Transcription factor nuclear factor erythroid 2-related factor 2 Nrf2 is a major regulator of antioxidant response element- ARE- driven cytoprotective protein expression. Additionally, sulforaphane is much more bioavailable than other Nrf2 activators. Bioavailable means the compounds actually reach the bloodstream so that they can have an effect in the body. Sulforaphane was 80 times more bioavailable than the bioactive compounds in turmeric! So what does that mean? It means that if we want to safely maximize our sulforaphane intake, we definitely need to eat more cruciferous vegetables!
That brings us to microgreens. More than twenty years ago, researchers at Johns Hopkins University were looking for food sources of bioactive compounds that induced phase 2 detoxification enzymes. Inducing phase 2 detox enzymes is important because it is protective against carcinogenesis and free radicals.
They stumbled across broccoli sprouts and found that sprouts contain high levels of bioactive compounds that induce these detoxification enzymes. Fast-forward fifteen years to the first microgreens nutrition paper. Academic research surrounding microgreens and sulforaphane has exploded, leading to more and more interest in sulforaphane as a potential agent for cancer treatment, reducing inflammation, and other health issues related to Nrf2 activation.
The difference between sprouts and microgreens is important. Sprouts are tiny plants that have just germinated, are eaten with the seed, and are grown in water or in very high humidity. Microgreens are baby plants that are grown for weeks, have sprouted their first leaves so that they undergo photosynthesis, and are grown hydroponically, or sometimes in soil or other substrates.
Both sprouts and microgreens often have much higher nutrient density than their mature plant counterparts. However, sprouts are grown in high-humidity environments and are frequently associated with foodborne illness , while microgreens are very safe to eat and have more flavor. Are you convinced that Nrf2 activation is really important for your health? Besides eating Nrf2-activating foods , there are lots of ways to sneak Nrf2 activators into your daily routine. As discussed above, exercise—especially strenuous exercise—is also known to activate Nrf2.
One of the most convenient ways to activate Nrf2 is to drink Microtea. If you hate vegetables but want the benefits of Nrf2, try drinking a cup of chamomile Relax Microtea before bed. One serving has over microgreens and is absolutely packed with all of the micronutrients and antioxidants your body needs. Upping your antioxidants decreases systemic inflammation, and this helps prevent disease and protect your health!
Please note, comments must be approved before they are published. Use this popup to embed a mailing list sign up form. Alternatively use it as a simple call to action with a link to a product or a page. Contact info beyondmicrogreens. Nrf2 activators: what they are, and why you should be eating them! May 1, What is an Nrf2 activator? Nrf2 and inflammation Inflammation is pervasive in modern lifestyles.
Instead, in the following sections we focus on the functions of NRF2 that are most pertinent for its roles in cancer. The NRF2—KEAP1 module is of primary importance in maintaining the homeostatic milieu because cells need to respond adaptively to many types of stress. Cells have incorporated highly toxic molecules into physiological signalling systems. Low concentrations of these potentially toxic molecules are used for adaptive intracellular signalling, and higher concentrations are used for self-defence against microorganisms However, physiological concentrations of molecules such as H2O2 and NO need to be tightly regulated, and NRF2 plays a crucial part in this process.
These highly reactive functional groups act as stress sensors. These modifications which include adduct formation result in a conformational change of KEAP1, thereby reversing the proteasomal degradation of NRF2, which then becomes transcriptionally active [ FIG. The NRF2—KEAP1 module is part of an entire network of proteins the thiol proteome 25 whose activity is regulated through modifications of cysteine residues in response to the cellular redox state.
The reactivity of these cysteine residues can be modulated not only by redox reactions 26 but also by NO S -nitrosylation 27 or guanine S -guanylation. Specific cysteine residues are thus thiol-based cellular switches that regulate the activity of their respective proteins 25 — 28 to provide a link between the cellular redox state and important cell fate decisions.
Classic examples are the multiple protein tyrosine phosphatases, all of which contain reactive cysteine residues in their active sites 29 and are crucial determinants of many aspects of cell physiology, differentiation and proliferation. Regulation of ubiquitylation of NFE2-related factor 2 NRF2 is a key process in the cellular response to drugs or oxidative and electrophilic stress.
This polyubiquitylation results in NRF2 being degraded by the proteasome. If NRF2 is not degraded, it can then migrate to the nucleus, where it becomes transcriptionally active after binding with one of the MAF proteins.
This figure is a greatly simplified representation of a complex process; molecular details are still being elucidated ARE, antioxidant response element. Different stressors may react differentially with various cysteine residues in KEAP1, suggesting that specific cysteine residues, individually or in combination, contribute to the overall activity of KEAP1 in a unique manner 23 , These proteins can be phosphorylated 30 , 31 or acetylated 32 , 33 , and KEAP1 can be modified by succination under pathological conditions as discussed below 34 ; thus, NRF2—KEAP1 interacts with multiple cellular networks.
How-ever, the in vivo importance of all of these additional modifications is not yet totally clear. There are more than genes that are regulated by NRF2.
NRF2 binds to response elements on DNA, known as antioxidant response elements AREs or electrophile response elements EpREs 16 , 18 , and regulates the expression of genes involved in the response to cellular stress. Furthermore, cells need protection from toxic xenobiotic molecules, and NRF2 again has a major role here, especially through its potent induction of glutathione, the primary cellular scavenger of electrophiles, as well as by its induction of enzymes of glucuronidation, which conjugate xenobiotics for excretion NRF2 can also influence drug transport through the induction of the multidrug resistance-associated gene family Thus, NRF2 can transduce aspects of cellular stress into adaptive, cytoprotective responses.
Moreover, it appears that NRF2 may also regulate many genes other than classic cyto-protective ones, particularly with respect to cell differentiation and proliferation. Thus, newborn Keap1 -knockout mice in which Nrf2 is constitutively overexpressed die from hyperplastic keratinization of the oesophagus and forestomach, which obstructively limits intake of food; this lethality can be reversed by simultaneous knockout of Nrf2 REF.
Recently there have been reports of the effects of NRF2 on differentiation or proliferation of stem cells in the bone marrow 37 or intestine Thus, NRF2 is a multifunctional transcription factor that induces a broad range of biological responses upon its activation. Beyond this immediate homeostatic response, NRF2 activity has longer-term consequences, which have been described in a recent review Thus, NRF2 is able to modulate many cellular activities beyond its immediate homeostatic, cytoprotective role and to influence processes as diverse as inflammation, proliferation, apoptosis, cell differentiation, tissue regeneration and even metabolism.
The capacity of cells to deal with stress is fundamental to life, and KEAP1 and NRF2 are at the core of this process, especially as they stabilize the thiol proteome of the cell. There is abundant evidence that activation of NRF2 can suppress carcinogenesis, especially in its earliest stages.
This topic has been extensively reviewed 5 , 18 , 19 ; thus we only provide brief details here. Suppression of carcinogenesis has been demonstrated in several experimental designs, either by showing that many drugs as well as genetic alterations that enhance the activity of NRF2 inhibit carcinogenesis, or by showing that genetic deletion of Nrf2 enhances susceptibility to development of cancer. In particular, the anti-carcinogenic activity of chemopreventive drugs many of which activate NRF2 has been shown to be either abolished or markedly decreased in Nrf2 -null mice.
Chemically diverse chemopreventive drugs have been used in studies of NRF2, including sulphoraphane, phenethyl isothiocyanate, oltipraz, curcumin, resveratrol, fumaric acid and its esters, and synthetic oleanane triterpenoids. Because many of these molecules are natural products that occur in food, it has been relatively easy to obtain acceptance by patients for their use in clinical trials of cancer prevention, although approval by regulatory agencies may still be required.
As would be expected of NRF2 activators, all have been shown to induce multiple cytoprotective and antioxidative enzymes phase 2 response , and many are anti-inflammatory as well; why such responses might be tumour preventive in these settings is discussed later.
A common property of these compounds is their ability to react with cysteine residues on target proteins, most notably KEAP1, and this thiol reactivity has been correlated with their ability to induce activity of NRF2.
Thus, different concentrations of any chemopreventive drug are expected to react with different subsets of cysteines in KEAP1 and other proteins to produce distinct biological responses 16 , 23 , As just two examples of NRF2 activators with chemopreventive activity, sulphoraphane a natural product and synthetic oleanane triterpenoids have been used extensively in mouse models of cancer. Sulphoraphane inhibits carcinogenesis at multiple organ sites, including skin, lung, bladder, breast, colon and stomach 5 , 18 , 19 , 52 — In many studies, the beneficial effects were obtained by administering sulphoraphane during the promotion or progression phase of carcinogenesis; in the case of suppression of carcinogenesis by sulphoraphane in the Apc Min mouse which expresses a truncated, non-functional form of the adenomatous polyposis coli protein , the benefit is clearly that of altering the further consequences of the expression of a genetic lesion 53 , Human cancer chemoprevention studies with sulphoraphane-rich extracts of broccoli are currently being pursued in China 9 , In these studies, drugs were not acting by minimizing DNA damage associated with initiation of carcinogenesis because they were not given until after mutation of DNA by a chemical carcinogen had occurred, or they were used in transgenic mouse models 59 — In prevention studies using genetic models of carcinogenesis, synthetic oleanane triterpenoids have delayed the onset of tumorigenesis driven by oncogenes as diverse as Kras , Trp53 , Brca1 and Erbb2 also known as Her2 or Neu in organs such as the pancreas or breast 61 , There has been particularly strong suppression of lung carcinogenesis by synthetic oleanane triterpenoids in a model in which Kras activity or mutations are induced by the carcinogen vinyl carbamate 59 , Because chemopreventive drugs have multiple cellular targets, a key tool for determining whether their tumour-suppressive effects are NRF2-dependent is the use of Nrf2 -knockout mice 18 , 19 , which were originally developed by Yamamoto and colleagues 1.
Thus, chemoprevention by oltipraz was greatly diminished in Nrf2 -knockout mice 4 , 63 , and many similar studies in Nrf2 -knockout mice have been carried out with agents that protect against skin carcinogenesis induced by ultraviolet light or chemicals 18 , 19 , Likewise, the ability of the triterpenoid CDDO-imidazolide to protect against aflatoxin-induced liver carcinogenesis appears to depend on its ability to induce NRF2-dependent cytoprotective enzymes, as such enzymes cannot be induced in Nrf2 -knockout mice Knockout mice have also shown a tumour-suppressive activity of NRF2 outside the setting of chemoprevention.
The susceptibility to carcinogenesis — induced by polycyclic hydrocarbons in the forestomach and skin, by inflammation in the colon or by a nitrosamine carcinogen in the bladder — is markedly increased in Nrf2 -knockout mice 4 , 63 , 64 , Additionally, mice with Nrf2 overexpression resulting from Keap1 knockout have been shown to have increased resistance to cancer cell metastasis to their lungs The importance of NRF2 activation for the action of chemopreventive agents has been reinforced by multiple studies using many of the same agents for protection from diseases other than cancer [ BOX 1 ].
Such widespread protective effects have created strong incentives to develop new potent enhancers of NRF2 activity for the prevention and treatment of many diseases several of which are presently incurable in which both inflammatory and oxidative stress have a key pathogenic role.
However, within the past 5 years there have been many new reports of the oncogenic activity of NRF2. These reports have led to increasing concerns about the safety of a long-term increase in NRF2 activity. NFE2-related factor 2 NRF2 is able to suppress such stress even the mutation of DNA and thus prevent disease, so the ability of pharmacological agents to activate NRF2 is an essential component of their desirable actions.
Selected examples of the beneficial effects of drugs that activate NRF2 include protection from acute insults to the lung 8 , , kidney , brain 6 , , liver , eye and heart that are caused by diverse factors such as cigarette smoke , hyperoxia , ischaemia—reperfusion injury and chemical toxins such as heavy metals , streptozotocin and the neurotoxin MPTP Data have also been obtained for NRF2-activating drugs that have a disease-preventive role in chronic diseases such as diabetes and obesity , and in genetic models of multiple neurodegenerative diseases — Importantly, although these drugs can target proteins other than NRF2 and thus have additional NRF2-independent mechanisms of action, their beneficial effects in many studies are NRF2-dependent because the effects are abolished or greatly diminished in Nrf2 -knockout mice.
As NRF2 promotes cell survival under stress, it is logical to argue that increased NRF2 activity could be tumour promoting by being protective for cancer cells.
Gain-of-function mutations in NRF2 are found mostly in squamous cell carcinomas of the oesophagus, skin, lung and larynx Using immunochemistry, an increase in NRF2 levels in tumour nuclei has been shown in tumour cells with NRF2 mutations, together with an increase in the expression of cyto-protective enzymes Loss-of-function mutations in human KEAP1 have been found in carcinomas of the lung 69 — 73 , gallbladder 74 , ovary 75 , breast 76 , 77 , liver 73 and stomach 73 ; these mutations result in constitutive NRF2 activity.
Clinically, it has been shown that decreased expression of KEAP1 and increased expression of NRF2 may be associated with poor prognosis. In an extensive study of lung cancer specimens 69 , immunohistochemical analysis of non-small-cell lung cancers showed abnormally high expression of NRF2 in the entire range of carcinomas in many patients, whereas relatively low expression of KEAP1 was only seen in patients with adenocarcinomas.
Both abnormalities could be correlated with poor prognosis, measured either as recurrence-free or overall 5-year survival Furthermore, this lung cancer study suggested that nuclear expression of NRF2 may play a part in resistance to platinum-based chemotherapy of squamous cell carcinoma.
Similar findings have been made in a recent study of 30 patients with epithelial ovarian carcinoma 75 , which showed that NRF2 staining in tumour cell nuclei was found in more than half of the patients by contrast, no staining was seen in control normal ovarian epithelium , with associated upregulation of NRF2-dependent genes.
Most importantly, this study suggested that high levels of NRF2 expression could be correlated with a relative resistance to platinum-based chemotherapy and with an inferior survival rate Thus, there are serious clinical concerns about the adverse effects of enhanced NRF2 activity with respect to drugs used in cancer chemotherapy.
Beyond the studies on clinical material, there have been extensive studies in cancer cell lines and in experimental animals, which have documented the ability of NRF2 to enhance drug resistance.
These studies have included a diverse range of drugs, such as cisplatin, carboplatin, 5-fluorouracil, paclitaxel, bleomycin, doxorubicin and etoposide 74 , 80 , It is clearly a serious problem, and many articles on this topic have concluded with the suggestion that the development of new inhibitors of NRF2 should be considered as a novel approach to the treatment of carcinomas 71 , 80 — The effector functions of NRF2 might cause chemotherapy resistance by several mechanisms: through suppression of the oxidative stress that can play an important part in the cytotoxic effects of chemotherapy; through drug detoxification by glutathione and other conjugating mechanisms; and through stimulation of ATP-dependent drug efflux pumps such as the multidrug resistance system, which again would lower effective drug levels.
Thus, oncogenes may promote tumorigenesis in part through an NRF2-dependent creation of a more favourable intracellular environment for the survival of tumour cells. Support for this contention was obtained in mouse models of pancreatic cancer, as well as in human pre-invasive pancreatic intraepithelial neoplasia PanIN and pancreatic ductal adenocarcinoma PDA One question still remains in interpreting these data: does an increase in NRF2 levels directly promote tumorigenesis, or are increased NRF2 levels a response to other, more fundamental stressful changes induced in cells by oncogenes?
These studies again raise important issues on the complex roles of ROS in cancer: mutagenic ROS may be involved during carcinogenesis in promoting and maintaining the oncogenic phenotype, suggesting that ROS levels should be suppressed for the prevention of cancer 5 , Conversely, drugs that increase ROS production and activity might be useful chemotherapy agents by further increasing oxidative stress and thus killing cancer cells 85 , Understanding the context of action and the dose—response to ROS would appear to be critical for practical drug development in this area.
How can we resolve the paradox that although high expression of NRF2 in cancer cells has poor prognostic implications for a patient, drugs and herbal agents that enhance activation of NRF2 are safely used worldwide to improve human health and even to try to delay the process of ageing?
There is little, if any, evidence that these chemopreventive drugs themselves are carcinogenic; in fact, many are potent and safe agents for the suppression of carcinogenesis in mouse models of cancer.
The simplest answer is that it is all a matter of context, particularly the different experimental contexts in which genetic or pharmacological data are obtained, and how these data are interpreted.
Thus, genetic studies leave little doubt that NRF2 or KEAP1 may be mutated in human cancers and that the resultant increase in NRF2 activity can lead to resistance to classic cytotoxic chemotherapeutic agents. If enhancement of oxidative stress represents an important therapeutic approach to cancer, then there is good reason to suggest that we should consider blocking NRF2 activity in fully malignant cells and thereby increase oxidative stress 85 , 86 , contrary to the NRF2-activating effects of the chemopreventive agents discussed above.
Fully malignant cells, which are characterized by their autonomy, are very different from dysplastic but not yet fully neoplastic cells in a premalignant lesion. Premalignant cells are under much greater control from inflammatory cells and other stromal cells in their microenvironment and, moreover, they have not yet reached a level of DNA damage that makes them autonomous. Therefore, enhancement of NRF2 activity, which would lessen both inflammatory and further oxidative or mutagenic stress, appears to be beneficial during premalignant states, and thus for the suppression of carcinogenesis.
As such, the biological time context is important: NRF2 activity is desirable for the host organism in early stages of tumorigenesis, when the host is seeking to control premalignant carcinogenesis, but is undesirable in later stages of tumorigenesis, when it could make fully malignant cancer cells become resistant to treatment [ FIG. Enhancing NFE2-related factor 2 NRF2 activity is important for the prevention of cancer, especially if low doses of drugs are used during the earliest stages of carcinogenesis.
However, in fully malignant cells, enhancement of NRF2 activity caused by mutations can protect tumours from the cytotoxic effects of reactive oxygen species ROS that are induced by chemotherapy or that may be produced endogenously by oncogenic signalling in advanced tumours. The effects of NRF2 inducers on cells at intermediate stages of tumorigenesis are still largely unknown and need further investigation. Zhang Y. Cell Metab.
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