High Fat Diets Impair Body's Antioxidant System Leading to Chronic Inflammation!

As you know, I have suggested that deficiencies in the Nrf2 pathway may lead to any number of conditions where oxidative stress is a factor. Just a few of these are chronic fatigue syndrome, fibromyalgia, cardiovascular disease and diabetes. As we have described before, the Nrf2 pathway includes a number of proteins that form the natural antioxidant system. Its main purpose is to neutralize reactive species that are formed from metabolic processes to avoid damage to cells and tissue. Nrf2 is conserved in many tissues and developed as a means to deal with aerobic metabolism. In the past, we have also discussed how many factors can effect its expression such as TNF-a, microRNa, methylation, hyperglycemia, hypertension and high-fat diets.

I like to take a systems approach when discussing the Nrf2 pathway, disease and provide information from a variety of sources. With this in mind, I want to address some key points that one author made about selenium deficiency and high-fat diets and their impact on the Nrf2 pathway in swine. Please note, physiological conditions in animals do not present exactly like they do in humans. However, there is much to be learned about human disease by studying them in different animal species. On the other hand, sometimes it is just more practical.

The following are just a few of the observations Yang made in pigs fed a selenium deficient, high-fat diet.

1. neutrophil phagocytosis was impaired.
2. significant generation of ROS and increase in oxidative stress
3. heat shock protein mRNA significantly elevated
4. altered levels of selenoproteins than the control
5. lower levels of Nrf2 and downstream target genes
6. increased levels of inflammatory cytokines Tnf-a and Il-1b
7. increase in mRNA of iNos, Il-6, NF-kb and others
8. decrease in anti-inflammatory cytokines
9. macrophage infiltration in adipose tissue resulting in changes in inflammatory cytokines

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Related Posts: 
 *Chemical in Vegetables Protect Against Gut Inflammation and Colon Cancer! 
 *Inflammation Starts in the Gut! Kick the High Fat Diet Habit!

Oxidative stress induced by Se-deficient high-energy diet implicates neutrophil dysfunction via Nrf2 pathway suppression in swine. Oncotarget, Vol. 8, No. 8. (21 February 2017), pp. 13428-13439 by Tianshu Yang, Zeping Zhao, Tianqi Liu, et al.

Meat May Contribute to Fatty Liver Disease in the Obese!

"Diets high in animal protein increase the risk for fatty liver disease among people who are overweight, according to new research published in Gut." Read more...

Animal Protein Linked to Non-Alcoholic Fatty Liver Disease. Physician's Committee for Responsible Medicine. August 13, 2018

 

Paraquat Produces Oxidative Stress in Dose-dependant Manner. Implications for Nrf2.

It was determined through a new study that exposure to dose dependent levels of Paraquat is responsive for increasing levels of oxidative stress. At lower level, production of oxidative stress was reduced by activation of the Nrf2. At higher dose levels, Nrf2 activation was inhibited which resulted in higher levels of oxidative stress and tissue damage.

This is important because Paraquat is an important agricultural herbicide that is used around the world. There are numerous reports that it crosses the blood brain barrier and accumulates in different brain regions. Because of this, it is believed that it does damage to dopamine neurons. It has also been found to cross the placenta and has been found in higher concentrations in the placenta than in the mother's blood. For this reason, the exposure to Paraquat may put a fetus at risk when the mother is exposed. In addition, Paraquat exposure has been linked to Parkinson's disease and Nrf2 inhibition at higher levels may to be blame for development of the disease. Of course, since oxidative stress is caused by exposure to Paraquat, people that have diseases or conditions where oxidative stress is a factor may be more negatively effected. (1)


Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells. Oxidative medicine and cellular longevity, Vol. 2016 (2016) by Tingting Dou, Mengling Yan, Xinjin Wang, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663008/

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.

Fatigue as a Consequence of Changes In Cellular Metabolism and Disturbed Sleep!

In a recent article the author writes, "persistent fatigue may be a consequence of chronic low-grade inflammation leading to an imbalance in energy availability and expenditure, which can be mediated and maintained by changes in circadian rhythms and sleep. He goes on to say that associations between persistent fatigue in CFS and CRF with alterations in cellular metabolism, disturbed sleep, and, to a lesser extent, disruptions in circadian rhythm. For both CRF (cancer-relate fatigue) and CFS, multi-causal models are generally suggested including low-grade inflammation and disturbed sleep, and also alterations in stress physiological responses, genetic vulnerability, and sociodemographic factors, among others. " 




The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Frontiers in behavioral neuroscience, Vol. 12 (2018) by Tamara E. Lacourt, Elisabeth G. Vichaya, Gabriel S. Chiu, Robert Dantzer, Cobi J. Heijnen

Fire Ant Pesticide Causes Neuroinflammation, Depression of the Natural Antioxidant System and Anxiety!

Bifenthrin is a pesticide that has commercial use for fire ants. Fire ants are a health and safety concern in many southern states of the U.S and there are over 200 species of fire ants spread out around the world. There venom is toxic and their bites can lead to allergic reactions and anaphylaxis in some people and animals. (1)

In the U.S., bifenthrin use is strictly labeled for the eradication of fire ants. As far as I know, there is no other use of it that is on label here in the US but is used extensively for agricultural use in other countries. In the past, the use of the chemical has been associated with the development of neurological disease and symptoms of anxiety. However, the mechanism of how it acts on the brain was not known.  In a recent study, it was demonstrated that rats exhibited anxiety after 60 of treatment with the chemical. In addition, it was discovered that these rats had extensive oxidation of lipids in two centers of the brain. Also, there was a decrease in glutathione and anti-oxidant activity and increased levels of oxidative stress and Tnf-a and reduced Nrf2. This is an important study in that it demonstrates how pesticides act on areas of the brain to cause neuroinflammation through activities of Nrf2/NF-kb pathway to promote anxiety. (2)


Wipedia. https://en.wikipedia.org/wiki/Bifenthrin


Inflammatory and oxidative mechanisms potentiate bifenthrin-induced neurological alterations and anxiety-like behavior in adult rats. Toxicology letters, Vol. 294 (15 September 2018), pp. 73-86 by Brahim Gargouri, Harsharan S. Bhatia, Michèle Bouchard, Bernd L. Fiebich, Hamadi Fetoui http://www.citeulike.org/user/kimberlykramer2015/article/14622148

Mold Toxin Causes Oxidative Stress, Inhibits Nrf2 and Regulates Autism Genes!

Ochratoxin A is a mycotoxin produced from Aspergillus and Penicillium species. It is commonly found in contaminated food products, water damaged buildings and heating ducts. Currently, it is one of 20 mycotoxins that is monitored in food. Ochratoxin A is known to be nephrotoxic, immunotoxic, and carcinogenic. Therefore, it is a health concern in both humans and animals. 

Generally, Ochratoxin A has been found to induce oxidative stress, inflammation and psychiatric conditions. In males, it is especially neurotoxic. Genes that it upregulates have an effect on autism-regulated genes that decrease Nrf2 and cause high levels of reactive species and oxidative damage.  Research has shown that males are more commonly effected because the genes are found on the x chromosome. 

Mezzelani A. (2017) Ochratoxin A and Epigenetics. In: Patel V., Preedy V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham

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. www.citeulike.org/user/kimberlykramer2015/article/14620230

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

A review of the diagnosis and treatment of Ochratoxin A inhalational exposure associated with human illness and kidney disease including focal segmental glomerulosclerosis. Journal of environmental and public health, Vol. 2012 (2012), doi:10.1155/2012/835059 by Janette H. Hope, Bradley E. Hope

Oxidative Stress and Environmental Illnesses!

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"The origin of oxidative stress is partly endogenous, as mentioned earlier. It is now, however, commonly admitted that environment and lifestyle may increase levels of oxidative stress. Smoking, pollution from pesticides, weed killers and endocrine disruptors (bisphenols and other plastic additives, parabens and phthalates) are the most common inducers of oxidative stress. All these compounds have some structural analogies with oestrogens and bind to oestrogen receptors, peroxisome proliferator-activated receptors, or both. Nutritional imbalance, food excesses, energy deprivation and excessive exercise also affect oxidative stress. Age increases basic oxidative stress, irrespective of gender."

 Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction. Reproductive biomedicine online, Vol. 33, No. 6. (December 2016), pp. 668-683 by Yves J. Menezo, Erica Silvestris, Brian Dale, Kay Elder https://www.rbmojournal.com/article/S1472-6483(16)30514-4/fulltext

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/