Tag: chronic pain

Nrf2 is an acronym for a substance that helps activate genes that protect against oxidative stress and the resulting inflammation from excess oxidative chemicals. Nrf2 is a lot easier to remember then: nuclear factor erythroid-2-related factor 2 (Nrf2). 

The list of chronic illnesses and genetic conditions that it may help prevent or treat is also quite long. The protective benefits against electromagnetic field radiation that was discussed in the last post may be due to the genes activation and resulting increased protection against oxidative stress chemicals – and this mechanism may be the same pathway for its beneficial role in preventing or treating the long list chronic illnesses.

It has been studied by a number of different groups in the prevention or treatment of: 

• Cardiovascular diseases including atherosclerosis, ischemic cardiovascular disease, vascular
  endothelial dysfunction, and heart failure;
• Neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS, Huntington’s diseases;
• Cancer (prevention);
• Chronic kidney diseases;
• Metabolic diseases: Type 2 diabetes; metabolic syndrome; obesity;
• Several types of toxic liver disease; (not from the pdf article (1) – Nrf2 helps the liver to better utilize free fatty acids and triglycerides as an alternate energy source during times of starvation/malnutrition, which speculatively then, a deficiency of Nrf2 might be a factor in fatty liver disease (8))
• Chronic lung diseases including emphysema, asthma, and pulmonary fibrosis;
• Sepsis;  — (sepsis is a serious type of infection that spreads throughout the blood system.)
• Autoimmune diseases;
• Inflammatory bowel disease;
• HIV/AIDS;
• Multiple sclerosis;
• Epilepsy;
• See Table 1 for the list of studies regarding Nrf2 and the above conditions: (1).

Other diseases or conditions that may also be helped by adequate levels of Nrf2 have been less well studied but the same mechanism of reducing oxidative stress might also benefit in the prevention or treatment of:

• “hemoglobinopathies including sickle cell
  disease and β-thalassemia [35], malaria [36],
• spinal cord injury [37], traumatic brain injury [38,39],
• altitude sickness [40,41], the
  three classic psychiatric diseases, major depression,
  schizophrenia and bipolar disorder [42–45],
• gastric ulcers [46,47],
  glaucoma [48], age-related macular degeneration [49],
  cataract [50,51],
• pathophysiological responses to herpes
  activation [52] and
• benign prostatic hyperplasia [53,54].”
• “Nrf2 was reported to lower skin sensitization produced by sensitizing chemicals [57,58].” — (“skin sensitization..” – this likely refers to chronic itch type of conditions that are exacerbated by chemicals that activate TRP channels, which I discuss in more detail in a series of posts. TRP channels are also a big topic that could use more discussion time: (2, 3, 4, 5,))
• See page 3, for the quotes and see the citation list of the pdf for the [__] references: (1).

Those are some common and severe conditions – so why aren’t we all aware of Nrf2? I don’t know. Possibly because the suggested treatment by the research discoveries are simple dietary changes which are not high profit margin treatments. However the list of foods that may help happens to overlap with those that I’ve been finding helpful for my own autoimmune and undiagnosed digestive problems. (There is a website with guidance about products that may be falsely claiming to have peer-reviewed studies showing that they are effective as Nrf2 activating compounds 2300 articles are mentioned as having been published on the topic of Nrf2, so I have some reading to catch up on. See: (9).)

So skipping the medical jargon, I’ll share some recipes and menu ideas that incorporate some of these foods and phytonutrients (list from the last post, the phytonutrients were quoted from this pdf: (1)

Specific foods or phytochemicals mentioned to help increase Nrf2 include:

• sulforaphane from cruciferous vegetables, (such as broccoli and cauliflower);
• foods high in phenolic antioxidants, (This is a large group including bright yellow and red fruits and vegetables, and deep purple produce. The group includes the subgroup flavonoids which include anthocyanins, flavonols, and it also includes the less familiar subgroup chalcones which are found in the commonly used fruits apples, pears and strawberries. The group also includes aldehydes which are found in vanilla and cinnamon, phenolic acids which include salicyclic acid, and tannins which are found in tea, coffee and wine. Baking cocoa and cherries, beans and whole grains are also mentioned, the summary point would be eat more fruits and vegetables; see: (11))
• the long-chained omega-3 fats DHA and EPA, (salmon, tuna, sardines, krill oil, ground flax meal, walnuts, hemp seed kernels);
• carotenoids (especially lycopene), (such as carrots, winter squash, sweet potatoes, cantaloupe, apricots, and lycopene is in tomato, watermelon, pink grapefruit, guava); 
• sulfur compounds from allum vegetables, (such as onions, garlic, shallots, green onions); 
• isothiocyanates from the cabbage group and
• terpenoid-rich foods. (Terpenes are found in real lemon and lime oil, rosemary, oregano, basil and other aromatic green herbs).
• The Mediterranean and the traditional Okinawan Diets are also mentioned as being Nrf2 promoting diets. See: (wakeup-world.1)

Menu ideas, a start –

• Add more fruits and vegetables to any meal or snack.
• Add a dash of real lemon or lime juice to salads or soups. A large spoonful can help aid digestion as we reach middle age. The digestive system tends to produce less natural acidity and it is needed for better absorption of B vitamins. Or sprinkle fresh lemon or lime zest grated from the peel or add a teaspoon of Ground Dried Lemons / Citron Seche Moulu / Limon Seco Molido which may be available at an India foods market. A spoonful of apple cider vinegar or other food grade vinegar could also aid digestion but would not provide the terpenoids found in lemon or lime oil. High quality apple cider vinegar or wine vinegar may contain other beneficial phytonutrients from the phenolic group from the above list as apples and wine are sources of some types.
• Add a teaspoonful or more or less or any, to taste, of dried green leafy herbs to your salad or soup for aromatic terpenoids and likely phenolic phytonutrients as well; such as Basil, Cilantro, Italian Seasoning, Tarragon, Thyme. Basil and Cilantro are mild and are also used fresh in larger amounts as part of the salad greens. Basil is used fresh or dried in larger amounts in Pesto sauces. Parsley is also used fresh in larger amounts in Tabouli salads.
• The herb Rosemary is also a good source of terpenoids but is slightly like pine needles and needs to be added to a dish that will be cooked about 20 minutes for better texture. I enjoy Rosemary with beta carotene rich orange flesh Sweet Potatoes which I cook as a skillet scalloped potato. I first saute an Onion sliced in thin rings (allium group) and then add thinly sliced triangles of Sweet Potato so they cook fairly quickly and a teaspoon to a tablespoon of Rosemary. Rosemary is strongly flavored and accidentally spilling too much in the pan can leave the dish inedible, scoop out the excess.
• Rosemary is a medicinal herb which may help with pain and in traditional folk medicine has been used as a strong tea for pain and inflammation conditions but several cups can have a diuretic effect similar to too much coffee.
• While discussing hot beverages, Herbal Teas, Green Teas and Black Teas, and Coffee provide phenolic phytonutrients and other antioxidants.
• Chamomile is a medicinal herb that is frequently used as an Herbal Tea. It has been studied in animal based cell research to increase Nrpf2. (10) The amount used in a cell based study is not something that I could calculate a human recommended serving size for but the traditional medicinal information is available here: (12), caution against its use for asthma, and some seasonal allergy sufferers is mentioned and it is not recommended for use in pregnancy due to a possible risk of miscarriage. Chamomile is a tiny daisy like flower with white petals and a yellow center. The bright yellow center may be a source of phenolic nutrients. (11) Medicinal uses mention digestive and skin complaints, inflammation, relief from muscle contractions, particularly in the intestines, and relief from anxiety. (12)
• Baking Cocoa is also a source of some phenolic and antioxidant nutrients and can quickly be made into a cup of Hot Cocoa by boiling  a cup of water and adding one or two large spoonfuls of the baking cocoa powder, to taste, along with a spoonful of sweetener. If richness is desired a half teaspoon of Coconut Oil can be stirred in for a hint of creaminess. Less processed/cold pressed Coconut Oil is also a source of phenolic nutrients. (6)
• Sugar itself can be a source of inflammation so limiting sugar in beverages or other foods is generally a good idea for a health promoting menu plan.
• Wine can be a source of phenolic nutrients, however it can also be a migraine trigger for some migraine sufferers (like me). Some of the benefits of wine are provided by the free (not-bound-within-a-larger-protein) amino acid content and other free amino acids in wine may be part of the migraine cause. Due to a genetic difference I found a bulk supplier of powdered free amino acids and tried Methionine and Glycine in water. A half teaspoon of each provides a cheerful mood boost without causing excess energy boosting effects – I tried a teaspoon of each initially and it could cause sleeplessness if taken late in the evening and almost too much of a energy boost to the point of increased heart rate. The free amino acids are acidic and cause a puckery tart wine effect. Adding an ounce or two, 2-4 Tablespoons of a 100% purple grape juice or cherry juice or black currant juice could add a hint of sweetness and makes the beverage slightly more juice or wine like. A deficiency of Methionine whether due to a genetic difficulty in metabolism such as I have or due to a dietary lack can increase the body’s need for Nrf2. (7) A deficiency of Nrf2 could negatively effect the body’s supply of the amino acids glycine and serine and it is involved in their biosynthesis pathways. (13) The pathway, called the pentose phosphate pathway, is shown in Figure 2: (14). So speculatively glycine wouldn’t be helping make Nrf2 but if there was a problem with supply of Nrf2 then there might be a shortage of glycine or serine, and they do have biological roles throughout the body.

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. Martin L Pall, Nrf2, a master regulator of detoxification and also antioxidant, antiinflammatory and other cytoprotective mechanisms, is raised by health
   promoting factors., Stephen Levine, Acta Physiologica Sinica, February 25, 2015, 67(1): 1–18  http://www.actaps.com.cn/qikan/manage/wenzhang/2015-1-01.pdf (1)  // quoted in: Joseph Mercola, The Harmful Effects of Electromagnetic Fields Explained, wakeup-world.com, Dec. 22, 2017, https://wakeup-world.com/2017/12/22/the-harmful-effects-of-electromagnetic-fields-explained/ (1)
2. https://effectiveselfcare.info/2017/10/15/g3-5-negative-stress-chemicals-may-cause-symptoms-like-itching-migraines-pain-or-ibs/ (2)
3. https://effectiveselfcare.info/2017/10/15/antihistamines-may-help-if-genetic-tendency-overproduce-histamine/ (3)
4. https://effectiveselfcare.info/2017/10/15/g3-6-1-calcium-sparklets-and-oxidative-stress/ (4)
5. https://effectiveselfcare.info/2017/10/15/trpv-channels-comfort-vanilla-heat-capsaicin/ (5)
6. Marina AM, Man YB, Nazimah SA, Amin I.,  Antioxidant capacity and phenolic acids of virgin coconut oil. Int J Food Sci Nutr. 2009;60 Suppl 2:114-23. https://www.ncbi.nlm.nih.gov/pubmed/19115123 (6)
7. Lin AH, Chen HW, Liu CT, Tsai CW, Lii CK., Activation of Nrf2 is required for up-regulation of the π class of glutathione S-transferase in rat primary hepatocytes with L-methionine starvation., J Agric Food Chem. 2012 Jul 4;60(26):6537-45. https://www.ncbi.nlm.nih.gov/pubmed/22676582 (7)
8. Yu-Kun Jennifer Zhang, Kai Connie Wu, Curtis D. Klaassen, Genetic Activation of Nrf2 Protects against Fasting-Induced Oxidative Stress in Livers of Mice., March 18, 2013, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059122 (8)
9. Which Nrf2 Products have Peer-Reviewed Studies – Beware of Phony Science, nrf2.com, http://www.nrf2.com/?page_id=38 (9) Stuff to read later list: */Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity. */Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. */Effects of a Water-Soluble Curcumin Protein Conjugate vs. Pure Curcumin in a Diabetic Model of Erectile Dysfunction. */Curcumin enhances non-opsonic phagocytosis of Plasmodium falciparum through up-regulation of CD36 surface expression on monocytes/macrophages. */Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver.– Curcumin is a vitamin/hormone D analog and is an extract of the root vegetable Turmeric which provides the bright yellow color to Indian curry spice mixes. CYP enzymes are actively involved in vitamin/hormone D metabolism.  /Yes, Vitamin D is needed to produce Nrf2: (15)/ */Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation. – so yes, speculatively, a deficiency might increase risk of fatty liver disease. */Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria. */Extremely low-frequency electromagnetic fields activate the antioxidant pathway Nrf2 in a Huntington’s disease-like rat model. */Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. */Chamomile Confers Protection against Hydrogen Peroxide-Induced Toxicity through Activation of Nrf2 -Mediated Defense Response.
10. Bhaskaran, Natarajan & Shukla, Sanjeev & Gupta, Sanjay. (2012). Abstract 2594: Chamomile (Matricaria chamomilla L.) upregulates heme oxygenase-1 through activation of ERK-Nrf2 signaling: Cytoprotective mechanism against oxidative damage. Cancer Research. 72. 2594-2594. 10.1158/1538-7445.AM2012-2594. https://www.researchgate.net/publication/275442168_Abstract_2594_Chamomile_Matricaria_chamomilla_L_upregulates_heme_oxygenase-1_through_activation_of_ERK-Nrf2_signaling_Cytoprotective_mechanism_against_oxidative_damage (10)
11. Maria de Lourdes Reis Giada, Chapter 4: Food Phenolic Compounds: Main Classes, Sources and Their Antioxidant Power, Biochemistry, Genetics and Molecular Biology » “Oxidative Stress and Chronic Degenerative Diseases – A Role for Antioxidants”, book edited by José A. Morales-González, ISBN 978-953-51-1123-8, Published: May 22, 2013    https://www.intechopen.com/books/oxidative-stress-and-chronic-degenerative-diseases-a-role-for-antioxidants/food-phenolic-compounds-main-classes-sources-and-their-antioxidant-power (11)
12. Roman Chamomile, Penn State Hershey Medical Center, http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000233 (12)
13. Gina M. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Jessica A. Sudderth, Zeping Hu, David Wu, Hao Tang, Yang Xie, John M. Asara, Kenneth E. Huffman, Ignacio I. Wistuba, John D. Minna, Ralph J. DeBerardinis, and Lewis C. Cantley., NRF2 regulates serine biosynthesis in non-small cell lung cancer., Nat Genet. 2015 Dec; 47(12): 1475–1481.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721512/ (13)
14. Albena T.Dinkova-Kostova, Andrey Y.Abramov, The emerging role of Nrf2 in mitochondrial function., Free Radical Biology and Medicine, Vol 88, Part B, Nov 2015, Pages 179-188, Part of special issue: Nrf2 Regulated Redox Signaling and Metabolism in Physiology and Medicine Edited by 
    G E Mann, H J Forman, M Yamamoto, T Kensler, J D Hayes,

    https://www.sciencedirect.com/science/article/pii/S0891584915002129 (14)

15. K Nakai, H Fujii, K Kono, S goto, R Kitazawa, S Kitazawa, M Hirata, M Shinohara, M Fukagawa, S Nishi, Vitamin D Activates the Nrf2-Keap1 Antioxidant Pathway and Ameliorates Nephropathy in Diabetic Rats., American Journal of Hypertension, Volume 27, Issue 4, 1 April 2014, Pages 586–595, https://academic.oup.com/ajh/article/27/4/586/2743232 (15)