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

Sep 08, 2019

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.

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.

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

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