Study: Strawberries Lower Inflammatory Marker And Reduces Pain!

Strawberries lowered inflammatory markers and reduced pain in a new study. Read more. 

Strawberries decrease circulating levels of tumor necrosis factor and lipid peroxides in obese adults with knee osteoarthritis.

Basu A¹, Kurien BT², Tran H³, Byrd B³, Maher J³, Schell J⁴, Masek E¹, Barrett JR⁵, Lyons TJ⁶, Betts NM⁴, Hal Scofield R².

Chronic Fatigue: The Nrf2 and Mitochondrial Connection

Chronic fatigue syndrome (CFS) is a condition where symptoms last more than 6 months. One identifying feature is that the overwhelming fatigue that comes with it is not resolved with rest. CFS is now recognized as a serious health condition that is known to effect the immune and neurological systems and have other physiological impacts. In my posts, I often classify CFS as an environmental illness for the sake of simplicity. I also consider multiple chemical sensitivity (MCS) and fibromyalgia (FM) as environmental illnesses. What is common in most patients with these illnesses, is that they have higher than normal levels of oxidative stress. Oxidative stress is produced by natural cellular processes or exposure to environmental toxicants. At high levels it leads to tissue damage and disease.  Currently, the true cause of these environmental illnesses are not known. 

While the cause of CFS might not be known, several theories have been proposed. One such theory is that mitochondrial dysfunction leads to the rampant increase of oxidative stress and overall, energy depletion. (1) This in turn leads to other inflammatory processes. Of course, the opposite could be true. In general, I believe that the inhibition of the Nrf2 pathway is at the root of environmental illness. The Nrf2 is a master gene regulater that regulates the natural antioxidant system in cells and neutralizes oxidative stress. It can be inhibited by many factors including TNF-a and abnormal methylation and xenobiotics. It is upregulated by natural phenols like EGCG, sulforaphane in broccoli, resveratrol and quercetin to name a few. Recent discoveries have also lead to a number of pharmaceuticals that increase expression of Nrf2. It is only in the past few years that researchers have identified a number of ways that the Nrf2 pathway promotes cellular respiration, ATP synthesis and provides other functions in the mitochondria. 

So how exactly does Nrf2 function in the mitochondria? It seems it does it in a number of ways including reducing oxidative stress by promoting the action of complex 1, regulating the expression of ATP synthase subunit α, allows for more efficient oxidative phosphorylation, increases the levels of ATP, there is better integration of fatty acid oxidation with the TCA cycle (a process that occurs through the action for example, of glucoraphanin which is the precursor of the classical Nrf2 activator sulforaphane ), it promotes biogenesis, increases PGC-1 and maintains mitochondrial integrity. (2)

While it is not known if mitochondrial dysfunction occurs in all environmental illnesses, it makes sense that it might be a possibility. In any case, there is a reason to believe that energy depletion from oxidative stress may be a factor in causing some symptoms. 

Related:
*Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

*Sexual Dimorphism in Mitochondrial Biogenesis! 
*Impairments in Muscle Function After Cigarette Exposure and Environmental Illness 
*Green Tea Catechins May Protect Cells From Particulate Matter!

1. Chronic fatigue syndrome and mitochondrial dysfunction International Journal of Clinical and Experimental Medicine, Vol. 2, No. 1. (2009), pp. 1-16 by Norman E. Sarah Myhill

2. The emerging role of Nrf2 in mitochondrial function. Free radical biology & medicine, Vol. 88, No. Pt B. (11 November 2015), pp. 179-188 by Albena T. Dinkova-Kostova, Andrey Y. Abramov.

The Evolution of Nrf2 and the Depletion of It in Chronic Fatigue Syndrome!

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. <sup>" (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.</sup>

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/

Depression in Environmental Illness May Be Relieved by Eating Broccoli!

"Depressive symptoms in environmental illnesses are more likely due to activation of TNF-a which presents as "sickness behavior". It would account for the fatigue and the depression. Because sulforaphane enhances expression of Nrf2, depressive symptoms may be relieved by prophylactic ingestion of broccoli. While some think that the depression is caused by activation of the corticosteroid system, I do not agree." If nothing else, it is worth the try!

 Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. The Journal of nutritional biochemistry, Vol. 39 (January 2017), pp. 134-144 by Ji-Chun C. Zhang, Wei Yao, Chao Dong, et al. http://www.citeulike.org/user/kimberlykramer2015/article/14619968

Intestinal Integrity with the Probiotic Bifidobacteria.

Hsieh found in a recent study that certain strains of Bifidobacteria reduce epithelial barrier disruption in the intestines. It is believed that intestinal barrier dysfunction leads to a number of diseases including inflammatory bowel disease. In this study, the author found that the actions on TNF-a were achieved by the whole Bifido cell. This shows, according to Hsieh, that bacterial metabolites must be produced that act to reduce TNF-a. He also found that different strains of Bifidobacteria achieve intestinal tight junction integrity better than others. This reinforces what I said in a previous post that more research is needed  on the benefits of different strains of probiotics.


For Further Reading:
   Inflammatory Bowel Disease, Helminths and High-fat Diets







Strengthening of the intestinal epithelial tight junction by Bifidobacterium bifidum Physiological Reports, Vol. 3, No. e12327. (16 March 2015) by Chen‐Yu Hsieh, Toshifumi Osaka, Eri Moriyama, et al