It has been a while since I have actually sat down and written a new blog. In fact, it has been several months. Things change but in no way, has the focus of my research changed. I still believe that many environmental illnesses are the consequence of depletion of Nrf2. In addition, I wonder if polymorphisms in the Nrf2 pathway can account for the development of diseases such as chronic fatigue syndrome and MCS. In the last several years, new studies point to the Nrf2 playing a role in at least chronic fatigue syndrome. Also, new studies on Prostandim, a supplement has had at least anecdotal benefits in fibromyalgia. Prostandim is a Nrf2 activator that has also demonstrated recovery benefits after exercise and in arthritis.
What is common in CFS, fibromyalgia and probably MCS is that patients have high levels of reactive species and oxidative stress. This is of course is what makes me think that the NRF2 antioxidant system is deficient. Oxidative stress can be caused by exogenous substances like chemicals and other pollutants or formed through normal and abnormal cellular metabolism. At high levels, it has the potential to damage tissue and if it goes unchecked, it can lead to disease. Scientists believe that aging causes higher levels of oxidative stress in the body. Many diseases of aging have been found to be caused by oxidative stress such as cardiovascular disease. Other diseases like diabetes also present with oxidative stress levels that can be considered abnormal.
Scientists believe that the Nrf2 system developed in eukaryotes to combat the rising levels of oxygen during what is known as the Global Oxygenation Event (GOE). This is when organisms progressed from anaerobic to aerobic metabolism. As one author writes, the problem with the development of aerobic metabolism is that it becomes necessary to "overcome the metabolic toxicity that results from use of highly reactive molecular oxygen. In aerobic respiration, enzyme catalysed four-electron reduction of oxygen is considered to be a relatively safe process producing water at the terminal end of the mitochondrial electron transport chain. The reductive environment of cells, however, provides ample opportunities for oxygen to undergo successive non-enzymatic univalent reduction, these processes being exacerbated by electrophilic xenobiotics and abiotic agents such as solar ultra-violet radiation. Oxidative stress is the net outcome of oxidative damage to biologically important molecules such as proteins, lipids, carbohydrates and nucleic acids caused by the generation of these reactive oxygen species (ROS). To survive in such a reactive oxygen environment, living organisms produce or sequester a variety of water- and lipid-soluble antioxidant compounds such as vitamins C and E. Oxygen metabolising organisms additionally produce an arsenal of antioxidant enzymes that inactivate ROS. Animal genomes often express over 200 antioxidant and xenobiotic detoxifying enzymes. " (1)
So what causes depletion of Nrf2? I expect that there are several pollutants that deplete Nrf2. Recent studies have shown that overexpression of TNF-a and methylation can also deplete it. I have already mentioned that polymorphisms in the Nrf2 can make it less readily available. One such instance is in inflammatory bowel disease, (2) where a polymorphism in Nrf2 contributes to the onset of the condition. One older study demonstrated that exposure in pigs to ochratoxin, a mold toxin, depleted Nrf2 in kidney cells.(3) It is important to note here that in another study, patients with chronic fatigue syndrome were found to have mold metabolites in their urine. (5) So we see here, the connection to Nrf2 depletion and CFS may be possible in humans from mold exposure.
In other blogs I have mentioned how a chemical found in broccoli activates Nrf2. Other chemicals in food that been demonstrated to active NRF2 is EGCG found in green tea, coffee, and resveratrol found in wine. The pharmacological industry is also engaged in numerous tests for agents that show Nrf2 activation. Incidentally, a new study has shown positive results of an edible fungus Sarcodon imbricatus, used in ancient Chinese medicine, in a mice model of Chronic fatigue syndrome to reduce fatigue by normalizing oxidative stress. (6)
1.Rising levels of atmospheric oxygen and evolution of Nrf2. Scientific reports, Vol. 6 (14 June 2016) by Ranko Gacesa, Walter C. Dunlap, David J. Barlow, Roman A. Laskowski, Paul F. Long. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906274/
2. Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. Pharmacological reviews, Vol. 70, No. 2. (April 2018), pp. 348-383 by Antonio Cuadrado, Gina Manda, Ahmed Hassan, et al.http://pharmrev.aspetjournals.org/content/70/2/348.long
3. Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo. Toxicology, Vol. 389 (15 August 2017), pp. 42-52 by Agnieszka Loboda, Anna Stachurska, Mateusz Sobczak, et al.
4. Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells. Journal of animal physiology and animal nutrition, Vol. 93, No. 5. (10 October 2009), pp. 547-554, doi:10.1111/j.1439-0396.2008.00838.x by C. Boesch-Saadatmandi, A. E. Wagner, A. C. Graeser, et al.
5. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins, Vol. 5, No. 4. (11 April 2013), pp. 605-617 by Joseph H. Brewer, Jack D. Thrasher, David C. Straus, Roberta A. Madison, Dennis Hooper. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705282/
6. Antifatigue Potential Activity of Sarcodon imbricatus in Acute Excise-Treated and Chronic Fatigue Syndrome in Mice via Regulation of Nrf2-Mediated Oxidative Stress. Oxidative medicine and cellular longevity, Vol. 2018 (2018) by Xue Wang, Yidi Qu, Yongfeng Zhang, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046126/
