Many current research studies on cancer have allowed health professionals to understand the way the body detoxes. By analyzing upregulated genes in tumorous cells, researchers discovered the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2. NRF2 is an important transcription factor which activates the human body’s protective antioxidant mechanisms in order to regulate oxidation from both external and internal factors to prevent increased levels of oxidative stress.
Table of Contents
Principles of Nrf2
NRF2 is essential towards maintaining overall health and wellness because it serves the primary purpose of regulating how we manage everything we’re exposed to on a daily basis and not become sick. NRF2 activation plays a role in the phase II detoxification system. Phase II detoxification takes lipophilic, or fat soluble, free radicals and converts them into hydrophilic, or water soluble, substances for excretion while inactivating exceptionally reactive metabolites and chemicals as a consequence of phase I.
NRF2 activation reduces overall oxidation and inflammation of the human body through a hormetic effect. To trigger NRF2, an inflammatory reaction due to oxidation must occur in order for the cells to produce an adaptive response and create antioxidants, such as glutathione. To break down the principle of Nrf2, essentially, oxidative stress activates NRF2 which then activates an antioxidant response in the human body. NRF2 functions to balance redox signaling, or the equilibrium of oxidant and antioxidant levels in the cell.
A great illustration of how this process functions can be demonstrated with exercise. Through every workout, the muscle adapts so that it can accommodate another workout session. If NRF2 becomes under- or over-expressed due to chronic infections or increased exposure to toxins, which may be observed in patients who have chronic inflammatory response syndrome, or CIRS, the health issues may worsen following NRF2 activation. Above all, if DJ-1 becomes over-oxidized, NRF2 activation will end too quickly.
Effects of NRF2 Activation
NRF2 activation is highly expressed in the lungs, liver, and kidneys. Nuclear erythroid 2-related factor 2, or NRF2, most commonly functions by counteracting increased levels of oxidation in the human body which can lead to oxidative stress. Nrf2 activation can help treat a variety of health issues, however, over-activation of Nrf2 may worsen various problems, which are demonstrated below.
Periodic activation of Nrf2 can help:
Aging (ie Longevity)
Autoimmunity and Overall Inflammation (ie Arthritis, Autism)
Cancer and Chemoprotection (ie EMF Exposure)
Depression and Anxiety (ie PTSD)
Drug Exposure (Alcohol, NSAIDs )
Exercise and Endurance Performance
Gut Disease (ie SIBO, Dysbiosis, Ulcerative Colitis)
Cancer (ie Brain, Breast, Head, Neck Pancreatic, Prostate, Liver, Thyroid)
Chronic Inflammatory Response Syndrome (CIRS)
Heart Transplant (while open NRF2 may be bad, NRF2 can help with repair)
Hepatitis C
Nephritis (severe cases)
Vitiligo
Furthermore, NRF2 can help make specific nutritional supplements, drugs, and medications work. Many natural supplements can also help trigger NRF2. Through current research studies, researchers have demonstrated that a large number of compounds which were once believed to be antioxidants were really pro-oxidants. That’s because nearly all of them need NRF2 to function, even supplements like curcumin and fish oil. Cocoa, for example, was shown to generate antioxidant effects in mice which possess the NRF2 gene.
Ways To Activate NRF2
In the case of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, stroke or even autoimmune diseases, it’s probably best to have Nrf2 upregulated, but in a hormetic fashion. Mixing NRF2 activators may also have an additive or synergistic effect, as occasionally it can be dose-dependent. The top ways to increase Nrf2 expression are listed below:
HIST (Exercise) + CoQ10 + Sun (these synergize very well)
Broccoli Sprouts + LLLT on my head and gut
Butyrate + Super Coffee + Morning Sun
Acupuncture (this is an alternative method, laser acupuncture may also be used)
Fasting
Cannabidiol (CBD)
Lion’s Mane + Melatonin
Alpha-lipoic acid + DIM
Wormwood
PPAR-gamma Activation
The following comprehensive listing containing over 350 other ways to activate Nrf2 through diet, lifestyle and devices, probiotics, supplements, herbs and oils, hormones and neurotransmitters, drugs/medications and chemicals, pathways/transcription factors, as well as other ways, is only a brief guide as to what can trigger Nrf2. For the sake of brevity in this article, we have left out over 500 other foods, nutritional supplements and compounds which can help activate Nrf2. The following are listed below:
Diet:
Acai Berries
Alcohol (Red wine is better, especially if there is a cork in it, as protocatechuic aldehyde from corks can also activate NRF2. In general, alcohol is not recommended, although acute intake increases NRF2. Chronic intake may decrease NRF2.
Algae (kelp)
Apples
Black Tea
Brazil Nuts
Broccoli Sprouts (and other isothiocyanates, sulforaphane as well as cruciferous vegetables like bok choy that have D3T)
Blueberries (0.6-10 g/day)
Carrots (falcarinone)
Cayenne Pepper (Capsaicin)
Celery (Butylphthalide)
Chaga (Betulin)
Chamomile Tea
Chia
Chinese Potato
Chokeberries (Aronia)
Chocolate (Dark or Cocoa)
Cinnamon
Coffee (such as chlorogenic acid, Cafestol and Kahweol)
Cordyceps
Fish (and Shellfish)
Flaxseed
Garlic
Ghee (possibly)
Ginger (and Cardamonin)
Gojiberries
Grapefruit (Naringenin – 50 mg/kg/d naringenin)
Grapes
Green Tea
Guava
Heart Of Palm
Hijiki/Wakame
Honeycomb
Kiwi
Legumes
Lion’s Mane
Mahuwa
Mangos (Mangiferin)
Mangosteen
Milk (goat, cow – via regulation of microbiome)
Mulberries
Olive Oil (pomace – hydroxytyrosol and Oleanolic Acid)
Omega 6 Fatty Acids (Lipoxin A4)
Osange Oranges (Morin)
Oyster Mushrooms
Papaya
Peanuts
Pigeon Peas
Pomegranate (Punicalagin, Ellagic Acid)
Propolis (Pinocembrin)
Purple Sweet Potatoes
Rambutan (Geraniin)
Onions
Reishi
Rhodiola Rosea (Salidroside)
Rice Bran (cycloartenyl ferulate)
Riceberry
Rooibos Tea
Rosemary
Sage
Safflower
Sesame Oil
Soy (and isoflavones, Daidzein, Genistein)
Squash
Strawberries
Tartary Buckwheat
Thyme
Tomatoes
Tonka Beans
Turmeric
Wasabi
Watermelon
Lifestyle and Devices:
Acupuncture and Electroacupuncture (via collagen cascade on ECM)
Exercise (Acute exercise like HIST or HIIT seems to be more beneficial for inducing NRF2, while longer exercise doesn’t induce NRF2, but does increase glutathione levels)
High Fat Diet (diet)
High Heat (Sauna)
Hydrogen Inhalation and Hydrogen Water
Hyperbaric Oxygen Therapy
Infrared Therapy (such as Joovv)
Intravenous Vitamin C
Ketogenic Diet
Ozone
Smoking (not recommended – acutely smoking increase NRF2, chronically smoking decreases NRF2. If you choose to smoke, Holy Basil may help protect against downregulation of NRF2)
Sun (UVB and Infrared)
Probiotics:
Bacillus subtilis (fmbJ)
Clostridium butyricum (MIYAIRI 588)
Lactobacillus brevis
Lactobacillus casei (SC4 and 114001)
Lactobacillus collinoides
Lactobacillus gasseri (OLL2809, L13-Ia, and SBT2055)
Lactobacillus helveticus (NS8)
Lactobacillus paracasei (NTU 101)
Lactobacillus plantarum (C88, CAI6, FC225, SC4)
Lactobacillus rhamnosus (GG)
Supplements, Herbs, and Oils:
Acetyl-L-Carnitine (ALCAR) and Carnitine
Allicin
Alpha-lipoic acid
Amentoflavone
Andrographis paniculata
Agmatine
Apigenin
Arginine
Artichoke (Cyanropicrin)
Ashwaganda
Astragalus
Bacopa
Beefsteak (Isogemaketone)
Berberine
Beta-caryophyllene
Bidens Pilosa
Black Cumin Seed Oil (Thymoquinone)
Boswellia
Butein
Butyrate
Cannabidiol (CBD)
Carotenioids (like Beta-carotene [synergy with Lycopene – 2 × 15 mg/d lycopene], Fucoxanthin, Zeaxanthin, Astaxanthin, and Lutein)
Chitrak
Chlorella
Chlorophyll
Chrysanthemum zawadskii
Cinnamomea
Common Sundew
Copper
Coptis
CoQ10
Curcumin
Damiana
Dan Shen/Red Sage (Miltirone)
DIM
Dioscin
Dong Ling Cao
Dong Quai (female ginseng)
Ecklonia Cava
EGCG
Elecampane / Inula
Eucommia Bark
Ferulic Acid
Fisetin
Fish Oil (DHA/EPA – 3 × 1 g/d fish oil containing 1098 mg EPA and 549 mg DHA)
Galangal
Gastrodin (Tian Ma)
Gentiana
Geranium
Ginkgo Biloba (Ginkgolide B)
Glasswort
Gotu Kola
Grape Seed Extract
Hairy Agrimony
Haritaki (Triphala)
Hawthorn
Helichrysum
Henna (Juglone)
Hibiscus
Higenamine
Holy Basil/Tulsi (Ursolic Acid)
Hops
Horny Goat Weed (Icariin/Icariside)
Indigo Naturalis
Iron (not recommended unless essential)
I3C
Job’s Tears
Moringa Oleifera (such as Kaempferol)
Inchinkoto (combo of Zhi Zi and Wormwood)
Kudzu Root
Licorice Root
Lindera Root
Luteolin (high doses for activation, lower doses inhibit NRF2 in cancer though)
Magnolia
Manjistha
Maximowiczianum (Acerogenin A)
Mexican Arnica
Milk Thistle
MitoQ
Mu Xiang
Mucuna Pruriens
Nicotinamide and NAD+
Panax Ginseng
Passionflower (such as Chrysin, but chyrisin may also reduce NRF2 via dysregulation of PI3K/Akt signaling)
Resveratrol (Piceid and other phytoestrogens essentially, Knotweed)
Rose Hips
Rosewood
Rutin
Sappanwood
Sarsaparilla
Saururus chinensis
SC-E1 (Gypsum, Jasmine, Licorice, Kudzu, and Balloon Flower)
Schisandra
Self Heal (prunella)
Skullcap (Baicalin and Wogonin)
Sheep Sorrel
Si Wu Tang
Sideritis
Spikenard (Aralia)
Spirulina
St. John’s Wort
Sulforaphane
Sutherlandia
Tao Hong Si Wu
Taurine
Thunder God Vine (Triptolide)
Tocopherols (such as Vitamin E or Linalool)
Tribulus R
Tu Si Zi
TUDCA
Vitamin A (although other retinoids inhibit NRF2)
Vitamin C (high dose only, low dose does inhibit NRF2)
Vitex/Chaste Tree
White Peony (Paeoniflorin from Paeonia lactiflora)
Wormwood (Hispidulin and Artemisinin)
Xiao Yao Wan (Free and Easy Wanderer)
Yerba Santa (Eriodictyol)
Yuan Zhi (Tenuigenin)
Zi Cao (will reduce NRF2 in cancer)
Zinc
Ziziphus Jujube
Hormones and Neurotransmitters:
Adiponectin
Adropin
Estrogen (but may decrease NRF2 in breast tissue)
Melatonin
Progesterone
Quinolinic Acid (in protective response to prevent excitotoxicity)
Serotonin
Thyroid Hormones like T3 (can increase NRF2 in healthy cells, but decrease it in cancer)
Vitamin D
Drugs/Medications and Chemicals:
Acetaminophen
Acetazolamide
Amlodipine
Auranofin
Bardoxolone methyl (BARD)
Benznidazole
BHA
CDDO-imidazolide
Ceftriaxone (and beta-lactam antibiotics)
Cialis
Dexamethasone
Diprivan (Propofol)
Eriodictyol
Exendin-4
Ezetimibe
Fluoride
Fumarate
HNE (oxidized)
Idazoxan
Inorganic arsenic and sodium arsenite
JQ1 (may inhibit NRF2 as well, unknown)
Letairis
Melphalan
Methazolamide
Methylene Blue
Nifedipine
NSAIDs
Oltipraz
PPIs (such as Omeprazole and Lansoprazole)
Protandim – great results in vivo, but weak/non-existent at activating NRF2 in humans
Probucol
Rapamycin
Reserpine
Ruthenium
Sitaxentan
Statins (such as Lipitor and Simvastatin)
Tamoxifen
Tang Luo Ning
tBHQ
Tecfidera (Dimethyl fumarate)
THC (not as strong as CBD)
Theophylline
Umbelliferone
Ursodeoxycholic Acid (UDCA)
Verapamil
Viagra
4-Acetoxyphenol
Pathways/Transcription Factors:
?7 nAChR activation
AMPK
Bilirubin
CDK20
CKIP-1
CYP2E1
EAATs
Gankyrin
Gremlin
GJA1
H-ferritin ferroxidase
HDAC inhibitors (such as valproic acid and TSA, but can cause NRF2 instability)
Heat Shock Proteins
IL-17
IL-22
Klotho
let-7 (knocks down mBach1 RNA)
MAPK
Michael acceptors (most)
miR-141
miR-153
miR-155 (knocks down mBach1 RNA as well)
miR-7 (in brain, helps with cancer and schizophrenia)
Notch1
Oxidatives stress (such as ROS, RNS, H2O2) and Electrophiles
PGC-1?
PKC-delta
PPAR-gamma (synergistic effects)
Sigma-1 receptor inhibition
SIRT1 (increases NRF2 in the brain and lungs but may decrease it overall)
SIRT2
SIRT6 (in the liver and brain)
SRXN1
TrxR1 inhibition (attenuation or depletion as well)
Zinc protoporphyrin
4-HHE
Other:
Ankaflavin
Asbestos
Avicins
Bacillus amyloliquefaciens (used in agriculture)
Carbon Monoxide
Daphnetin
Glutathione Depletion (depletion of 80%–90% possibly)
Gymnaster koraiensis
Hepatitis C
Herpes (HSV)
Indian ash tree
Indigowoad Root
Isosalipurposide
Isorhamentin
Monascin
Omaveloxolone (strong, aka RTA-408)
PDTC
Selenium Deficiency (selenium deficiency can increase NRF2)
Siberian Larch
Sophoraflavanone G
Tadehagi triquetrum
Toona sinensis (7-DGD)
Trumpet Flower
63171 and 63179 (strong)
The nuclear erythroid 2-related factor 2 signaling pathway, best known by the acronym Nrf2, is a transcription factor which plays the major role of regulating the protective antioxidant mechanisms of the human body, particularly in order to control oxidative stress. While increased levels of oxidative stress can activate Nrf2, its effects are tremendously enhanced through the presence of specific compounds. Certain foods and supplements help activate Nrf2 in the human body, including the isothiocyanate sulforaphane from broccoli sprouts.
Dr. Alex Jimenez D.C., C.C.S.T. Insight
Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More
Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.
Key sections:
00:01:14 – Cancer and mortality
00:19:04 – Aging
00:26:30 – Brain and behavior
00:38:06 – Final recap
00:40:27 – Dose
Full timeline:
00:00:34 – Introduction of sulforaphane, a major focus of the video.
00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
00:02:12 – Prostate cancer risk.
00:02:23 – Bladder cancer risk.
00:02:34 – Lung cancer in smokers risk.
00:02:48 – Breast cancer risk.
00:03:13 – Hypothetical: what if you already have cancer? (interventional)
00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
00:04:38 – Sulforaphane and cancer.
00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
00:08:32 – Inhibition of breast cancer stem cells.
00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
00:19:04 – Beginning of aging section.
00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
00:20:34 – Importance of low inflammation for longevity.
00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
00:37:19 – Sulforaphane and duchenne muscular dystrophy.
00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
00:41:01 – Anecdotes on sprouting at home.
00:43:14 – On cooking temperatures and sulforaphane activity.
00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
00:44:56 – Cooking techniques and cruciferous vegetables.
00:46:06 – Isothiocyanates as goitrogens.
According to many current research studies, the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2, is a fundamental transcription factor which activates the cells’ protective antioxidant mechanisms to detoxify the human body from both external and internal factors and prevent increased levels of oxidative stress. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .
Curated by Dr. Alex Jimenez
Additional Topic Discussion: Acute Back Pain
Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.
The information herein on "The Role of Nrf2 Activation" is not intended to replace a one-on-one relationship with a qualified health care professional or licensed physician and is not medical advice. We encourage you to make healthcare decisions based on your research and partnership with a qualified healthcare professional.
Our information scopeis limited to Chiropractic, musculoskeletal, acupuncture, physical medicines, wellness, contributing etiological viscerosomatic disturbances within clinical presentations, associated somatovisceral reflex clinical dynamics, subluxation complexes, sensitive health issues, and/or functional medicine articles, topics, and discussions.
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