The Role of Nrf2 Activation

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.

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)
• Kidney Disease (ie Acute Kidney Injury, Chronic Kidney Disease, Lupus Nephritis)
• Liver Disease (ie Alcoholic Liver Disease, Acute Hepatitis, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Cirrhosis)
• Lung Disease (ie Asthma, Fibrosis)
• Metabolic And Vascular Disease (ie Atherosclerosis, Hypertension, Stroke, Diabetes)
• Neurodegeneration (ie Alzheimer’s, Parkinson’s, Huntington’s and ALS)
• Pain (ie Neuropathy)
• Skin Disorders (ie Psoriasis, UVB/Sun Protection)
• Toxin Exposure (Arsenic, Asbestos, Cadmium, Fluoride, Glyphosate, Mercury, Sepsis, Smoke)
• Vision (ie Bright Light, Sensitivity, Cataracts, Corneal Dystrophy)

Hyperactivation of Nrf2 can worsen:

• Atherosclerosis
• 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)
• Blue light
• Brain Games (increases NRF2 in the hippocampus)
• Caloric Restriction
• Cold (showers, plunges, ice bath, gear, cryotheraphy)
• EMFs (low frequency, such as PEMF)
• 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)
• Pau d’arco (Lapacho)
• Phloretin
• Piceatannol
• PQQ
• Procyanidin
• Pterostilbene
• Pueraria
• Quercetin (high doses only, lower doses inhibit NRF2)
• Qiang Huo
• Red Clover
• 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.
• 00:23:40 – Mid-video recap: cancer, aging sections
• 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
• 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
• 00:26:30 – Beginning of brain and behavior section.
• 00:27:18 – Effect of broccoli sprout extract on autism.
• 00:27:48 – Effect of glucoraphanin on schizophrenia.
• 00:28:17 – Start of depression discussion (plausible mechanism and studies).
• 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
• 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
• 00:33:01 – Beginning of neurodegeneration section.
• 00:33:30 – Sulforaphane and Alzheimer’s disease.
• 00:33:44 – Sulforaphane and Parkinson’s disease.
• 00:33:51 – Sulforaphane and Hungtington’s disease.
• 00:34:13 – Sulforaphane increases heat shock proteins.
• 00:34:43 – Beginning of traumatic brain injury section.
• 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
• 00:35:55 – Sulforaphane and neuronal plasticity.
• 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.

EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor?

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