NRF2 Pathway

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Identified more than 20 years ago, and the subject of over 5500 published papers, Nrf2, or nuclear factor (erythroid-derived 2)-like 2, is a very important redox-sensitive transcription factor in all mammals.[1] It has been referred to as the activator of cellular defence, the master antioxidant switch and the guardian and gatekeeper for health and longevity.[1]

Activation of Nrf2 creates a downstream production of proteins and antioxidant enzymes, which provide benefits beyond direct-acting antioxidants.

Antioxidant supplements have a direct action on the oxidative effect of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). However, with the discovery of Nrf2 and its signalling pathway, it is now possible to indirectly enhance cellular defence systems.[1] By regulating a large network of cell protecting (cytoprotective) genes, Nrf2 activation is critical for the body’s ability to cope with internal and external stressors, including inflammatory, oxidative and environmental.[2] It is also very important for mitochondrial homeostasis and structural integrity.[3]

Nrf2 is an intrinsic key that modulates gene expression of the cell’s primary antioxidant, detoxification and inflammatory mechanisms.[1]

THE GENE TARGETS OF NRF2

Nrf2 regulates more than 600 genes. Over 100 of these are encoded for cytoprotective proteins, which increase toxin metabolism and removal, lower oxidative stress and maintain cellular homeostasis.[2,4] Nrf2 targets genes involved in:

Glutathione synthesis and conjugation

Antioxidant proteins and enzyme activity

Xenobiotic metabolising enzyme and transporter activity

Metabolism

Transcription.[4]

Activation of Nrf2 creates a downstream production of proteins and antioxidant enzymes, which provide benefits beyond direct-acting antioxidants.

These resulting products are not fully consumed in redox reactions (unlike direct-acting antioxidants such as vitamin C) and can restore some endogenously produced antioxidants, such as CoQ10 and vitamin E, back to their reduced state. Additionally, they have a long duration of action, so they do not need to be continuously produced.[1]

Some of the most protective enzymes and proteins critical for ROS and RNS reduction, and activated by Nrf2, include:

Catalase and superoxide-dismutase (SOD)

GSH synthase, GSH-peroxidases and GSH-reductase

Thioredoxin and thioredoxin reductase

Heat shock protein 70 (HSP70)

Haem oxygenase-1 (HO-1).[5]

The ability of Nrf2 to induce phase 2 liver enzymes also makes it a powerful detoxification agent. Prime examples are the NAD(P)H:quinone reductase (NQO1) gene, which is one of the strongest responders to chemical and genetic Nrf2 activation, and glutathione-S-transferases (GSTs). Both are required for steroid and toxin detoxification.[1,6]

Other phase 2 enzymes upregulated by Nrf2 activation are UDP-glucuronosyltransferase, N-acetyltransferases and sulphotransferases. Although most of the research has focused on phase 2, Nrf2 also affects the cytochrome P450 monooxygenase system of phase 1 liver detoxification.[5]

The downstream products of Nrf2 are often regulated through a promoter element found in many cytoprotective genes, called an Antioxidant Response Element (ARE). When combined with Nrf2 and a binding protein called Kelch-like ECH-associated protein 1 (Keap1), a cellular survival system is formed—the Keap1-Nrf2-ARE signalling pathway.[4,6]

THE KEAP1-NRF2-ARE PATHWAY

The stability, control and release of Nrf2 relies predominately on the inhibitory protein, Keap1.[7] When Nrf2 is not being used, Keap1 will bind to Nrf2 inhibiting its release and mediating proteasomal degradation.[3,5]

Keap1 is also a highly tuned sensor of a wide array of activators or inducers, especially oxidative and electrophilic stress. When inducers are present, they block the breakdown of Nrf2 and disrupt the binding interface.[3,4] This allows Nrf2 to travel to and accumulate within the cell’s nucleus.

Here it forms a complex with a small protein (Maf), binds to AREs, and initiates gene transcription.[3]

AREs, also called Electrophilic Response Elements (EpREs), play a pivotal role in cellular defence, and are found in the regulatory promoter region of hundreds of genes.[1,6] The discovery of AREs unravelled the molecular mechanisms behind Nrf2 and Keap1.[7] These promoter elements increase gene transcription, and therefore the production of the beneficial enzymes and proteins, which protect the cell from oxidative damage.[8]

THE EFFECT OF NRF2 ON HEALTH AND DISEASE

Oxidative stress and inflammation contribute to a large number of chronic diseases, including atherosclerosis, inflammatory bowel disease (IBD), rheumatoid arthritis, cancer, diabetes, obesity, metabolic syndrome, and many more. Although the pathology of each of these diseases is different, Nrf2 plays a role in many of them.[6]

It is considered a major protective factor against these oxidative stress-related conditions.[9]

“Thus, Nrf2 activation or inhibition responding to cellular oxidative and electrophilic stress, and designed to restore redox homeostasis, paves a new way to understand, prevent, or even cure these complex diseases.”[6]

While oxidative stress activates Nrf2, researchers have looked for other ways to induce this protein for human benefit. Interestingly, there are a large number of Nrf2 activators in foods and dietary supplements, and even in lifestyle choices.

PHYTOCHEMICAL ACTIVATORS OF NRF2

Consuming fruits and vegetables not only meets nutritional needs but also provides a rich source of antioxidants.[7] However, extensive preclinical research now demonstrates that many phytochemicals in foods and supplements also regulate Nrf2; thereby increasing intrinsic and longer-lasting antioxidant support.[8] These include:

astaxanthin (from algae, fish and yeast)

blueberry

catechins (from tea, cocoa, legumes and grapes)

coffee

curcumin (from turmeric)

ellagic acid (from berries, fruit and nuts)

garlic

ginger

herb extracts from: milk thistle, cinnamon, rosemary, fennel, ginseng, schisandra, magnolia

isoflavones (from legumes)

kiwi fruit

naringenin (from citrus)

nutrients: vitamin D, zinc, chromium and arginine

pomegranate

purple sweet potato

resveratrol (from grapes, peanuts and berries)

sulforaphane (from cruciferous vegetables)

whey protein.[8-15]

The most well-known and widely used nutritional Nrf2 activators are sulforaphane, resveratrol and curcumin.[8]

SULFORAPHANE

A powerful inducer of the Nrf2 pathway,[8] sulforaphane’s low molecular weight and lipophilic nature means it also has a high bioavailability.[1] Although it does not have a direct antioxidant effect,[1] sulforaphane specifically interacts with the Nrf2-Keap1 complex, allowing nuclear translocation and activation of ARE-responsive genes.[8] As part of this interaction with Nrf2, sulforaphane is a potent phase 2 enzyme inducer.[1]

RESVERATROL

Known for its direct antioxidant effect and wide-ranging biological actions, preclinical research has also shown that resveratrol effectively activates the Nrf2/ARE complex.[8,16] Although the exact mechanism is not known, it may be by directly binding to NrF2 or Keap1.[16]

Diabetes studies demonstrate that resveratrol reduces hypoglycaemic-induced oxidative stress and renal inflammation, through its ability to improve renal expression of Nrf2/Keap1 and the downstream regulatory proteins.[10] Resveratrol also limits lipid peroxidation through this pathway, with resulting upregulation of SOD and HO-1.[16]

CURCUMIN

A direct and indirect antioxidant, curcumin has been shown to strongly induce phase 2 detoxification enzymes, such as HO-1, though the activation of the Nrf2-ARE pathway.

This cancer preventative measure was supported in a long-term in vivo study. It appears curcumin blocks the inhibitory Keap1 protein, while increasing Nrf2-ARE binding.[7]

“The elucidation of the mechanism by which Nrf2 acts as a cytoplasmic ‘switch’ to activate a battery of cytoprotective genes arguably heralds a new paradigm in nutrition science.”[1]

OTHER HEALTHY ACTIVATORS OF NRF2

The process by which the body responds to sub-lethal stress levels is called hormesis.

This is a concept that proposes low pro-oxidant levels of stress are healthy and can prolong longevity. Moderate exercise, calorie restriction and pro-oxidant exposure are all hormetic stressors.[5] It appears that Nrf2 also follows a hormetic rule, being activated by mild pro-oxidant signals and inhibited by large oxidative assaults.[1]

Moderate exercise and calorie restriction may therefore be valuable health promoting activities. Any exercise increases glucose and oxygen transport through the mitochondria with a resulting increase in ROS. In moderate exercise, a low pro-oxidant effect is created, which induces mitochondrial biogenesis and increased SOD and HO-1 expression.[5] Research indicates that Nrf2 signalling and activity are impaired by age, which may contribute to increased age-related disease risk in the elderly. Fortunately, preclinical trials show that this decline can be reduced with moderate exercise.[6] Additionally, calorie restriction has been linked to slowing of the metabolism, reducing ROS and decreasing the development of ROS-related disease.[5]

Adequate dietary protein is also important for Nrf2 activation. One property shared by all inducers is their ability to react with sulphur groups; therefore, sulphur amino acids from protein rich foods are necessary for the

Keap1-Nrf2-ARE pathway to function.[1]

OVERACTIVATION OF NRF2

Research has indicated that continued and persistent activation of Nrf2 may produce a negative effect in some cancer cells.[6] However, this may only occur with high dose pharmaceutical manipulation, genetic mutations of Keap1 and Nrf2, and changes in physiology due to the cancer.[7] This activation is different from the intermittent and beneficial effects of foods, herbs, supplements and moderate exercise.[6]

Although, high-dose antioxidants may inhibit the Nrf2 pathway, evidence is still emerging. Presumably, it would depend on various factors, such as cell type, health status, dose and type of antioxidant. It is therefore recommended that low to moderate dosing is the most beneficial for Nrf2 activation, while specifically targeting disease prevention, disease recurrence prevention or slowing of disease progression in early stage illness.[6]

In conclusion, Nrf2 plays a profound role in physiological and pathological processes. A master regulator of the antioxidant response and xenobiotic disposal, it is also a modulator of inflammation, metabolic programming, cell proliferation and survival. Activation of this critical pathway is now possible with many healthy nutritional and lifestyle interventions.

REFERENCES

Houghton CA, Fassett RG, Coombes JS. Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician’s expectation be matched by the reality? Oxid Med Cell Longev 2016;2016:7857186. [Full text]

 

Eggler AL, Savinov SN. Chemical and biological mechanisms of phytochemical activation of Nrf2 and importance in disease prevention. Recent Adv Phytochem 2013;43:121-155. [Full text]

 

Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 2015;88(Pt B):179-188. [Full text]

 

Lu MC, Ji JA, Jiang ZY, et al. The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev 2016;36(5):924-963. [Abstract]

 

Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Front Chem 2015;3:4. [Full text]

 

Gao B, Doan A, Hybertson BM. The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders. Clin Pharmacol 2014;6:19-34. [Full text]

 

Huang Y, Li W, Su ZY, et al. The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 2015;26(12):1401-1413. [Full text]

 

Jiménez-Osorio AS, González-Reyes S, Pedraza-Chaverri J. Natural Nrf2 activators in diabetes. Clinica Chimica Acta 2015;448:182-192. [Abstract]

 

Hodges RE, Minich DM. Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application. J Nutr Metab 2015;2015:760689. [Full text]

 

Bhakkiyalakshmi E, Sireesh D, Rajaguru P, et al. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol Res 2015;91:104-114. [Abstract]

 

Dong Q, Hou H, Wu J, et al. The Nrf2-ARE pathway is associated with Schisandrin b attenuating benzo(a)pyrene-induced HTR cells damages in vitro. Environ Toxicol 2016;31(11):1439-1449. [Full text]

 

Fan J, Liu D, He C, et al. Inhibiting adhesion events by Panax notoginseng saponins and Ginsenoside Rb1 protecting arteries via activation of Nrf2 and suppression of p38 – VCAM-1 signal pathway. J Ethnopharmacol 2016;192:423-430. [Abstract]

 

Kerasioti E, Stagos D, Tzimi A, et al. Increase in antioxidant activity by sheep/goat whey protein through nuclear factor-like 2 (Nrf2) is cell type dependent. Food Chem Toxicol 2016;97:47-56. [Abstract]

 

Sun Z, Park SY, Hwang E, et al. Dietary Foeniculum vulgare mill extract attenuated UVB irradiation-induced skin photoaging by activating of Nrf2 and inhibiting MAPK pathways. Phytomedicine 2016;23(12):1273-1284. [Abstract]

 

Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants (Basel) 2015;4(1):204-247. [Full text]

 

Poulose SM, Thangthaeng N, Miller MG, et al. Effects of pterostilbene and resveratrol on brain and behavior. Neurochem Int 2015;89:227-233. [Abstract]

 

 

 

Activate the Anti-Oxidant Benefits of Nrf2

Oxidative stress is a major player in the formation of pathological conditions such as cancer, diabetes, heart disease, accelerated aging and neurodegeneration.  Anti-oxidant rich foods, herbs and supplements are used to protect the body from unwanted oxidative stress.  Recent research has found a new signaling pathway that plays an enormous role in amplifying the effects of anti-oxidants on the body.  In this article, you will discover 5 ways to activate the anti-oxidant benefits of the Nrf2 gene pathway.

The body adapts to function in a state of homeostasis or balance.  When the body is confronted with major stressors the cells must quickly modulate their antioxidant capacity to counteract the increased oxidative stress.  In order to do this the body is able to activate a massive anti-oxidant effect in a matter of nanoseconds through a specific genetic pathway.

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The Keap1-Nrf2 Pathway and Your Health:

Nrf2 (NF-E2-related factor 2) is a transcription factor in humans encoded by a specific gene that regulates the expression of a set of antioxidant and detoxifying genes.  This pathway is activated under times of oxidative stress to enhance the expression of a multitude of antioxidant and phase II liver detoxification enzymes that restore homeostasis to the ox/redox cycles in the body (1, 2, 3).

An enzyme named (Keap1) which sits on the cytosol of the cell interacts with Nrf2 and activates it.  Keap1 is rich in the amino acid cysteine, and acts as a sensor that is constantly reading the environment for any increase or decrease in oxidative stress.  Under times of increased stress, Keap1 activates Nrf2 which then migrates into the cell nucleus and bonds to the DNA to active the Antioxidant Response Element (ARE).  ARE then upregulates a variety of powerful antioxidant enzymes and detoxifying proteins (4, 5, 6).

This Keap1-Nrf2 pathway regulates over 600 genes involved in cellular protection and anti-oxidant defenses.  These various genes act to boost major anti-oxidant and detoxifying enzymes such as glutathione and superoxide dismutase.  They also promote anti-inflammatory prostaglandins and enzymes and improve tissue healing and repair (7, 8).

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Nrf2 and Cancer Prevention:

High levels of oxidative stress damage normal cells, affecting the DNA and inducing cancer causing mutations.  Oxidative stress also activates chronic inflammatory pathways that create an optimal environment for cancer development.  The Keap1-Nrf2 pathway has been shown to be protective against tumor formation (9, 10).

Nrf2 has a dark side in that cancer cells can use a mutated form of this pathway to protect themselves against the bodies immune system and chemotherapeutic agents.  Mutations in the Keap1-Nrf2 pathway can lead to fast growing and highly resistant tumor growths (11, 12).

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Nrf2 and Brain Health:

We have an epidemic of neurodegenerative disorders in the western world.  The Keap1-Nrf2-ARE pathway has been researched to be a key player in the development or prevention of neurodegeneration (11, 12, 13)

Additionally, mood disorders such as depression, bipolar, addictions, etc. have shown to be linked to chronic inflammation.  The Nrf2 pathway has been researched to be a major factor in the development of mood disorders and poor neurotransmitter function (14, 15, 16).

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Nrf2 and Diabetes Prevention:

Type II diabetes is characterized by chronic inflammation and oxidative stress.  Diabetes is also the major cause of chronic kidney disease and peripheral neuropathy worldwide.  It is also a major factor in the formation of cardiovascular disease.  Research has indicated that the Nrf2 pathway is markedly reduced in type II diabetes and this is associated with hyperglycemia and the heavy formation of advanced glycolytic end products that provoke tissue damage (17, 18).

Research has indicated that having stability in the Keap1 and Nrf2 pathway is crucial to the prevention of type II diabetes (19, 20).  Activating the Keap1 and Nrf2 pathway is also protective to the body against the tremendous metabolic stress that diabetes creates (21).  Additionally, the pathway helps to stabilize blood sugar levels and reverse some of the damage of this disorder (22, 23).

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Nrf2 and Auto-Immunity:

The Keap1-Nrf2 pathway appears to play an important role in proper immune coordination.  Studies observing Nrf2 deficient mice have shown that they are at great risk of developing a wide-variety of auto-immune disorders including lupus, multiple sclerosis, hemolytic anemia, rheumatoid arthritis and many others (24, 25, 26, 27, 28).

Nrf2 deficient mice developed normal body structures but they displayed a variety of auto-immune disorders and a shortened lifespan.   It is thought that the decreased glutathione production from the Nrf2 deficient mice leads to immune malcoordination and hyperinflammatory processes.

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Nrf2 and Hormonal Health:

Aging and high levels of physical, chemical and emotional stress are associated with the loss of progesterone in women and testosterone in men.  When these key hormones are depleted it causes a state of estrogen dominance.  This state of estrogen dominance is one of the major factors associated with degenerative disease processes (29, 30, 31).

Estrogen dominance can lead to menstrual and menopausal issues in women.  This includes the following major health issues:

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The Keap1-Nrf2 pathway regulates the expression of antioxidant enzymes such as glutathione perioxidase and NAD(P)H-quinone oxidoreductase 1 that help to remove toxic estrogen metabolites (32, 33).  This is extremely critical due to the ubiquitous nature of artificial estrogen molecules in our society.

Estrogen is a growth factor and stimulates growth patterns in many forms of breast, uterine, cervical, ovarian, prostate and colon cancers.  Research has shown that activation of the Nrf2 pathway inhibits the estrogen signaling pathway in various forms of breast cancer (34, 35).

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Nrf2 Activators:

There are several compounds that can be found in nature and ingested through specific foods and herbs that enhance the Keap1-Nrf2 pathway.  The most powerful nutrients that support the activation of the anti-oxidant amplifying Nrf2 pathway include curcumin, stilbenes, catechins, and sulforaphane.

You can find these nutrients in turmeric (curcumin), resveratrol in grape skin and berries (stilbenes), green tea and dark chocolate (catechins) and cruciferous veggies (sulforaphane).  It is highly adviseable to consume these compounds everyday to keep anti-oxidant systems in balance.  This will result in positive adaptations that improve aging, reduce disease formation and improve quality of life.

There is also benefit to consuming these ingredients together as they have a synergetic effect that amplifies their effects on the Keap1-Nrf2 pathway.  The easiest way this is done is through key supplements that are specifically designed to upregulate this pathway.

From a food and nutritional perspective, one could have steamed Brussel sprouts with grass-fed butter (fat-soluble carrier) or coconut oil melted on top.  Add generous amounts of turmeric to the dish, broccoli sprouts and a pinch of black pepper.  Consume this with green tea and some red wine.  Finish with a small bite of minimally processed dark chocolate.

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Turmeric and Curcumin:

The orange Asian herb turmeric has been traditionally used for centuries by Ayurveda and Chinese medicine.  Curcumin is the most powerful active anti-inflammatory compound within turmeric.  Curcumin has been shown to be a powerful suppressor of chronic inflammatory mediated disease processes.

Curcumin has been shown to reduce inflammatory mediating prostaglandins, cytokines and other molecules such as interleukin 6, Nuclear Factor Kappa Beta (NF-kb) and tumor necrosis factor-alpha (TNF – alpha) (36,37). With a high enough dosage this has the ability to pull the body out of a strong inflammatory cascade and reset anti-inflammatory behavior at the cellular level.

Curcumin exerts both direct and indirect antioxidant effects by scavenging reactive oxygen species (ROS)(38) and inducing the expression of cytoprotective proteins in an Nrf2-dependent way (39).  Human studies showed a significant increase in curcumin absorption when co-administered with black pepper extract.

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Sulforaphane (SFN):

This is the compound found in cruciferous veggies and most densely in broccoli sprouts.  SFN was identified as a chemopreventive agent over a decade ago on the basis of its capability to induce phase II detoxification enzymes, and to inhibit phase I enzymes involved in the activation of carcinogens (40).

Research demonstrates that sulforaphane, through induction of Nrf2-dependent phase 2 enzymes, protects the brain against hypoxic-ischemic injury and may improve cognitive function when administered following traumatic brain injury (41, 42).  Additionally, it protect the brain from neurodegenerative states and amyloid plaque buildup as seen in the pathogenesis of Alzheimer’s disease (43, 44)

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Pterostilbene – Resveratrol:

This is a naturally occurring phenolic compound/analog of resveratrol that has comparatively better oral bioavailability, has been shown to possess cytotoxic, cytokine-inhibiting, and antioxidant properties (45).  This compound has also been shown to slow the process of aging by reducing telomerase activity (46).

Resveratrol has also been shown to increase the protein and mRNA expression of Nrf2. There is evidence that Nrf2-mediated attenuation of oxidative stress and cytokine induction could be partially responsible for resveratrol’s potential effect on cell-life regulation (47). This compound has profound effects on regulating estrogen metabolism and inducing cancer cell apoptosis (48)

In rat and animal studies, resveratrol/pterostilbene have been shown to upregulate a significant number of genes involved in mitochondrial function as well as to modulate cholinergic neurotransmission and improve cognition (49)

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Green Tea:

Green tea is rich in the polyphenol anti-oxidant catechin called epigallocatechin-3-gallate (EGCG).  This anti-oxidant is thought by most to be responsible for the health benefits linked to green tea consumption.  EGCG has been identified to have a profound effect on the Nrf2-ARE pathway (50)

Research has shown that EGCG stimulates the Nrf2 anti-oxidant activity in immune cells, liver and intestinal cells (51, 52).  Through this mechanism it also modulates cancer cell proliferation, differentiation, apoptosis, adhesion, angiogenesis and metasisis (53, 54).

A study published in December 2004 in Cancer Research discussed how ECGC in green tea was able to decrease insulin-like growth factor-1 (IGF-1) while increasing levels of IGF binding protein-3, which binds IGF-1.  This reduces the risk of breast, colon, prostate & lung cancer.  It also inhibits key cancer survival proteins and reduces the expression of compounds associated with cancer metastasis (55).

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My Favorite NrF2 Enhancing Supplement:

As a clinician, I believe this supplement is the best way to boost antioxidant defenses by increasing the activity of the Nrf2 pathway and positively affecting the development of antioxidant genes.

I use this supplement with all of my chronic disease patients and those that have chronic inflammation.   It is also something I personally take to prevent inflammation and improve my overall performance.

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