Nrf2 and Nf-Kb pathways – one restorative, one inflammatory

Many phytonutrients and other chemicals have been found to promote the production of the Nrf2 gene and its encoded Nrf2 protein, both of which have varying impacts on other genes causing an increase in immune strength and in our own production of antioxidants. Other research has focused on nutrients and chemicals that inhibit or promote the inflammatory Nf-Kb pathway – a chemical cascade of reactions starting outside the cell and ending in the cell with an increase in the cell’s production of inflammatory cytokines and Tumor Necrosis Factor (TNF).

The foods and chemicals often interact with both pathways but in opposite directions, promoting one and inhibiting the other. The reason is unlikely to be a coincidence, the night/day rhythms of circadian biology also tend to promote one and inhibit the other. The Nrf2 growth/repair/detoxification system is more active during sleep/dark and the NF-kB action/inflammation pathway is more active during the wake/light hours. See 1.4, 1.41, 1.42 in this draft book to read more: Preventative Health for Multifactorial Disorders.

Nrf2 Promoting Foods & Phytonutrients:

See G10: Nrf2 Promoting Foods, effectivecare.info for the reference in the graphic (Sun 2017) and more food ideas and information.

Nrf2 Promoting Foods and Phytonutrients

Neurotransmitters also vary in activity level due to the circadian cycle and can affect whether the Nrf2 or the NF-kB pathway is more active.

The neurotransmitters and neuromodulators mentioned in the last post are part of the circadian biology rhythms. Acetylcholine, attention and memory neurotransmitter, (Pepuo 2004), is more active during the day and GABA the calming neurotransmitter is more active at night. It is inhibitory, reducing activity of other neurotransmitters such as norepinephrine and serotonin that are active during wakefulness helps the body move into sleep. Low levels of GABA are associated with insomnia and disrupted sleep (Siegel 2004), and with anxiety, chronic stress, depression, difficulty concentrating and memory problems, muscle pain and headaches, and substance use disorders. (3 AmazingBenefits of GABA/PsychologyToday)

GABA which is known to have antioxidant and anti-inflammatory benefits may achieve it in part due to increasing the Nrf2 pathways growth, repair, and detoxification activity and by inhibiting the NF-kB and Caspase 3 pathways. (Zhu 2019) Resveratrol was found to help protect endothelial cells in animal models of Type 2 Diabetes and aging. It reduces oxidative stress by increasing the Nrf2 pathways, “improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring Caspase 3 activity and DNA fragmentation). (Ungvari 2010)

Lycopene is a phytonutrient that can help reduce inflammation by promoting the Nrf2 and inhibiting the NF-kB pathways.

The antioxidant lycopene was used in a study for use as a food additive in animal feed to help reduce oxidative stress caused by heat stress. The research team were concerned about the negative effects of heat stress on the Nrf2 and Nf-Kb pathways, causing decreased activity of the Nrf2 and increased activity of the Nf-Kb pathway. A brief description of the roles in the body is in the abstract: “The transcription entity nuclear factor-kappa light chain enhancer of B cells (NF-κB) controls the expression of genes involved in a number of physiological responses, including immune inflammatory responses, acute-phase inflammatory responses, oxidative stress responses, cell adhesion, differentiation, and apoptosis. The nuclear factor-2 erythroid related factor-2 (Nrf2), the redox-sensitive transcription factor, plays a key role in regulating induction of phase II detoxifying or antioxidant enzymes.  “ (1)

Several carotenoids in addition to lycopene also reduce inflammatory pathways and increase beneficial ones.

Lycopene is a carotenoid, one of a group of red and yellow colored antioxidants found in carrots, cantaloupe and other fruits and vegetables that tend to be orange or red in color, The best known carotenoid is beta-carotene, a form of vitamin A that is made with two of the vitamin A retinol molecules. Other carotenoids, including beta-carotene, lutein, alpha-cryptoxanthin, and zeaxanthin, also can inhibit the NF-kB pathway and increase the Nrf2 pathways, reducing inflammatory cytokine production and increasing beneficial antioxidant production. Other phytonutrients that also increase the Nrf2 and inhibit the NF-kB pathways include:

Other phytonutrients that inhibit inflammatory and promote anti-inflammatory pathways:

  • sulforaphanes and I-3-C, from broccoli sprouts, broccoli, kale, mustard greens, turnips and other cruciferous vegetables,
  • andrographolides (and other diterpenoids – found in Gingko biloba, sage, rosemary, (sciencedirect/diterpenoids)), andrographolides are found in the medicinal plant Andrographis paniculata, (Okhuaroba 2014),
  • quercetin found in “leafy vegetables, broccoli, red onions, peppers, apples, grapes, black tea, green tea, red wine, and some fruit juices“, (integrativepro.com) ,
  • curcumin from turmeric,
  • silymarin, an extract from milk thistle, a medicinal herb,
  • genistein from soy,
  • chlorophyll, the green pigment in plants, and
  • resveratrol, found in “grapes, wine, grape juice, peanuts, cocoa, and berries of Vaccinium species, including blueberries, bilberries, and cranberries.” (lpi.oregonstate.edu)
  • (See 1.42, Preventative Health for Multifactorial Diseases)

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

That list is a start, there are other beneficial phytonutrients that decrease inflammatory pathways and increase anti-inflammatory pathways, including: ginger/zerumbone/gingerol, green tea/EGCG/gallic acid, garlic/aged garlic extract, hot pepper/capsaicin, fish oil/omega 3 fatty acids, black pepper/piperine, Hops/xanthohumol, Plumbago auriculata/plumbagin, a medicinal herb used for lead poisoning. (de Paiva 2005) (Sun 2017) (Gupta 2010)

Protecting health over the long term and every day can be as simple as adding more variety of herbs and spices to your meals, along with more colorful fruits and vegetables and whole grains, nuts, beans, and seeds.

Colorful and flavorful foods can help keep the body more in the restorative Nrf2 pathways and reduce the inflammatory NF-kB pathway. The same nutrients or chemical groups effect both because the pathways are coordinated by the light/dark wake/sleep circadian cycle and share a need for the same type of protein – as if both need the same tool – they both can’t use it exactly at the same time. (CREB protein, see section 6: Li, 2008)

Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual health guidance. Please see a health care professional for individualized healthcare guidance.

References

  1. Sahin K, Modulation of NF-κB and Nrf2 pathways by lycopene supplementation in heat-stressed poultry, World’s Poultry Sci J Vol 71, Issue 2, June 2015 , pp. 271-284 https://www.cambridge.org/core/journals/world-s-poultry-science-journal/article/modulation-of-nfb-and-nrf2-pathways-by-lycopene-supplementation-in-heatstressed-poultry/4E2AFAAFDF88B0B438BE3A19A1FB0A9B

Fennel Seed Diet

New/extra short term goal- regain health, reduce inflammation and lose weight by adding fennel seeds back to my daily diet. I ran out of them earlier this summer and since then hurt my knee and gained weight with the decreased activity, (Rest, Ice, Compression, Elevate (RICE) can help sprained ankles and strained ligaments but 6-8 weeks is expected for recovery).

Fennel seeds are used as an after meal dessert or breath freshener in India and elsewhere. They also are a digestive aid and may help preserve bone density/prevent osteoporosis from reading I did on the topic last winter when I first added them to my daily diet. It turns out they also are thought to help weight loss based on search results-(fennel seed weight loss). I love the internet. More specific information includes potential help with anxiety & depression and also mentions the possible help as digestive aid and weight loss as an appetite suppressant : “21 Health Benefits of Fennel, and Risks & Side Effects,”  selfhacked.com. Excessive amounts daily are not recommended however the crunch and taste are lasting and a pinch, ~ 1/2 teaspoon, is a little like chewing minty gum for little while.

So my simple plan – try to eat my healthy meal choices and have a teaspoon of fennel seeds after meals and whenever I feel like snacking in between meals – and just see if that helps curb the desire for more snacking. /Day one, already feeling some positive effects./

Fennel seed are an alkalizing food – meaning after digestion the body system is more alkaline than acidic which promotes health more and may help reduce cancer risk: Alkalizing foods refers to the alkalinity after digestion.

From my wintertime notes: 

A gift from nature to help us build Nrf2 (10) and which may improve digestion  (11) and bone density (12) are the licorice flavored Fennel Seeds that might be served in a tiny dish as an appetizer or after a meal at an Indian food restaurant. The tiny crunchy seeds can be eaten directly raw or may be toasted.  A few pinches, a teaspoon or two are a reasonable digestive health aid and even seem to freshen the breath somewhat as there is also a slight minty flavor to the more predominant licorice flavor. They are sold in larger quantities, (400 gram package), in India food markets but may be found in a one ounce jar in the spice section as they are also added to soups in Western recipes.

One interaction caution is for women using estrogen based birth control pills. Fennel also contains estrogen like phytonutrients which may interfere with the use of the birth control pills as a pregnancy preventative. (11) Regarding quantity for health benefits – a study on bone density effects in post menopausal women did not find 300 mg per day effective (12) – that would be less than an 1/8th of a teaspoon. I have seen a portion described as “a handful” in an unlinked source, which is about 1/4 – 1/2 cup, and which would be a lot compared to what I eat in a day but an 1/8th teaspoon wouldn’t be much at all. I eat a pinch or two, 1/4 to 1/2 teaspoon at a time several times per day. So a tablespoon (three teaspoons) to an 1/8th cup (two tablespoons or 6 teaspoons) might be consumed throughout the day when snacking from an open dish as seen in the image below. They do seem to help settle my stomach after a meal.

Not as conducive to weight loss, but delicious – putting ground fennel powder in cookies – they were incredible: Fennel Cookies-lightly licorice.

Fennel seeds, raw.

Looking to any food to resolve weight gain issues may be too simple if the problem is actually too much exposure to EMF, electromagnetic frequencies, in your environment from laptops, smartphones and other WiFi devices, and/or problems with poor sleep or oxygen intake; discussion by a neuroscientist who got curious about his own health: Tensegrity 5: Your Magnetic Sense, Dr Jack Kruse, jackkruse.com.

/Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./

Brain cells and aging

Within the majority of the brain the type of brain cells that send nerve signals generally do not get replaced, however they also generally don’t lose function. Dementia – loss of memory and other cognitive skills – is not a normal part of healthy aging. Age related forgetfulness has to do with loss of the connections between brain cells but the brain cells remain functional – so continuing to take part in learning and social activities may help prevent dementia and forgetfulness by helping to maintain current connections between brain cells and add new connections formed during learning or socializing. 

And yet Alzheimer’s dementia now “afflicts 5% to 10% of the U.S. population over the age of 65 and as much as 45% of the population over 85.” (page 694, Neuroscience, 6th. edition, 1)

Research for medications for Alzheimer’s treatment have focused on reducing the levels of certain types of protein that collect in the damaged areas of the brain of a patient with the condition, however even if successful at reducing the amount of the protein the medications have not been found very helpful for restoring the patient’s cognitive health. (previous post) People with normal brain function also can have excess of the protein and it is also found in the brains of people with autism disorder – confusing, yes. Adequate quality sleep may help the brain waste removal system keep the levels of excess protein from building up to damaging amounts. (previous post on sleep and the glymphatic system)

Things that may increase risk include chronic stress and the excess cortisol and inflammatory oxidative stress chemicals production. Moderate exercise may help reduce stress and promote detoxification of inflammatory chemicals. Staying socially and mentally active also may be protective of brain function. Prevention is the best medicine for conditions that cause irreversible degenerative changes such as the damage in Alzheimer’s Disease. Learning about new foods and recipes and then making healthy meals to share with others can be a way to combine physical and mental activity and gain from nutrients that help detoxify inflammatory oxidative stress chemicals. (previous post, Foods for beneficial T-cells) – (Nrf2 promoting foods)

T cells are a type of blood cell with immune system functions. Beneficial T cells can help clear excess protein found in Alzheimer’s (2) while other types can increase inflammation and the types can transform based on the level of oxidative stress chemicals that are present so having antioxidants and other phytonutrients in daily meals can help signal the T-cells to take the beneficial forms instead of the inflammatory forms. (The non euphoria producing endogenous cannabinoid 2-AG (acts at the CB2 receptor, somewhat similar to CBD) may also help signal T cells towards the less inflammatory type, and reduce migration of them. page 96)

Nrf2 is a gene and protein that help promote the more beneficial types of T cells and help the immune system in other ways and also promote our own production of antioxidants for reducing the oxidative stress chemicals that are a natural waste product left from energy metabolism – when blood sugar is turned into a usable form of energy.

The long story is complicated, the short story remains,

  • include moderate exercise most days of the week,
  • have adequate sleep, 6-8 hours/night, ideally with complete darkness, blackout curtains and cover the light from an electric bedside alarm clock (put it in a nearby drawer or cover it with something),
  • get some natural sunshine or full spectrum light during the day if possible (may help with vitamin D, bioactive sulfate, and circadian rhythm metabolism within the body which includes production of melatonin,
  • stay mentally and socially active,
  • reduce stress when possible and/or practice relaxation techniques,
  • drink adequate water and regularly eat a good variety of colorful fresh produce, whole grains, nuts, beans, seeds, and include omega 3 fatty acid sources on a daily or weekly basis.
  • Clean air quality is also important. Formaldehyde (from secondhand smoke or even excessive use of decorative candles), and other air pollutants (released by plastics or new carpeting/flooring for example) can collect in poorly ventilated buildings. See this post for more information about formaldehyde sources and ways to reduce it: Formaldehyde: Health Risks, and Environmental and Dietary Sources.(effectiveselfcare.info)
  • Adequate water, not getting dehydrated regularly, is important enough to repeat because dehydration allows toxins within the body, including formaldehyde, to collect, instead of being removed by the glymphatic/lymphatic and vascular system, and to then be excreted by the kidneys. Brain Formaldehyde is Related to Water Intake Behavior, Ting Li, et al, 2016, (PubMed) A discussion of how much water is typically needed for health each day, and how much protein to eat for basic needs without being too much for long term kidney health, is available in a previous post: Make Every Day Kidney Appreciation Day. (effectiveselfcare.info)

More of the long story – the Cannabinoid Receptor Type 2 is also activated by a phytonutrient called beta-caryophyllene (BCP) which is found in many aromatic herbs and spices including: oregano, cinnamon,  clove , rosemary,  thyme, black pepper, (4), and copaiba oil. (5) Benefits may include reducing inflammation and pain, anti-anxiety, anti-cancer, (4), and protection of the brain by helping reduce increased activity after brain trauma which can lead to scar like tissue walling off the area of trauma instead healing.(5)

The problem in Alzheimer’s may not be the protein itself but instead the cells that over-actively making it in response to inflammatory signals so the solution would be not trying to remove excess protein but to stop the production of excess protein by signaling the overactive cells that all is well again, stop walling off the supposed injury. Formalin, a more dilute buffered form of formaldehyde was the toxin used to create inflammation in an animal based study of the potential benefits of beta-caryophyllene. A dose of 5 mg/Kg purified beta-caryophyllene essential oil given by mouth (rather than by an injection) was found to help reduce inflammatory pain from the formalin. (4) For a 75 kilogram adult that would be a capsule with 375 milligrams of the purified oil.

The herb rosemary is pine needle like plant that has been used as a pain killer in traditional folk medicine for arthritis pain and was thought of a s a memory aid. Studies more recently have found the essential oil beneficial for improving memory. (6)  **Use care when purchasing essential oils, some are intended only for external use either on the skin when diluted in a small amount of milder oil such as almond oil for massage or topical pain relief, or as an aromatic for scent (example, put a few drops on a cotton ball that is attached to a fan or on the outlet of a humidifier to circulate the aroma through a room).

/Disclosure: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./

  1.  Neuroscience, 6th Edition, Editors D. Purves, G.J. Augustine, D. Fitzpatrick, W.C. Hall, A.S. LaMantia, R.D. Mooney, ML. Platt, L.E. White, (Sinauer Associates, Oxford University Press, 2018, New York) (Barnes&Noble)
  2. Anna Mietelska-Porowska and Urszula Wojda, “T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers,” Journal of Immunology Research, vol. 2017, Article ID 4626540, 17 pages, 2017. https://doi.org/10.1155/2017/4626540. https://www.hindawi.com/journals/jir/2017/4626540/
  3. edited by Karsten Sauer, Klaus Okkenhaug, Lipid Signaling in T Cell Development and Function, Frontiers Media SA, Nov 12, 2015 page 96
  4. A.-L.Klauke, I.Racz, B.Pradier, et al., The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. European Neuropsychopharmacology, Vol. 24, Issue 4, April 2014, Pages 608-620, https://www.sciencedirect.com/science/article/pii/S0924977X13003027
  5. Guimarães-Santos A, Santos DS, Santos IR, et al. Copaiba Oil-Resin Treatment Is Neuroprotective and Reduces Neutrophil Recruitment and Microglia Activation after Motor Cortex Excitotoxic Injury. Evidence-based Complementary and Alternative Medicine : eCAM. 2012;2012:918174. doi:10.1155/2012/918174. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291111/
  6. Rachel Hosie, Surge in Rosemary Sales as Aromatic Herb Found to Boost Memory, May 19, 2017, independent.co.uk,  https://www.independent.co.uk/life-style/health-and-families/rosemary-sales-surge-herb-boost-memory-holland-barrett-a7745231.html