Suppression of the Antioxidant System By Insecticide Chemicals Can Lead to Obesity and Diabetes!

The Nrf2 pathway controls the transcription of at least 200 genes necessary to carry out functions that include neutralizing oxidative stress. Oxidative stress is a process that occurs through the natural metabolism of the cell. It was only recently that other process for the Nrf2 pathway have been found and include activating processes that are important for mitochondrial biogenesis and dictating the metabolism in adipose tissue and regulating adipogenesis. As discussed previously, pyrethroids are insecticides used in agriculture. One of their effects is that they may depress the Nrf2 pathway in adipose tissues through methylation and negatively impact adipose metabolism and function that leads to inflammation, obesity and possibly diabetes.

So how does Nrf2 activity prevent obesity? Sahin writes, "obesity is induced by adipose size and number. and their differentiation is dependent on metabolic, hormonal, gene and cell morphology changes. Several transcription factors control fat homeostasis as they regulate gene necessary for fat accumulation, fatty acid transport and lipolysis. (1) Oxidative stress is an important cause of obesity- related diseases. To counteract this, the Nrf2-Ho-1 pathway neutralizes the free radicals that cause oxidative stress. Interestingly, Ho-1 metabolic role goes beyond oxidative stress. Therefore, the Nrf2-HO-1 pathway may be a link to preventing obesity and its related diseases.

To understand how Nrf2 pathway prevents obesity, Sahin used butein, a chalcone derived from natural plants as an Nrf2 activator. Butein had also been reported to inhibit adipocyte differentiation  and used to treat inflammation. The purpose of the study was to determine if Nrf2 is responsible for the activation of adipocyte transcription factors known to effect fat homeostasis. To determine this, preadipocytes were treated with butein. After 6 days, the researchers found that treatment with butein significantly decreased lipid accumulation than fully differentiated adipocytes. Next, they showed that butein greatly increases Nrf2 translocation to the nucleus and transcription of Ho-1 in a dose dependent manner. The results suggested that the butein-induced Ho-1 reduced  lipid accumulation through key adipogenic transcription factors such as PPARγ and C/EBPα. In summary this study showed that butein inhibits lipid accumulation through the inhibition of key adipogenic regulators and also upregulates the Nrf2/HO-1 antioxidant pathway. (1)



1. Inhibitory Effects of Butein on Adipogenesis through Upregulation of the Nrf2/HO-1 Pathway in 3T3-L1 Adipocytes. Preventive nutrition and food science, Vol. 22, No. 4. (December 2017), pp. 306-311 by Jinwoo Yang, Jeehye Sung, Younghwa Kim, Heon Sang S. Jeong, Junsoo Lee

Green Tea Catechins May Protect Cells From Particulate Matter!

 

       I have discussed Nrf2 and how its downregulation may be related to at least some symptoms of environmental illness, including MCS. The Nrf2 is a master regulator of the cell's antioxidant system. It regulates over 400 genes including those genes for HO-1, PGC-1a and others like SOD and catalase. Downregulation of Nrf2 has been linked to a variety of diseases including autoimmune disease, environmental illness, aging, type 2 diabetes and cancer. In addition, upregulation has also been linked to cancer which is why most often Nrf2 supplementation in not advised. There is a variety of foods that are known as Nrf2 activators, which upregulate Nrf2 for only a short period of time. Many of the Nrf2 activators are high in polyphenols including EGCG. A catechin found in green tea.
      In other studies, EGCG has been shown to be protective against cardiovascular disease.
 In this new study, Yang et al.

"used EGCG to determine its impact on oxidative stress and endothelial dysfunction from particulate matter (PM2.5) on a model for endothelial cells. During the study, PM2.5 in HUVAC cells caused oxidative stress and cell death which were inhibited in the presence of EGCG. Also, it was demonstrated that both Nrf2 and HO-1 was upregulated by EGCG. This provides evidence that EGCG may protect cells from environmental damage from particulate matter." (Yang) 

      While the above study is an experimental model using EGCG, it is important to note that epithelial tissue lines the esophagus and digestive tract and the lungs.  Drinking green tea has been shown in other studies to reduce the prevalence of some digestive system cancer including Barrett's esophagus.(Rejuvenation Science)

Epigallocatechin-3-Gallate Protects HUVECs from PM2.5-Induced Oxidative Stress Injury by Activating Critical Antioxidant Pathways. Molecules (Basel, Switzerland), Vol. 20, No. 4., pp. 6626-6639 by Guang-Zhao Z. Yang, Zhao-Jun J. Wang, Feng Bai, et al.  http://www.citeulike.org/user/kimberlykramer2015/article/13584172

Green Tea Exhibits Anticancer Effect in Barrett's Associated Esophageal Adenocarcinoma. Rejuvenation Science. http://www.rejuvenation-science.com/n_green-tea_cancer.html

For further reading: How Activation of Antioxidant System Nrf2 Reverses Endothelial Dysfunction in Vascular Disease and Environmental Illness!

Omega 3 Fats are Nrf2 Activators - A Key Ingredient to a Healthy Diet!



It is believed the Western diet wholly or partially contributes to disease. "Sixty-five percent of Americans over 20 years of age are obese. 64 million people suffer from one or more type of cardiovascular disease." (Cordain) Many experts believe that one cause of the American diet's contribution to cardiovascular disease is the imbalance of fats. More specifically, a higher ratio of saturated fat and Omega 6 to omega 3 which are good fats.  Generally, the higher the consumption of omega-3 fats to other fats is correlated to a lower incidence of heart disease. (Dhalla) A recent study has shown that EPA omega 3 polyunsaturated fats protect against oxidative stress which contributes to heart disease. This is achieved by the EPA activating Nrf2 and Ho-1. (Lee)



For further reading:

     A Mediterranean Diet is Better Than Exercise and Can Halve the Risk of Heart Disease!
     The Mediterranean Diet : The Key to Preventing Disease and Life Extension?
     Natural Foods that Activate the Body's Antioxidant Response Against Cellular Stress


Origins and evolution of the Western diet: health implications for the 21st century The American Journal of Clinical Nutrition, Vol. 81, No. 2. (1 February 2005), pp. 341-354 by Loren Cordain, S. Boyd Eaton, Anthony Sebastian, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13571703

Effects of eicosapentaenoic acid (EPA) on the cytoprotection via Nrf2-mediated heme oxygenase-1 in human endothelial cells. Journal of cardiovascular pharmacology (26 March 2015) by Seung Eun E. Lee, Gun-Dong D. Kim, Hana Yang, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13571703

Role of oxidative stress in cardiovascular diseases. Journal of hypertension, Vol. 18, No. 6. (June 2000), pp. 655-673 by N. S. Dhalla, R. M. Temsah, T. Netticadan. http://www.citeulike.org/user/kimberlykramer2015/article/11296916

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

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissues and endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and dysfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signaling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of health consequences in many of them.

 

Link to citations.