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

Foods and phytonutrients that may benefit T cells

T cells are a group of white blood cells with immune functions that may be beneficial or which may promote inflammation. They can change from one type of T-cell to another based on the amount of oxidative stress chemicals present in their surroundings. Our own body can produce antioxidants that reduce oxidative stress when we have adequate Nrf2. We also can get antioxidants from foods and often the foods that are good sources of antioxidants also contain phytonutrients that promote our own production of Nrf2 which then can help us produce our own types of antioxidants. Other nutrients are also helpful for promoting T cells to become the less inflammatory producing types. (1)

Reduced antioxidant production and prevalence of the more inflammatory type of T cells may be involved in aging and many types of chronic illnesses including cardiovascular diseases, neurological disorders, carcinoma’s and leukemia’s, autoimmune disorders, inflammatory bowel disease and vitiligo. For more details see: (1) Figure 13)

See Table 3: Antioxidant Compounds of Natural Dietary Products with Role in T Cell Function. (1)

  • Green tea: Catechin hydrate (CH) and Epigallocatechin 3-gallate (EGCG). Teas (white, green, and oolong), cocoa, grapes, berries, apples; Catechins are monomers of Flavan-3-ols; see more:(Flavonoids)
  • Carrot, celeriac, parsnip, and parsley: Aliphatic C(17)-polyacetylenes. The Apiaceae plant family, see more: (Aliphatic C(17)-polyacetylenes) Commonly used herbs spices in the plant family include caraway seeds, coriander seeds/cilantro leaves, cumin seeds, dill, fennel; see more: (Apiaceae plants)
  • Turmeric (yellow spice in curry powder): Curcumin (diferuloylmethan). See more: (Curcumin)
  • Garlic: Ajoene. Organosulfur compound, others also present in onions, see more: (Ajoene/organosulfur compounds).
  • Plant foods/beverages with yellow pigments: Chalcones (precursors for flavones). Chalcones are found in many plant foods including; “fruits (e.g., citruses, apples), vegetables (e.g., tomatoes, shallots, bean sprouts, potatoes) and various plants and spices (e.g., licorice),” see more: (Chalcones). Flavones, (found in Parsley, thyme, celery, hot peppers), are part of the Flavonoid group; see more: (Flavonoids). 
  • Anthocyanin (purple/blue pigments): Wild blueberry, bilberry, cranberry. Red, blue, or purple berries; red and purple grapes; red wine, Anthocyanidins combined with sugar molecules are anthocyanins; see more: (Flavonoids).
  • Proanthocyanidin: Grape Seed and Jamapa Bean. Apples, berries, cocoa, red grapes, red wine; Proanthocyanidins are dimers and polymers of Flavan-3-ols; see more: (Flavonoids).
  • Resveratrol: Peanuts; Grape skins, red wine; dark colored berries including blueberries, bilberries, and cranberries; dark cocoa; see more: (Resveratrol.
  • Lycopene: Tomatoes; guava, watermelon, papaya, pink grapefruit, mango; red sweet peppers, asparagus, purple cabbage, carrots: (Lycopene).
  • Carrots and other orange/yellow fruits and vegetables: Beta-carotene (orange/yellow pigment, precursor to Vitamin A). Sweet potato, squash, carrots, apricots, cantaloupe, mango; broccoli, greens; red sweet peppers; tomato juice; black-eyed peas, beans; see more: (Vitamin A – provitamin A, beta-carotene, is found in plant sources)
  • Vitamin A: Carrots, cheese, eggs, and meat. Liver; fish oils; fortified milk; see more: (Vitamin A-preformed, retinol, is from animal sources primarily).
  • Vitamin B6: Whole grains, vegetables; liver, meats and fish; nuts; chickpeas/garbanzo beans and other beans, tofu; cottage cheese; banana; see more: (vitamin B6).
  • Vitamin C: Citrus fruits, cantaloupe, kiwifruit, strawberries, cauliflower, the cabbage family, tomatoes, peppers, and greens, green peas, potatoes – see more: (vitamin C).
  • Vitamin D: Cod liver oil, egg yolk. Fortified dairy products or orange juice, or other fortified foods such as breakfast cereals or meal replacement bars; salmon, tuna, sardines, krill oil; liver; some types of mushrooms; – see more: (vitamin D).
  • Vitamin E: Wheat germ oil, sunflower oil. Nuts, greens, asparagus, pumpkin, mango, avocado – see more: (vitamin E).
  • (1)

Disclaimer: Opinions are my own and the 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. Kesarwani P, Murali AK, Al-Khami AA, Mehrotra S. Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease. Antioxidants & Redox Signaling. 2013;18(12):1497-1534. doi:10.1089/ars.2011.4073. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603502/ (1)
  2. Flavonoids, Linus Pauling Institute, Oregon State University, https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/flavonoids
  3. Christensen LP, Aliphatic C(17)-polyacetylenes of the falcarinol type as potential health promoting compounds in food plants of the Apiaceae family. Recent Pat Food Nutr Agric. 2011 Jan;3(1):64-77. https://www.ncbi.nlm.nih.gov/pubmed/21114468
  4. Apiaceae: Parsley or Carrot Family. Identify herbs, plants, and flowershttps://www.wildflowers-and-weeds.com/Plant_Families/Apiaceae.htm
  5. Curcumin, Linus Pauling Institute, Oregon State University,  https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/curcumin
  6. Garlic and Organosulfur Compounds, Linus Pauling Institute, Oregon State University, https://lpi.oregonstate.edu/mic/food-beverages/garlic
  7. Orlikova B, Tasdemir D, Golais F, Dicato M, Diederich M. Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes & Nutrition. 2011;6(2):125-147. doi:10.1007/s12263-011-0210-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092904/
  8. Resveratrol, Linus Pauling Institute, Oregon State University,  https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/resveratrol
  9. Top 10 Foods Highest in Lycopene, myfooddata.com,  https://www.myfooddata.com/articles/high-lycopene-foods.php
  10. Vitamin A: Health Professional Fact Sheet, National Institutes of Health, https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/
  11. Vitamin B6: Health Professional Fact Sheet, National Institutes of Health, https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/
  12. Vitamin C: Health Professional Fact Sheet, National Institutes of Health, https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/
  13. Vitamin D: Health Professional Fact Sheet, National Institutes of Health, https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  14. Vitamin E and Health, Harvard T. H. Chan School of Public Health, https://www.hsph.harvard.edu/nutritionsource/what-should-you-eat/vitamins/vitamin-e/

Pumpkin seeds – rich in zinc

Pumpkin seed kernels, raw, unsalted.

Pumpkin seed kernels are a good source of protein, essential fats, fiber, magnesium and other vitamins and minerals – and a great source of zinc which may be lacking in vegetarian or vegan diets. (Pumpkin Seeds – Benefits, nutrition and dietary tips.) (Other vegetarian sources of zinc.)

Work is progressing on the development of pumpkin seed flour for use as a food thickening substance for use in gravies or other sauces or stews. It would increase the protein, essential fatty acids, and other trace nutrient content of the resulting foods. (10) The use of pumpkin seeds in the diet may also prove to be protective against cancer and liver or kidney injury; and as a good source of antioxidants such as carotenoids (vitamin A family of nutrients) the use of pumpkin seeds in the diet may prove to be helpful against many conditions that involve excess oxidative stress. (4, 5, 6, 7, 8, 9) They are also a source of vitamin E (tocopherols), other phytosterols, and linoleic acid, a beneficial polyunsaturated fat. Pumpkin seed oil may be helpful in wound healing. (15) Pumpkin seeds are also a good source of phospholipids, (16), which are important for skin and membrane health.

Pumpkins are considered a drought tolerant plant for gardeners. Adequate water is needed to grow larger pumpkin and squash but the vines can survive limited water conditions. The seeds of other summer and winter squash are also nutrient rich and also may be more drought tolerant plants. (11, 12) Enough but not too much water at the right times are critical. Flooding or severe drought may both harm the garden yield. Mulching and drip irrigation or other watering methods applied at optimal stages of growth can be the water thrifty solution for best yield. (13, 14)

The seeds of butternut squash and some types of winter squash can be collected when trimming the squash and later toasted and eaten as a crunchy nutritious snack. India grocery markets may also have shelled squash seeds available for sale. They are slightly smaller and paler in color than the shelled pumpkin kernels in the image above.

Magnesium is one of the beneficial nutrients found in pumpkin seeds. It is a mineral that is needed in greater quantity during pregnancy and high blood pressure/hypertension can be a symptom of deficiency. Preeclampsia and the more severe eclampsia are complications characterized by high blood pressure and edema/swelling that can occur during pregnancy. Toxins collect in the excess fluid buildup and can risk a brain condition similar to hypertension encephalopathy in the more severe eclampsia. Seizure activity can result and death for the woman and expected infant are risks. Magnesium is used as an intravenous or intramuscular injection to reduce risk of the seizures during eclampsia. The mineral seems to help protect the blood brain barrier and reduce swelling in the brain during eclampsia. It’s role as an antioxidant to reduce free radical toxins may be involved but the exact mechanism for its benefit in eclampsia is not known. (2, page 139)

More information about preclampsia is available in a previous post, and more information about food sources and supplement sources of magnesium is also available in a previous post.

I have several writing projects in draft mode however they overlap – pumpkin seeds, a good source of magnesium and zinc, helped my previous prenatal clients who had a history of preeclampsia or high blood pressure in a previous pregnancy prevent a reocurrence of the problem. Why? Possibly because of the magnesium and other beneficial nutrients which could be protecting the blood brain barrier and might then also be helpful for preventing harm to oligodendrocytes and protect against demyelination – a risk that can occur with some types of encephalopathy (3).

Disclaimer: Opinions are my own and the 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827242/Megan Ware, What are the health benefits of pumpkin seeds?, July 24, 2018, https://www.medicalnewstoday.com/articles/303864.php
  2. Mehmet Kaya, Bulent Ahishali, Chapter 9: The role of magnesium in edema and blood brain barrier disruption, page 139, in the book edited by Robert Vink, Mihai Nechifor, Magnesium in the Central Nervous System, University of Adelaide Press, 2011, adelaide.edu.au, free ebook pdf, https://www.adelaide.edu.au/press/titles/magnesium/magnesium-ebook.pdf  (2
  3. S. Love, Demyelinating Diseases, J Clin Pathol. 2006 Nov; 59(11): 1151–1159.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860500/ (3)
  4. Scientific Studies collection on a commercial website by Pepo Farms, https://pepofarms.com.au/scientificstudies/ (4) which includes:
  5. M. Gossell-Williams, A. Davis, N. O’Connor, Inhibition of Testosterone-Induced Hyperplasia of the Prostate of Sprague-Dawley Rats by Pumpkin Seed Oil. Jun 2006, Vol. 9, No. 2 : 284 -286. 
  6. C. Z. Nkosi, A. R. Opoku, S. E. Terblanche, Antioxidative effects of pumpkin seed (Cucurbita pepo) protein isolate in CCl4-Induced liver injury in low-protein fed rats.
  7. Fahim AT Abd-el Fattah AA Agha AM Gad MZ
    Effect of pumpkin-seed oil on the level of free radical scavengers induced during adjuvant-arthritis in rats.
    In: Pharmacol Res (1995 Jan) 31(1):73-9 ISSN: 1043-6618
  8. Suphakarn VS Yarnnon C Ngunboonsri P, The effect of pumpkin seeds on oxalcrystalluria and urinary compositions of children in hyperendemic area. In: Am J Clin Nutr (1987 Jan) 45(1):115-21 ISSN: 0002-9165
  9. Matus Z Molnar P Szabo LG [Main carotenoids in pressed seeds (Cucurbitae semen) of oil pumpkin (Cucurbita pepo convar. pepo var. styriaca)] Olajtok (Cucurbita pepo convar. pepo var. styriaca) magjabol nyert presmaradek ossz-karotinoid-tartalmanak es karotinoid-osszetetelenek meghatarozasa. In: Acta Pharm Hung (1993 Sep) 63(5):247-56 ISSN: 0001-6659 (Published in Hungarian)  * The main carotenoids included per the Pepo Farms site: “The main components of the press-residue were lutein [3,3′-dihydroxy-alpha-carotene = (3R,3’R,6’R)-beta,epsilon-carotene-3,3′-diol; 52.5%] and beta- carotene (beta,epsilon-carotene; 10.1%). In addition to the above- mentioned pigments it was successful to reveal the presence of violaxanthin, luteoxanthin, auroxanthin epimers, lutein epoxide, flavoxanthin, chrysanthemaxanthin, 9(9′)-cis-lutein, 13(13′)-cis- lutein, 15-cis-lutein (central-cis)-lutein, alpha-cryptoxanthin, beta- cryptoxanthin and alpha-carotene (beta,epsilon-carotene) in small quantities.”  (4)
  10. Initial food technology research on the preparation and use of pumpkin seed flour for use in more nutritious gravy type sauces: Sharma G, Lakhawat S., Development, Quality Evaluation and Acceptability of Pumpkin Seed Flour Incorporated in Gravy. J Nutr Food Sci 7:613. doi: 10.4172/2155-9600.1000613      https://www.omicsonline.org/open-access/development-quality-evaluation-and-acceptability-of-pumpkin-seed-flourincorporated-in-gravy-2155-9600-1000613.php?aid=91345
  11. EllenB, Growing Drought Tolerant Vegetables, June 9, 2009, ThriftyFun.com, https://www.thriftyfun.com/Growing-Drought-Tolerant-Vegetables.html (11)
  12. Troy Scott, Drought Tolerant Vegetables for your Garden, July 9 2018, HeavenlyGreens.com http://www.heavenlygreens.com/blog/drought-tolerant-vegetables-for-your-garden (12)
  13. Joan Morris, Vegetable Gardening in a Drought, mercurynews.com, April 1, 2015,  https://www.mercurynews.com/2015/04/01/vegetable-gardening-in-a-drought/ (13)
  14. Extension Utah State University, Vegetable Irrigation: Squash and Pumpkin, Horticulture/Vegetables/2015-4,   https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=1744&context=extension_curall (14)
  15. Bardaa S, Ben Halima N, Aloui F, et al. Oil from pumpkin (Cucurbita pepo L.) seeds: evaluation of its functional properties on wound healing in rats. Lipids in Health and Disease. 2016;15:73. doi:10.1186/s12944-016-0237-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827242/ (15)
  16. Zh.Y. Petkova, G.A. Antova, Changes in the composition of pumpkin seeds (Cucurbita moschata) during development and maturation. Grassas Y Aceites, 66 (1), Jan–March 2015, e058. http://grasasyaceites.revistas.csic.es/index.php/grasasyaceites/article/viewFile/1523/1658 (16)