NSAIDs are COX1 and COX2 Inhibitors, while Antioxidants are COX2 Inhibitors

The mechanism involved in why NSAID medications like ibuprofen have been found to not help with treatment of COVID19 and may worsen the patient’s health instead has not been stated, however it likely involves COX1 and/or COX 2 inhibition.

NSAID medications (like ibuprofen and aspirin) or phytonutrients that act like NSAID medications (like wintergreen berries which contain methyl salicylate, chemically similar to aspirin, (3)) can be a cause of edema due to the COX 1 and COX2 inhibition effects of the drug. (1) The COVID19 virus is known to cause lung edema even in the early stages of the infection process before the symptoms are obvious. (2)

*Addition, an CDC/MedCram Update: Coronavirus Pandemic Update 40: Ibuprofen and COVID-19 (are NSAIDs safe?), trials of HIV medications, (7), includes the mechanism and controversy. Ibuprofen’s inhibition of COX2 would lead to a reduction in antibody production which wouldn’t help fight an infection, but it might also inhibit viral replication – net result, not sure whether to recommend using or not using it. Too large a dose might increase risk however. Aspirin has more activity than COX2 inhibition so it might be more of a risk for causing lung edema, especially if taken in large quantity. In the flu pandemic of 1918 a large increase in death rate occurred shortly after aspirin, a new medication at the time, was being recommended and in doses that are far larger than would be typically used now. (7)

(I was eating wintergreen berries in quantity,* 1/8-1/4 cup when I had problems with leg edema. They are botanically related to cranberries and are similar in tanginess and texture but taste like wintergreen/mint when raw. The wintergreen flavor isn’t retained after being cooked. *Don’t try this at home. ūüėČ

Antioxidants can also be COX2 inhibitors (4) which can also be a cause of edema. Larger doses of a NSAID medication or phytonutrient would be more likely to cause fluid and sodium retention by the kidneys and lead to swelling due to edematous fluid build up in extracellular areas of the body. Non-selective NSAIDs inhibit both COX1 and COX2 and selective NSAIDs were developed that only inhibit the COX2 enzyme. (5)

We do need extra antioxidants during stress and infectious processes because the body is using them in greater quantities. We would also likely not be able to make as many of our own internally because our bodies would be dedicating more effort to making inflammatory cytokines to fight the infection. Too many inflammatory cytokines can become a problem though and providing extra antioxidants in the diet can help protect the body during conditions of infection such as a severe influenza. (6)

Dose makes the cure, dose makes the poison.

/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./

Reference List

  1. J. Depew, Pomegranate extract update ‚Äď has similar mechanism to NSAIDs, Aug 3, 2018, transcendingsqure.com, https://transcendingsquare.com/2018/08/03/pomegranate-extract-update-has-similar-mechanism-to-nsaids/
  2. The ASCO Post Staff, Pulmonary Pathology of Early COVID-19 Pneumonia Identified Retrospectively in Two Patients With Lung Cancer, ascopost.com, March 5, 2020 https://ascopost.com/news/march-2020/pulmonary-pathology-of-early-covid-19-pneumonia-identified-retrospectively-in-two-patients-with-lung-cancer/
  3. SpinSolve, Traditional Undergraduate Experiment: Synthesis of Aspirin. magritek.com, http://www.magritek.com/wp-content/uploads/2015/03/Lab-Manual-Synthesis-of-Aspirin-web.pdf
  4. Laube M, Kniess T, Pietzsch J. Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy-A Hypothesis-Driven Review. Antioxidants (Basel). 2016;5(2):14. Published 2016 Apr 19. doi:10.3390/antiox5020014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931535/
  5. Raymond C. Harris and Matthew D. Breyer, Update on Cyclooxygenase-2 Inhibitors. CJASN March 2006, 1 (2) 236-245; DOI: https://doi.org/10.2215/CJN.00890805 https://cjasn.asnjournals.org/content/1/2/236
  6. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy.¬†Cell Mol Immunol. 2016;13(1):3‚Äď10. doi:10.1038/cmi.2015.74 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/
  7. Roger Seheult, MD, Coronavirus Pandemic Update 40: Ibuprofen and COVID-19 (are NSAIDs safe?), trials of HIV medications. CDC/MedCram.com https://youtu.be/dT6mHi_8V5E

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-őļB) 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-őļB 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 flowers. https://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/