Nrf2 & NF-kB - 2 proteins to know.

Nrf2 stands for the gene & the anti-inflammatory protein it transcribes. NF-kB is an inflammatory protein. Both take part in complex chemical pathways and are linked by our day/night circadian cycle.

The title is misleading in the scope of this article - Can two proteins and eight letters really be the answer? No, not really, but they are a big part. We are going to also visit with the proteins or chemicals: Histamine, methyl folate, Retinoic acid, Retinol dehydrogenase, NAD+, niacin, p300, TNF-alpha, N-Acetyltransferase and Acetyl CoA, insulin, T3 thyroid hormone, iodine, bromide, fluoride, “Calcium Pyruvate, Pantethine Powder, [B5], Dimagnesium Malate, Acetyl L-carnitine Hcl, L-Cysteine HCI, [similar to NAC].” (9), EPA and DHA omega 3 fatty acids, and vitamin D and many others too.

Nutrients - We need them all! (post)

Summary, copied from later:

NF-kB promotes cytokines which activate Mast Cells which release histamine which causes symptoms and inflammatory damage in excess. Retinoic Acid also activates Mast Cells. NF-kB can promote some viral infections that may promote excessive activation of vitamin A and carotenoids to Retinoic Acid that may be a need during an infection but seems to continue for life in some Chronic Fatigue sufferers and theoretically some vaccine injured. Feasibly a similar mechanism of action may be occurring with SARS-CoV-2.

Summary 2, copied from farther down later:

We want to promote p300/Nrf2; and N-acetyltransferase/acetyl CoA which needs mitochondrial support nutrients including niacin, and adequate insulin and T3 thyroid hormone; and have adequate but not excessive vitamin A or histamine.

Nrf2 - anti-inflammatory gene & protein linked to our circadian cycle.

Nrf2 is a gene, and the protein it produces. It is involved in promoting our own production of glutathione, DNA repair, and immune function. Some phytonutrients may promote the gene transcription or modulate it and others may affect the protein. 

Nrf2, whether the gene transcription or the protein’s activity, is promoted by many phytonutrients in common foods, and as a dietary health bonus - Nrf2 promoters are also NF-kB inhibitors possibly because of a shared circadian cycle protein. The two complex pathways are linked metabolically - chemically. (1)

NF-kB - inflammatory protein linked to Nrf2 and our circadian cycle.

The inflammatory NF-kB (and others) pathway is more active in the daytime and the growth and repair Nrf2 (and others) pathway is part of our night-time clean up. 

The bad news then - anything inflammatory about modern life that affects our circadian cycle (and a good night’s sleep) - is also promoting NF-kB, like CoV spike and other toxins, and causing inflammatory (Covid-19 like) symptoms. This can include fear and worry, isolation, anger, or overwork, loud noise, EMF, or an infection or immune challenge from an injection. For more detail see selfhack.com, (11), or (Gupta, et al, 2010). (6)

SARS-CoV-2 promotes NF-kB, which inhibits Nrf2.

CoV reduces Nrf2 by promoting NF-kB.  The two are linked by a shared need for a specific protein that is in limited supply - so we can’t have one chemical pathway active and the other one active at the same time - they share one machine in common.

Nrf2 is promoted by many phytonutrients and foods, and Nrf2 promoters are also NF-kB inhibitors, possibly because of the shared circadian cycle protein. Like a shared assembly line, the inflammatory pathway is more active in the daytime and the growth and repair Nrf2 pathway is part of our night-time clean up. The crews work in shifts, day shift - action oriented but also inflammatory; night shift - maintenance during the down time for the busy factory.

NF-kB promotes many inflammatory cytokines that are elevated in Covid-19, including IL-1a, IL-6, IL-10, IL-17, and TNF-alpha, and latent viral infections may also be promoted including HIV-1 and EBV (Epstein-Barr Virus). (Figure 2, 6) Inflammatory cytokines can cause immune cells to differentiate into forms that might help fight an infection but in excess may cause autoimmune damage or lead to fibrotic scarring. Excessive Mast Cell activity (MCAS) can be caused by inflammatory cytokines or Retinoic Acid - the active form of vitamin A or beta-carotene.

Histamine and MCAS - Mast Cell Activation Syndrome

Mast cells release even more cytokines and histamine. They are allergy immune cells and too much activity causes seasonal allergy type symptoms, but even more excess histamine can affect thinking and mood. Histamine normally is a modulator in our brain, keeping our roller coaster rolling along with some ups and downs. Excess can cause hyperexcitability which escalates whatever the person is thinking - all up, or all down. Mania or suicidal urges, or extreme anxiety may occur.

Diagnosing histamine issues based on lab tests is not very accurate and sufferers more typically are diagnosed with schizophrenia, bipolar disorder, or eventually Alzheimer’s dementia. (17) The histamine excess tends to damage the hippocampus (NMDA receptors are involved (18)) and the mania/anxiety can resemble schizophrenia.

Methyl Folate: Adequate methyl folate is a simple solution that may help as it is needed to break down histamine. Simple if you don’t have a methylation gene defect or are severely ill and not functioning at peak metabolic fitness.

See MCAS/Histamine on jenniferdepew.com and Histamine Food Lists (document).

LongCovid seems to frequently involve histamine excess which might also have a similar issue with a post viral infection change in activation of vitamin A to the active Retinoic Acid.

Retinoid Toxicity - too much activation of Vitamin A to Retinoic Acid.

Latent EBV may be a factor for people with Chronic Fatigue Syndrome and a history of EBV, or Retinoid Toxicity from an ongoing excessive activation of vitamin A and carotenoids to retinoic acid.  See post series: Retinoid Toxicity. Avoiding all rich sources or supplements of vitamin A or carotenoids is the solution. Easy to say, hard to do.

Many things in life are easy to say and hard to do. Like staying on topic - what do Nrf2 and NF-kB have to do with histamine or Retinoid Acid?

Summary:

NF-kB promotes cytokines which activate Mast Cells which release histamine which causes symptoms and inflammatory damage in excess. Retinoic Acid also activates Mast Cells. NF-kB can promote some viral infections that may promote excessive activation of vitamin A and carotenoids to Retinoic Acid that may be a need during an infection but seems to continue for life in some Chronic Fatigue sufferers and theoretically some vaccine injured. Feasibly a similar mechanism of action may be occurring with SARS-CoV-2.

Viral Infection leading to permanent gene change in Retinol dehydrogenase.

The viral infection leading to increased retinoic acid is odd because normally it is beneficial for immune function, which is particularly seen in the severity of measles risk. It may help EBV to infect epithelial cells by causing their differentiation, maturing into a slightly different form.

“Abstract: Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation.” (13)

How could they affect Retinoic acid availability? How do we make it?

“The conversion of retinol into its active form, retinoic acid, requires retinol dehydrogenase enzymes.” (13)

The virus increases our transcription of the gene for retinol dehydrogenase enzymes - so we make more of the enzyme that converts vitamin A or carotenoids into the active Retinoic acid form.

“Here we show that AGS gastric carcinoma cells containing the lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA [Retinoic Acid].” (13)

Retinoic Acid, and vitamin A, are helpful in smaller amounts and harmful in larger amounts. Carotenoids are considered benign as generally they are not converted to the more active Retinoic Acid form unless there is a need.

NAD+ and Niacin

Retinol dehydrogenase involves NAD+: “NAD+-dependent retinoid-active short-chain dehydrogenase/reductase” (14) is a synonym name for a retinol dehydrogenase. The conversion of inactive vitamin A to the active form requires NAD+. (15) Adequate niacin, B3, either nicotinic acid (niacin flush type) or niacinamide (non-flush) can help provide NAD+ as a later stage product of niacin metabolism. (16)

And flavonoids enter our story, by helping prevent breakdown of NAD+:

“An alternative approach to raising NAD+ is to inhibit its degradation either by inhibiting PARPs or NADases, also known as glycohydrolases. The major NADase in mammals, CD38, is inhibited in vitro at low micromolar concentrations by flavonoids including luteolinidin, kuromanin, luteolin, quercetin, and apigenin (IC50 < 10 mM) .” (16)

p300, Retinoic Acid and TNF-alpha in arthritis

Both Retinoic Acid excess and TNF-alpha, which is increased by NF-kB, can lead to arthritic damage. Excess vitamin A can make it worse, but so can a deficiency in vitamin A. (2)

“Regulation of retinoid signalling is critical for the development and maintenance of cartilage.“ (2)

Promoting the protein p300, acetyltransferase, (4), may help is in the conclusion. (2) What is known about p300? It affects Nrf2. (3)

“Highlights

• p300 has a novel function in stabilizing NRF2 and increases NRF2 protein abundance.

• p300 acetyltransferase activity is necessary for NRF2 stabilization.

• p300 promotes NRF2 nuclear accumulation.

• p300 increases oxidative stress resistance and cell viability.” (3)

…so basically promoting Nrf2 is the solution being recommended by Rockel et al, 2008, in addition to avoiding excess vitamin A or Retinoic Acid. (2) That solution may help more inflammatory conditions than arthritis.

N-Acetyltransferase

“The human NATs [N-acetyltransferases, a group] catalyze the transfer of an acetyl group from acetylcoenzyme A to arylamines, arylhydroxylamines, and arylhydrazines (Blum et al., 1990).” (4, 5)

…so having adequate acetylcoenzyme A is also likely to be helpful for chronic inflammatory issues. It is a cofactor used in the mitochondrial Citric Acid Cycle.

Acetyl CoA

Acetyl-CoA is ancient, early life on earth, chemistry, that turns CO2 into other slightly larger chemicals - "formate, acetate, and pyruvate from H2 and CO2 " reducing it from a more electrically active form. (7) CoA is needed in the Citric Acid Cycle within mitochondria. Promotion of acetyl Co-A production helped age associated cognition (in mice) by helping mitochondrial homeostasis (8) - balance instead of excessive inflammation.

“…two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147” … “preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement.” (8)

A product designed to promote CoA in humans includes other mitochondrial support nutrients: “Calcium Pyruvate, Pantethine Powder, [B5], Dimagnesium Malate, Acetyl L-carnitine Hcl, L-Cysteine HCI, [similar to NAC].” (9, *unaffiliated - note the product does not contain CoA.) Insulin, T3 thyroid hormone, and the presence of glucose promote production of Acetyl CoA and the presence of EPA/DHA modulate the production. (10)

Iodine - Nutrients - we need them all, and in balance.

Well, to have adequate T3 thyroid hormone, that functions, we need adequate iodine and not excessive bromide and fluoride. Our mitochondria need T3 for regulation, (19) and T2. (20) Thyroid health is associated with energy level because the hormones do a variety of regulatory functions that affect mitochondria and directly affect mitochondrial gene transcription. T3 regulates the expression of Nrf1 and Nrf2, (20), so hypothyroidism would be increasing risk for inflammation and lack of glutathione and DNA repair - functions of Nrf2.

“T3 positively regulates the expression of intermediate factors, such as nuclear respiratory factors (NRF)-1 and -2, which enhance the expression of mitochondrial transcription factor-A, a nuclear-encoded transcription factor essential for replication, maintenance, and transcription of mitochondrial DNA. T3 also controls the expression of coactivator of peroxisome proliferator activated receptor γ (PPARγ) PGC-1α (Weitzel et al., 2001), a central regulator of mitochondrial gene expression and biogenesis (Puigserver, 2005). PGC-1α regulates gene expression through its interactions with DNA-bound transcription factors, including TR, PPAR, and NRF-1 (Knutti and Kralli, 2001, Figure 1).” (20)

Being healthy isn’t easy, as modern life includes too much bromide and fluoride and not enough iodine to balance the negative halides. See page G9. Iodine and Thyroid (effectivecare.info) and page G10. Nrf2 promoting foods has menu and beverage ideas for including more Nrf2 promotine/NfKb inhibiting phytonutrients in your diet.

Nrf2 and NF-kB/TNF-alpha - did we forget them? Not really - EPA/DHA, omega 3 poly unsaturated fatty acids are Nrf2 promoters and NF-kB inhibitors.

Summary 2:

We want to promote p300/Nrf2; and N-acetyltransferase/acetyl CoA which needs mitochondrial support nutrients including niacin, and adequate insulin and T3 thyroid hormone; and have adequate but not excessive vitamin A or histamine.

“Your mission, should you choose to accept it.” - Solomon Lane, Mission Impossible.

…could be very delicious!

Nrf2 Promoting Foods & Phytonutrients

For menu ideas see G10. Nrf2 Promoting Foods, effectivecare.info.

Basic dosing and safety limits for most Nutrients and many important Cofactors on jenniferdepew.com.

I got some odd reactions to my site slogan “Short term goal: contain COVID, long term: Sustainable Planet," as if - How dare she - she can’t do that! I can try. I was surprised because I think bigger picture and figured that was a collective goal - aren’t we all trying to end Covid and help the planet?

I have mostly contained symptomatic Covid in myself and some family members and have a guide in the works for sharing what I’ve learned in my reading of medical research and trying things, and from others who are actively trying to help contain Covid in various ways. Protocol Collation & Therapy Goals.

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. 

Reference List

1. Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans. 2015;43(4):621-626. doi:10.1042/BST20150014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613495/

2. Rockel, J.S., Kudirka, J.C., Guzi, A.J. et al. Regulation of Sox9 activity by crosstalk with nuclear factor-κB and retinoic acid receptors. Arthritis Res Ther 10, R3 (2008). https://doi.org/10.1186/ar2349 https://arthritis-research.biomedcentral.com/articles/10.1186/ar2349

3. Ganner A, Pfeiffer Z-C, Laura Wingendorf L, et al., The acetyltransferase p300 regulates NRF2 stability and localization, Biochemical and Biophysical Research Communications, Volume 524, Issue 4, 2020, Pages 895-902,

   ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2020.02.006.

   https://www.sciencedirect.com/science/article/pii/S0006291X20302667

4. Acetyltransferase, ScienceDirect.com https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/acetyltransferase

5. Pharmacogenomics and Personalized Medicine,

   Richard A. McPherson MD, MSc, in Henry's Clinical Diagnosis and Management by Laboratory Methods, 2022; *Paywall, excerpt viewable in 3, https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323673204000754

6. Gupta SC, Sundaram C, Reuter S, Aggarwal BB. Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10-12):775–787. doi:10.1016/j.bbagrm.2010.05.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955987/ Figure 2: https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html.jpg

7. William F Martin, Older Than Genes: The Acetyl CoA Pathway and Origins | Microbiology, frontiersin.org, https://www.frontiersin.org/articles/10.3389/fmicb.2020.00817/full#B81

8. Currais A, Ling Huang L, Joshua Goldberg J, et al., (2019) Elevating acetyl-CoA levels reduces aspects of brain aging, eLife 8:e47866. https://elifesciences.org/articles/47866

9. Coenzyme-A Technologies Pure CoenzymeA™ Total Body Health Enhancer Dietary Supplement. qfc.com, https://www.qfc.com/p/coenzyme-a-technologies-pure-coenzymea-total-body-health-enhancer-dietary-supplement/0069796306015

10. Kim YJ, Lee MS, Lee HJ, Wu Y, Freake HC, Chun HS, Kim Y. Hormones and nutrients regulate acetyl-CoA carboxylase promoter I in rat primary hepatocytes. J Nutr Sci Vitaminol (Tokyo). 2005 Apr;51(2):124-8. doi: 10.3177/jnsv.51.124. PMID: 16022200. https://pubmed.ncbi.nlm.nih.gov/16022200/

11. Joe Cohen, All About NF-kB: Function, Inhibitors & Activators, March 4, 2020, selfhack.com, https://selfhack.com/blog/nuclear-factor-kappa-b/ *131 references - there is an abundance of medical research on this topic.

12. J Depew, Small Molecules Inhibiting NF-kB, expansion of (Gupta, et al, 2010) (6), https://docs.google.com/document/d/11UinDp4Vryl5kInU5U0iUxi7PoyJsQNuGOk3rQ-PHC0/edit?usp=sharing

13. Jones RJ, Dickerson S, Bhende PM, Delecluse HJ, Kenney SC. Epstein-Barr virus lytic infection induces retinoic acid-responsive genes through induction of a retinol-metabolizing enzyme, DHRS9. J Biol Chem. 2007 Mar 16;282(11):8317-24. doi: 10.1074/jbc.M608667200. Epub 2007 Jan 22. PMID: 17244623. https://www.jbc.org/content/282/11/8317.long

14. 1.1.1.105: all-trans-retinol dehydrogenase (NAD+). Synonym/Name: “NAD+-dependent retinoid-active short-chain dehydrogenase/reductase”, brenda-enzymes.org, https://www.brenda-enzymes.org/all_enzymes.php?ecno=1.1.1.105&table=Natural_Substrates_Products

15. Retinol-dehydrogenase, ScienceDirect.com, https://www.sciencedirect.com/topics/medicine-and-dentistry/retinol-dehydrogenase

16. Rajman L, Chwalek K, Sinclair DA, Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism 27, March 6, 2018, https://doi.org/10.1016/j.cmet.2018.02.011 https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30122-0.pdf

17. Sedeyn JC, Wu H, Hobbs RD, Levin EC, Nagele RG, Venkataraman V. Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures. Biomed Res Int. 2015;2015:937148. doi: 10.1155/2015/937148. Epub 2015 Nov 30. PMID: 26697497; PMCID: PMC4677161. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677161/

18. Stojić-Vukanić Zorica, Hadžibegović Senka, Nicole Olivier, Nacka-Aleksić Mirjana, Leštarević Sanja, Leposavić Gordana. CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease? Frontiers in Immunology

    Vol 11, 2020, DOI=10.3389/fimmu.2020.566225 https://www.frontiersin.org/articles/10.3389/fimmu.2020.566225/full

19. Wrutniak-Cabello C, Casas F, Cabello G. Thyroid hormone action in mitochondria. J Mol Endocrinol. 2001 Feb;26(1):67-77. doi: 10.1677/jme.0.0260067. PMID: 11174855. https://pubmed.ncbi.nlm.nih.gov/11174855/

20. Lombardi1A, Moreno M, de Lange P, et al., Regulation of skeletal muscle mitochondrial activity by thyroid hormones: focus on the “old” triiodothyronine and the “emerging” 3,5-diiodothyronine, Front. Physiol., 21 August 2015, Sec. Striated Muscle Physiology, https://doi.org/10.3389/fphys.2015.00237 https://www.frontiersin.org/articles/10.3389/fphys.2015.00237/full