Natural NRF2 Activators

This is a list of key polyphenols that are known to activate the Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) pathway, enhancing the body’s antioxidant defenses and protecting against oxidative stress:

Resveratrol

• • Sources: Found in red wine, grapes, berries, and peanuts.
  • Mechanism: Resveratrol activates Nrf2, promoting the expression of antioxidant enzymes and anti-inflammatory proteins.

Resveratrol, a polyphenolic compound, is found in grape skins, berries, and other plants. It stands out in the field of natural health and wellness. This molecule can activate the Nrf2 signaling pathway, which is crucial for the body’s antioxidant and anti-inflammatory defenses.

Resveratrol targets the Nrf2 pathway, leading to numerous benefits. It’s known for its antioxidant properties but does much more. Studies show it can improve cardiovascular health by helping maintain healthy blood pressure and cholesterol levels. It also supports endothelial function.

Moreover, resveratrol has neuroprotective effects, making it a potential treatment for neurodegenerative diseases. Its impact on the Nrf2 pathway could also benefit mood disorders and oxidative stress conditions. It boosts antioxidant enzymes and reduces inflammation, which can improve symptoms and overall well-being.

As research deepens, resveratrol’s health benefits become more evident. It’s clear this natural compound is vital for natural health strategies. By activating Nrf2, resveratrol supports cardiovascular, neurological health, and overall wellness.

Evidence from clinical studies on resveratrol supplementation has shown significant improvement in cognitive functions in healthy older adults and improvement in the integrity of the blood–brain barrier through an enhancement in the antioxidant system by activating the Nrf2 signaling pathway. Many studies confirm that resveratrol could positively modulate autophagy by reducing oxidative stress (Armeli 2024)

 

Pterostilbene

• • Sources: Found in blueberries and grapes; chemically similar to resveratrol but has better bioavailability.
  • Mechanism: Pterostilbene activates Nrf2, enhancing antioxidant responses and protecting against cellular stress.

PTE stimulates the nuclear translocation of Nrf2 and inhibits inflammation and ROS production in the IL-1β-induced chondrocytes. The activation of Nrf2 pathway promotes the transcription of antioxidant genes and inhibits ROS production, as well as the inflammation. PTE could prevent the cartilage degeneration and activate Nrf2 in the OA cartilage. (Xue 2017)

 

Epigallocatechin Gallate (EGCG)

• • • Sources: Primarily found in green tea.
    • Mechanism: EGCG activates Nrf2 and promotes the expression of antioxidant genes, helping to mitigate oxidative damage.

EGCG has shown many redox and specific inhibitory activities, in cell lines and rodent models, which may be applicable for the prevention and treatment of COVID-19. The possible anti-COVID-19 activities of EGCG are outlined in Fig. 4 . EGCG may suppress SARS-CoV-2 infection via suppressing the expression of cell surface ACE2 and TMPRSS2 via activating Nrf2. EGCG may also inhibit SARS-CoV-2 M^pro — a protease essential for viral reproduction. (Zhang 2021)

 

Quercetin

• • • • Sources: Present in onions, apples, capers, and various berries.
      • Mechanism: Quercetin activates Nrf2, leading to the upregulation of antioxidant enzymes and protective proteins.

Quercetin, a flavonoid found in various fruits, vegetables, and herbs, is known for its potent antioxidant and anti-inflammatory effects. It activates the Nrf2 signaling pathway, a key system that helps protect the body against oxidative stress and inflammation.

Studies show quercetin’s benefits for immune function, cognitive health, and cardiovascular wellness. It modulates the Nrf2 cascade, reducing oxidative stress and inflammation. These factors are linked to many health issues, including mood disorders.

Quercetin’s main action is as a powerful antioxidant. It neutralizes harmful free radicals, protecting cells and supporting overall health. Its anti-inflammatory effects are also significant, aiding in managing conditions like autoimmune diseases and chronic illnesses.

Quercetin’s ability to activate Nrf2 is linked to its neuroprotective effects. It regulates genes involved in oxidative defense and detoxification. This could help maintain cognitive function and support brain health, making it a promising supplement for cognitive enhancement and neurological health.

Quercetin’s wide-ranging benefits, including Nrf2 pathway activation, make it a valuable supplement. It supports immune function, cognitive health, and overall well-being. As research continues, quercetin may become a natural choice for enhancing health and wellness.

Kaempferol

• • Sources: Found in kale, spinach, strawberries, and various tea.
  • Mechanism: Kaempferol can activate Nrf2 and exert antioxidant effects, promoting cellular defense mechanisms.

Fisetin

• • • Sources: Found in strawberries, apples, onions, and cucumbers.
    • Mechanism: Fisetin activates Nrf2, which can enhance the expression of genes involved in antioxidant defense.

Genistein

• • • • Sources: Found in soy products such as tofu..
      • Mechanism: Genistein activates Nrf2, promoting the expression of cytoprotective genes and antioxidant enzymes.

Apigenin

• • • • Sources: Found in parsley, celery, chamomile, and citrus fruits.
      • Mechanism: Apigenin activates Nrf2, contributing to protective effects against oxidative stress.

Bromelain

• • • • Sources: Derived from the pineapple plant.
      • Mechanism: While primarily known for its proteolytic activity, bromelain can also activate Nrf2 and enhance antioxidant defenses.
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These polyphenols are associated with the activation of the Nrf2 pathway, enhancing the body’s ability to counteract oxidative stress and maintain cellular health. Incorporating foods rich in these compounds into your diet may provide additional protection against oxidative damage and other stressors.

 

These compounds can enhance the body’s antioxidant defenses and contribute to cellular protection against oxidative stress and inflammation. Here are some notable non-polyphenol natural Nrf2 activators:

Sulforaphane

• Source: Found in cruciferous vegetables like broccoli, Brussels sprouts, kale, and cauliflower.
• Mechanism: Sulforaphane is a powerful Nrf2 activator known for its ability to induce protective enzymes in the body, enhancing the antioxidant response.

Studies show sulforaphane’s ability to boost cellular defense, reduce oxidative stress, and have anti-inflammatory effects.

Sulforaphane also offers resilience against stress and shows antidepressant-like effects in animal studies. This suggests it could be a natural option for mood disorders, possibly as an alternative or complement to traditional treatments.

Broccoli and broccoli sprouts are rich in sulforaphane, making them easy to add to daily meals. This allows people to tap into sulforaphane’s benefits, enhancing their body’s defense systems and potentially improving health.

Benzyl Isothiocyanate (BITC)

• Source: Found in Mustard, horseradish, and wasabi.
• Mechanism: BITC activates Nrf2, leading to increased expression of antioxidant genes and providing protection against oxidative damage.

Indole-3-Carbinol

• Source: Present in cruciferous vegetables, especially in broccoli and Brussels sprouts.
• Mechanism: Indole-3-carbinol can activate Nrf2 and has been shown to possess anticancer properties by enhancing cellular defense mechanisms.

Curcumin

• Source: Found in turmeric.
• Mechanism: Curcumin also has distinct mechanisms that act to activate Nrf2 and enhance cellular resilience against stressors.

Curcumin, a key compound in turmeric, has drawn considerable interest for its extensive health benefits. It’s a strong activator of the Nrf2 pathway, known for reducing oxidative stress and inflammation. This makes it a promising natural remedy for various health issues.

Research has shown curcumin’s antidepressant-like effects related to it impact on the Nrf2 signaling pathway and neuroinflammation reduction. It may ease depression symptoms by targeting oxidative stress and inflammation in the brain.

Curcumin’s diverse mechanisms of action enhance its versatility. Besides activating Nrf2, it’s a potent antioxidant and anti-inflammatory agent. This versatility positions it as a valuable natural remedy for conditions like cardiovascular diseases and neurodegenerative disorders.

Adding turmeric to your diet or considering supplements with a healthcare professional’s advice can support overall health naturally and holistically.

L-Theanine

• Source: Found in green tea.
• Mechanism: Although it is an amino acid and not a polyphenol, L-theanine has been shown to have neuroprotective effects and can modulate Nrf2 activity indirectly.

Alpha-Lipoic Acid

• Source: Found in small amounts in spinach, broccoli, and organ meats.
• Mechanism: This antioxidant can promote Nrf2 activation, helping to regenerate other antioxidants in the body and enhance overall antioxidant defense.

Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity…. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties. (Fayez 2018)

 

Omega-3 Fatty Acids

• Source: Found in fatty fish (e.g., salmon, mackerel), flaxseeds, and walnuts.
• Mechanism: These fatty acids can activate the Nrf2 pathway, contributing to anti-inflammatory and antioxidant effects.

Emerging evidence indicates that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their electrophilic derivatives may trigger a protective response via NRF2 activation, rescuing or maintaining cellular redox homeostasis. (Davinelli 2022)

 

Zinc

• Source: Found in seafood, meat, legumes, nuts, and dairy products.
• Mechanism: Adequate zinc levels are essential for Nrf2 activation, as zinc can stabilize Nrf2 and enhance its activity in response to oxidative stress.

by systemic investigation using human renal tubule HK11 cells, we have defined the essential role of Zn in maintaining Nrf2 normal expression and transcription function. The underlying mechanism for the essential role of Zn for Nrf2 is Akt/GSK-3β-mediated inhibition of Nrf2 nuclear exporter Fyn. (Li 2014)

 

Selenium

• Source: Found in Brazil nuts, seafood, and organ meats.
• Mechanism: Selenium can enhance the activity of several antioxidant enzymes and may promote Nrf2 activation.

researches have shown that the antioxidant system regulated by Se is closely related to the Nrf2 pathway. Nrf2 is an important regulator of redox homeostasis and the key transcription factor regulating antioxidant and detoxification enzyme genes, thereby protecting organs from oxidative damage (Wang 2023)

 

Coenzyme Q10 (CoQ10)

• Source: Found in meat, fish, nuts, and whole grains.
• Mechanism: CoQ10 is involved in energy production in mitochondria and can enhance antioxidant defenses by modulating the Nrf2 pathway.

Melatonin

Melatonin is a hormone from the pineal gland, is key to managing our sleep-wake cycles. It’s also a  powerful antioxidant and anti-inflammatory, thanks to its Nrf2 pathway activation.

It is shown that melatonin ameliorates LTP-induced depression-like behaviors in mice and suppress the production of mitochondrial and cytosolic ROS and NF-κB signaling through Sirt2/Nrf2 pathway (Zuo 2022)

 

See Here for more on melatonin and cell signaling

Summary

These natural Nrf2 activators work by enhancing the body’s ability to respond to oxidative stress and reduce inflammation. Incorporating a diet rich in these compounds could provide significant health benefits by promoting cellular defense mechanisms and supporting overall well-being.