Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses

Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.


Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others.  Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)

Notes:

• EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
• Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
• Aging influences increased expression of GSK-3b. (Mercado-Gomez)

For Further Reading:

• GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
• Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

Original article and citations located here.

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

A preliminary study suggests that a polymorphism in the DISC1 gene is associated with chronic fatigue syndrome. These findings, if found to be true, have important implications for the conditon, as well as, may have an influence on research findings of other environmental illnesses. DISC1 is also known as Disrupted in Schizophrenia and has been associated with a number of mental health conditions including schizophrenia, bipolar disorder and major depression. Just recently the gene has also been implicated in playing a role, in addition to other genes, in autism. We have noted before that some experts believe that conditions such as ADHD and certain types of MCS are in fact, autism spectrum disorders. As one author points out, DISC1 is responsible for a number of physiological activities including the production of new neurons during brain development and adult neurogenesis. A defective DISC1 gene which has been demonstrated in schizophrenia could lead to a reduction in dendritic spines and also influence nerve cells to maintain weaker connections with neighboring neurons and for the purpose of simplification, reduce the "cross-talk" between neurons by influencing dopamine production. If similar disruptions through mutation in DISC1 were to occur, it does make sense it may be involved in the development of autism because of its effect on the central nervous system. (Tsai)


Of course, the idea that it plays a role in chronic fatigue syndrome is a novel finding. From my standpoint, the idea that DISC1 may play a role in CFS makes a lot of sense. As I have described in other blogs, a protein called GSK-3b is an on/off switch for Nrf2 which provides a protective role against endogenous threats that may negatively influence neurotransmission  in autism. Recently, it was demonstrated that the Wnt pathway is a pathway involved in ammonia and urea excretion that also involves the activities of GSK-3b. Biochemically, one researcher writes that DISC1 inhibits GSK-3b and therefore, this pathway has been suggested to play the important role in a number of mood disorders which we noted earlier. Like most anything in cell biology, too much activity or too little can have dramatic effects on function. In the case of GSK-3b, blocking its abherrant signaling has been associated with symptomatic benefits in MS, colitis, sepsis and arthritis and conditions involving inflammation. The latter implicates an inhibitory role of GSK-3b signaling on Nrf2. Elevations of GSK-3b activity are also present in patients with Parkinson's disease and Alzheimer's. A recent report from MIT demostrates that DISC1 knock-out present with behaviors including hyperactivity, a characteristic of schizophrenia and GSK-3b inhibitors reversed these behaviors. The author suggests that the scewed balance of neural cell development and alterations in signaling may lead to compromised cognition and behavior alterations. (Halber) A polymorphism in DISC1 that has been suggested in CFS could very well lead to abherrant signaling from GSK-3b, elevations in oxidative stress and uncontrolled expression of inflammatory proteins and changes in redox because of subsequent loss of Nrf2 signaling. Of course, other factors such as genetic SNPs in Nrf2 and suppression of gene expression should also be considered.

Citations and Original Document

GSK-3b and the Inflammatory Response in Environmental Illnesses

Some experts believe that Il-6 is an important cytokine in the activation of autoimmune and inflammatory diseases, some forms of cancer and present at high levels in PTSD. GSK-3b has been our recent topic of discussion and some important considerations for the actions of this protein is its overexpression may contribute to a number of mental and physical health conditions. Its activities provide a sort-of "on-off" switch for the antioxidant system Nrf2 and inhibits the expression of PGC-1 and for this reason is an important regulator of cellular homeostasis and energy metabolism. It has also been demonstrated GSK-3b inhibits heat shock factor which has important implications for studies of lifespan. Heat shock factor assists in the control of stress response activation through heat shock proteins which have protective properties that "aid in folding, transport, regulation, and degradation of cellular proteins under normal conditions, and their expression during stress is essential for cell survival." (Xavier) Heat shock factor has the ability to "repress" the expression of Il-1 through a transcription mechanism associated with Il-6 and thereby, limiting inflammatory responses. (Xie) These studies suggest that overexpression of GSK-3b (ie. that may occur from endotoxin-induced production of Tnf-a) may contribute to activation of immune responses that are "autoimmune or inflammatory" in nature. It also provides more evidence of the role of Nrf2 in autoimmune-type responses and that inhibition of PGC-1a may contribute to dysregulation of metabolism associated with environmental illness.

Notes:

• SIRT1 regulates the expression of HSF which can be elevated by resveratrol.

Xavier et al. Glycogen Synthase Kinase 3B Negatively Regulates Both DNA-Binding and Transcriptional Activities of Heat Shock Factor 1. June 2000. http://www.citeulike.org/user/HEIRS/article/6590895
Ishihara, K. and Hirano, T. (2002). Il-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine & growth factor reviews, 13(4-5):357-368. http://www.citeulike.org/user/HEIRS/article/4365589
Maes, M. (1999). Elevated serum interleukin-6 (il-6) and il-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45(7):833-839. http://www.citeulike.org/user/HEIRS/article/4509997
Xie, Y., Chen, C., Stevenson, M. A., Auron, P. E., and Calderwood, S. K. (2002). Heat shock factor 1 represses transcription of theil-1β gene through physical interaction with the nuclear factor of interleukin 6. Journal of Biological Chemistry, 277(14):11802-11810. http://www.citeulike.org/user/HEIRS/article/6590793
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in pgc-1  alpha muscle-specific knock-out animals. The Journal of biological chemistry, 282(41):30014-30021. http://www.citeulike.org/user/HEIRS/article/1907765
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648

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 tissuesand 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 in contrast 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 disfunction. 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 signalling 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 conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

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Original Article and Citations:

Regulatory T cells activity is potentiated by glycogen synthase kinase 3beta inhibition.

Comment: It has been suggested that chemical sensitivity and other conditions related to other environmentally-induced syndromes are a consequence of "loss of tolerance" which may be attributed to a reduction in the production of regulatory T cells that can suppress autoimmune responses and also may help in glucose homeostatic regulation. GSK-3b is similar to the on/off switch for the antioxidant system and is upregulated in inflammatory conditions.  Insulin and exercise have been shown to inhibit GSK-3b and other studies report that inhibiting GSK-3b may also reduce Il-6.

"Inhibition of GSK-3beta leads to increased suppression activity by Tregs."

CiteULike: Suppressive Treg cell activity is potentiated by glycogen synthase kinase 3beta inhibition.:

Related: GSK-3b

GSK-3b - Regulator of Intestinal Inflammation

Well gee, have I not been saying this for months now???? GSK-3b also promotes neuroinflammation and may be responsible for brain inflammatory responses by intestinal inflammation. "Since this protein can inhibit neuroprotective antioxidant system -- this is probably highly likely." HEIRS_Health

A disturbed regulation of Toll-like receptor (TLR) signal transduction resulting in the exclusive activation of proinflammatory signaling pathways may be critical for the perpetuation of established chronic colitis. Glycogen synthase kinase 3-[beta] (GSK3-[beta]) was recently identified as an important regulator of TLR signaling mediating excessive inflammatory responses.

Read more: HEIRS Blog Tags: GSK-3b
*****HEIRS Library Tag: GSK-3b


Glycogen synthase kinase 3-[beta]: A master regulator of toll-like receptor-mediated chronic intestinal inflammation

Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

When you are talking about biological pathways there is never a linear path where one protein action only leads to another. It would make understanding these pathways alot simpler but it just does not work that way. Of course, if this were so, it would be so easy for everything to just stop working if something went wrong. When there are multiple pathways that intersect, run parallel or make feedback loops on proteins that ultimately activate other proteins, it results in a kind of "checks and balance system" inside a cell. This provides a safety mechanism so processes keep working or at least "keep chugging along" even if one protein or even a few proteins that make up a pathway are damaged, are lost or their signals get misdirected. It is easy to get confused when thinking about all those protein interactions at the same time. For me.... it is easier to break the activities down and focus on the processes individually. It makes it easier to understand how these pathways work and easier to remember just what they do! (If you would like to see a graphical depiction of the tangled mess these pathways make - click here!) Today's focus is on mostly on the PGC1a pathway and its relevance to the molecular biology of environmental illnesses.

In a recent blog, I wrote about my interest in nutrition as well as, a variety of other topics I have studied that impact health and wellness. In that blog, I discussed how a number of dietary excesses or deficiencies may influence environmental disease. Specifically dietary deficiencies include vitamin D, vitamin B and folate and also may include methionine(either too little or too much). I added changes in human dietary patterns and lifestyles over the last several decades or more may have contributed to this. There is debate on whether we get too much or too little methionine from our diet. The most recent articles provide evidence that methionine actually increases mitochondrial stress and lack of DNA repair even though others recommend supplementation of methionine. Generally, our bodies use methionine to make something called s-adenosyl methionine (SAM) which is used for biosynthesis of hormones like dopamine and serotonin. (Deth, Cully) It breaks down into homocysteine which can be toxic at excess amounts but with the help of B6, B12 and folate it recycles back into methionine or glutathione. (This means we have to have substantial amounts of these nutrients too!) Methionine can also be used to make cysteine, cartinine, taurine and lecithin. Excess levels of homocysteine (homocysteinemia) has been demonstrated to have negative effects on the cardiovascular system, impair the urea cycle and may produce problematic cognitive effects. It has recently been demonstrated that PGC-1a effects homocysteine metabolism and overexpression of the antioxidant may elevate levels of homocysteine and lower PGC-1a expression is associated with lower plasma homocysteine levels. Low levels of homocysteine can alter the normal metabolism of glutathione, taurine and sulfate and therefore can be a health concern. Because homocysteine is the intermediate in the production of methionine to cysteine, it may make one more susceptible to oxidative stress and certain toxic exposures. In these cases, NAC, methionine and taurine are often recommended.

Now that we have reviewed how PGC-1a interacts with the methionine synthase pathway, let us now discuss more about this protein and its importance for maintaining overall cellular metabolism and homestasis. Homeostasis inside cells can be severely impaired without proper expression of PGC-1a because its expression influences the regulation of a number of other proteins including the PPARS, estrogen, thyroid hormone, glucocorticoids and the pregnane X receptor, just to name a few. (Finck) To demonstrate this take for example how the pregnane X receptor interacts with PGC-1a in the synthesis of CYPA26 and CYPA34. These are two enzymes necessary for the metabolism and/or detoxification of certain anesthetics, antidepressants, nicotine and other contaminants like certain molds. Additional key targets for PGC-1a include NRF1 and NRF2 which regulate mitochondrial function. The former, NRF1, is regulated by Nrf2 and taken together, Nrf2 and PGC-1a are responsible for most of the activities that promote oxidative stress resistance and cellular survival in toxic environments. PGC-1a also interacts with vitamin D and "because the expression of PGC-1α is regulated by environmental stimuli, such as diet and lower temperatures, it follows that the function of VDR could be influenced in response to these external stimuli in the tissues that exhibit an overlap in the expression of PGC-1α." (Savkur)

The PGC-1a gene responds to a number of different environmental cues including diet like fasting, caffeine, exercise and cold exposure and is preferentially expressed in tissues with high oxidative capacity. (Finck) On the other hand, it is inhibited by obesity, lack of exercise and the exposure to endotoxin. These factors lead one to consider important policy and regulatory concerns for the elderly and vulnerable populations, those with access issues to proper nutrition or individuals living with unhospitable conditions like contaminated water supplies. In general, the inhibition of PGC-1a expression has a variety of physiological effects including lower cardiac function, lower mitochondrial function, endothelial and epithelial dysfunction, poor thermoregulation, lower protection against environmental toxins, reduced energy metabolism, alterations of muscle fiber type and numerous others. One will note, all of these contribute to a variety of complications indentified in patients with environmental illnesses. As Patti describes, one complication from reduced PGC-1a expression leading to oxidative stress and altered cellular metabolism is insulin resistance and diabetes. As we noted earlier, PGC-1a interacts with NRF-1 a nuclear respiratory factor. This author demonstrates that although NRF-1 is reduced in diabetics, a number of other proteins that interact with and including PGC-1a such as PGC-1b, PPAR-gamma and NRF1 are also reduced in members of their families. From this it is assumed that decreased expression of PGC-1a is responsible for a decrease in NRF genes and the associated disturbances of insulin resistance and diabetes.

At this point, it would be worth suggesting here that metabolic disturbances may not only be the result of a reduction in expression in PGC-1a but may also be due to a reduction in the expression or regulation of NRF1 by Nrf2 at least in some cell types. One protein that has been implicated in a number of mental and physical health disorders, GSK-3b, is like an off and on switch for the Nrf2 antioxidant system that allows for cellular stress resistance. Also, other proteins may participate and PGC-1a inhibition. Tnf-a from cigarette smoke inhibites PGC-1a and may be a "key step" to vascular and myocyte dysfunction. (Tang) Both NRF1 and NRF2 are involved in the generation of the respiratory chain and it seems NRF1's role includes inducing gene expression and maintaining cytochrome C levels. An interesting article explains that several pathways exist that inhibit PGC-1a which may be different in different tissues. In addition to possible inhibition of PGC-1a in hepatocytes by Akt/PKB, there is evidence expression of PGC-1a can be dependant on reduction of a ligase called Cdc4 or through the activation of GSK-3b which also contributes to neuroinflammation. GSK-3b increases in response to oxidative stress and can regulate the TH1/Th2 balance (Ohtani) and its inhibition according to one author may lead to "stabilization of PGC-1a". Cdc4 is elevated in Parkinson's disease and as one author mentions, "it will be interesting to see if Cdc4 is responsible for the reduction of PGC-1a in the brains of PD patients." (Olson) For GSK-3b, metallothionein which can be upregulated by Nrf2 is an effective inhibitor of GSK-3b and prevents a number of diabetic-induced changes in inflammation, nitrosative stress and energy metabolism. (Wang) In cardiac cells the presense of metallothionein "abrogates mitochondrial damage, loss of mitochondrial DNA and downregulation of PGC-1a and its downstream targets. In this article the author proposes eNOS uncoupling induces the down-regulation of PGC-1a, NRF1, NRF2 and other proteins which contributes to the loss of mitochondrial biogenesis while saying further the precise mechanism for loss of mitochondrial biogenesis under eNOS uncoupling is not known. It might be important to stress here that it is now understood that Nrf2 is an important protective component against eNOS uncoupling. (Heiss) Recent evidence provides evidence of an alternative mechanism involving elevations in CO and H2O2 activates mitochondrial biogenesis through PGC-1a independantly of eNOS. In any event, PGC-1a expression is vital for normal heart function, because reductions in expression of PGC-1a results in compromised function. Other important inducers of PGC-1a include cAMP, CAMKII, AMPK and NO.

Numerous studies demonstrate and as we mentioned earlier, exercise elevates both PGC-1a gene and protein expression. As Wright explains, "with this discovery it was initially believed that exercise-induced biogenesis was mediated by increases in PGC-1a but suggests that activation of PGC-1a mediates mitochondrial biogenesis rather than the increases in protein expression." His study provides support for this because a) PGC-1a regulates binding of NRF1 and NRF2 and he demonstrates that their binding increased after exercise but before there was an increase in PGC-1a protein expression and b) a number of mitochondrial constituents were increased beforeelevations in protein levels. Other studies have demostrated that P38 activation is linked to an adaptive increase in mitochondrial biogenesis. Wright agrees and believes that generally PGC-1a production occurs in this order 1) exercise activates P38 which in turn activates PGC-1a 2) PGC-1a activates transciption factors and nuclear receptors that regulate mitochondrial expression which is part of the first phase of an adaptive response, 3) activation of the PGC-1a by the promoter and transcription factors coactivated by PGC-1a results in an increase in PGC-1a expression and 4) this mediates the second phase of an adaptive response and includes sustaining and enhancing mitochondrial biogenesis by PGC-1a. With all this in mind, one must consider that mitochondrial biogenesis and homostastic metabolism is dependant at least in part on participation of Nrf2 antioxidant system because it also regulates NRF1 and therefore, impairments of this system may contribute to conditions in metabolism where PGC-1a plays a central role.

Notes:

• Lipoic acid increases mitochondrial biogenesis and improves muscular energy through a AMPK-PGC-1a pathway which increases GLUT4 expression in aged mice. (Wang)

Original document and citations.

Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease.

Background: Nrf2 is a regulator of the antioxidant system including the production of HO-1 that provides protection against a number of toxic insults and GSK-3b acts as an on/off switch of that system. In addition, it has been shown that GSk-3b regulates the inflammatory response of LPS endotoxin through modulation of toll receptors. TLR4 has been shown to be instrumental in initializing and maintaining neuropathic pain.

Infante, J., García-Gorostiaga, I., Sánchez-Juan, P., Sierra, M., Martín-Gurpegui, J. L., Terrazas, J., Mateo, I., Rodríguez-Rodríguez, E., Berciano, J., and Combarros, O. (2009). Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease. European Journal of Neurology, 9999(9999). http://www.citeulike.org/user/HEIRS/article/6426071


HEIRS Library Tags: GSK-3b, HO-1

Supplemental citation: Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/2605
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., and Watkins, L. R. (2008). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (tlr4). The European journal of neuroscience, 28(1):20-29. http://www.citeulike.org/user/HEIRS/article/2997140

T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.

One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.

Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.

Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)

It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.

Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.




For original document and citations.


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Reduction of Signalling of GSK-3B May Reduce Some Problems in Non-alcoholic Liver Disease~!

High fat diets may caugment environmental illness by disrupting processes in a variety of pathways such as the Nrf2 and contributes to a variety of patholgies including non-alcoholic liver disease. GSK-3b is a protein that can serve as an "on-off switch" for the antioxidant system. A new study shows that knock-down of this protein may provide cells with more resistance to some of the damaging effects of saturated fats in the diet.

 Ibrahim, S. H. et al. Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis. Journal of hepatology (2010). URL http://dx.doi.org/10.1016/j.jhep.2010.09.039. http://www.citeulike.org/user/HEIRS/article/8365324

Intestinal bacteria drive obesity and metabolic disease in immune-altered mice

"Mice lacking a gene called TLR5 have an altered ability to recognize and control bacteria in their intestines, leading them to develop obesity and insulin resistance, which is often referred to as "pre-diabetes." The bacteria appear to influence appetite and metabolism rather than how well calories are absorbed. Obesity and insulin resistance can be transferred from TLR5-deficient mice via intestinal bacteria."
Intestinal bacteria drive obesity and metabolic disease in immune-altered mice

Notes:

• GSK-3b regulates TLR production including TLR5. Studies have demonstrated that TLR signaling increases IL-10 which has an anti-inflammatory effect and inhibition of GSK-3b may be protective against endotoxic shock.
• Changes in inflammatory cytokines may influence TLR functioning in mesenchymal stromal cells.

Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/260512
Abreu, M. T. (2010). Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Reviews Immunology, 10(2):131-144. http://www.citeulike.org/user/HEIRS/article/6589668
Palmer, Eric. Innate immune defense against intestinal bacteria. Videocast. National Institutes of Health. Retrieved on Monday March 1, 2010. http://videocast.nih.gov/ram/iig102109.ram

Activation of {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine

Background: It has been suggested that environmental illnesses such as chemical sensitivity entails a "loss of tolerance". Interestingly, it has also been proposed that the condition also be associated with inflammation in the gut and supports claims that it often develops after infection. Endotoxin activates the protein GSK-3b which has been shown to negatively influence the activities of beta-catenin and also the Nrf2. A new study by Manicassamy et al supports the necessity for beta-catenin in the development of tolerogenic dendritic cells. Another important note is the role of DISC1 which has been implicated in a number of mental disorders and subset of chronic fatigue syndrome inhibits GSK-3b activity. The beta-catenin pathway is also responsible for toxin removal of ammonia.


Activation of {beta}-Catenin in Dendritic Cells Re... [Science. 2010] - PubMed result: "Activation of {beta}-Catenin in Dendritic Cells Regulates Immunity Versus Tolerance in the Intestine."

Protein shown to be natural inhibitor of aging in fruit fly model

Protein shown to be natural inhibitor of aging in fruit fly model: "Sestrins are highly conserved small proteins that are produced in high amounts when cells experience stress. Sestrin function, however, remained puzzling until the Karin group found that these proteins function as activators of AMP-dependent protein kinase (AMPK), and inhibitors of the Target of Rapamycin (TOR). AMPK and TOR are two protein kinases that serve as key components of a signaling pathway shown to be the central regulator of aging and metabolism in a variety of model organisms, including the worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and mammals."

Note:

• Incidentally, AMPK is an important mediator of GSK-3b which is implicated in a number of mood disorders as well as, provides a mechanim for the shut-off of the antioxidant system. Because the antioxidant system, Nrf2 and it associated proteins, are important for a number of processes of cellular homeostasis, the regulation of AMPK is a very crucial step in maintaining resistance to cell stress.
• EGCG has been demonstrated to activate this same pathway. (Huang)

For further reading:

• HEIRS Research Blog Tag: AMPK ,
• HEIRS Library Tag:  Rapamycin, GSK-3b,

Huang, C.-H., Tsai, S.-J., Wang, Y.-J., Pan, M.-H., Kao, J.-Y., and Way, T.-D. (2009). Egcg inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of ampk in p53 positive and negative human hepatoma cells. Molecular Nutrition & Food Research, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/5402238

Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling

Background: GSk-3b has been shown to be an "on-off" switch for the Nrf2 antioxidant system. The following article discusses how metallothionein ( MT)prevent changes in heart function from diabetes by inactivation of this protein. MT which can be regulated by Nrf2 also have also been demonstrated to abrogate other changes in the mitochondria from O2 production and the downregulation of PGC-1a and its downstream targets.


CiteULike: Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling: "Wang, Y., Feng, W., Xue, W., Tan, Y., Hein, D. W., Li, X.-K., and Cai, L. (2009). Inactivation of gsk-3β by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes, 58(6):1391-1402."

Autism, Ammonia, Irritable Bowel Syndrome, Inflammatory Bowel Disease and Environmental Odorants

It is often asked whether or not intestinal problems such as irritable bowel syndrome and inflammatory bowel disease are associated with environmental illnesses such as chemical sensitivity. As a researcher, I would say undoubtedly so and to explain some of the reasons for this and present some interesting hypotheses and studies as well. First, it is true there is still no general consensus on what causes irritable bowel syndrome. However, in the last few years inroads have been made on settling the debate. In a preliminary report out of Heidelberg, the author states they have found mutations possibly associated with IBS, that "appear to cause changes in the composition or number of receptors on the cell surface. "The signal transduction in the digestive tract may be disturbed and this may lead to over stimulation of the intestine. Resulting disturbances in fluid balance could explain the occurrence of diarrhea," says Johannes Kapeller, a PhD student in the team.  Other studies and researchers have found similar findings and other possible causative agents for the development of both conditions.

I recently discussed at length the potential relationship of high ammonia levels in autism, in addition to the fact it may be implicated as a causal factor in a number of environmental illnesses including multiple chemical sensitivity and irritable bowel syndrome. Chemical sensitivity in autism has been noted for many years and I find it curious that a writer from 2003 notes several things about autism including autism therapies (Deth, Cully) that are similar to therapies for treatment of MCS in Pall's book "Unexplained Illness" and the NO/ONOO cycle. While the true cause of autism is still unknown, for the last several years, a number of health experts have proposed that symptoms of autism may be associated with small bacterial overgrowth (SIBO) and excess ammonia in the intestinal tract. Recent reports also suggest a role of bacteria and high ammonia in the inflammatory and pain and anxiety conditions, inflammatory bowel disease and irritable bowel syndrome, respectively. Enterochromaffin cells are secretory cells in the digestive tract and regulates intestinal responses depending on the immunological profile of the inflammatory response (TH1/Th2). In post-infectious IBS (PI-IBS) the enterocromaffin cells which are associated with serotonin secretion are implicated in some of the "mood" issues including anxiety and depression as well as, responding to the chemical composition of gut contents and pathophysiological contractions. (Nozawa) Of MCS significance, Tack has recently identified that "odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells" that may influence gut motility, nausea, vomiting and IBS. (Braun) Also, TRPV1 nociception which has been implicated in MCS also may alter motility through EC cells. (Nozawa, Pall)  Kim explains that the normal mucosal layers of the intestinal tract may play a role in the chronic inflammatory process in inflammatory bowel disease. Further he says,  "the enteric microbiota may drive the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD although the precise etiology is still unknown. However, the interactions with microbiota with T cells, intestinal epithelial cells, dendritic cells have all been implicated as contributors to the condition. (Kim) It might be wise to consider that environmental triggers might influence the constituents of the microbiota to act differently that lead to more pathogenic behavior. In colitis, a recent report suggests that a higher level of serotonin is the result of an increase in enterochromaffin cells (EC), and/or more serotonin in them and a decrease in the serotonin exporter RNA. (Bertrand)  Other reports show the involvement of GSK-3b protein which interacts with something called the Wnt/Catenin pathway and may increase ammonia levels as well as, shut of the astrocyte protective and antioxidant system Nrf2 which increases the likelihood of tissue injury and potential nerve damage from intestinal inflammation. Inhibitors of GSK-3b have been protective of endotoxic shock and also show significant benefits in treating mood disorders, prevent weight loss and activations of the inflammatory cascade by a protein called NF-kappaB. (Whittle) These mechanisms also support a recent discovery of a significant communication pathway of regulation between the gut and the brain, and even more strongly supports why inflammation in the gut may lead to changes in neurotransmission and upregulate or downregulate a number different genes and therefore, play a part in sickness syndrome.

Two decades ago, a study determined that H pylori, a bacteria in the gut, causes elevations of gastric juice ammonia (which can also bind transition metals) and subsequent findings include alterations in other gastric juices and enterochromaffin cells, changes in stomach mucosa and general injury and inflammation. (Lichtenberger) As far as the role of bacterial overgrowth goes as an important factor in IBS, this is still somewhat controversial, however, the idea is gaining in popularity. Spiller explains that recovery from post infectious-IBS can take 5 years or more and that time-table does not include potential for reinfection. The most recent studies on some strains of probiotics show promise for treatment and these findings are interesting because they support ammonia involvement in intestinal issues. Hyperammonemia is a common complication of acute and chronic liver disease and therapy may consist of antibiotics and lactulose that slows down the production and absorption of ammonia. In treating, hepatic encephalopathy lactulose works by reducing absorption from the gut to prevent the toxin from getting to the brain. Under pathological conditions, ammonia can pass through the blood brain barrier and may impair brain function, cause confusion and in the most severe cases, coma. (NetDoctor) Elevated levels can be consistent with chronic conditions and as we noted before, have been implicated in causing symptomatic issues in autism. Nicaise et al demonstrates that in his study probiotics decrease blood and fecal levels of ammonia and were better at it than lactulose. He found the study probiotics strains were able to convert ammonia to alanine to reduce ammonia levels. Astrocyte swelling is reduced with probiotic use and expression of Nrf2 has been shown to protect astrocytes from damage in hyperammonemia. Also, the probiotics decreased hyperammonemia by acting on the ammonia transporter and genetically-altered-probiotic-consuming NH3 strains reduced ammonia levels even farther. Recently, other studies show probiotics may be used effectively in IBS, colitis and Crohns and are able to modulate IL-10 an anti-inflammatory cytokine. This same cytokine is implicated in modulating sickness syndrome and is regulated by HO-1 which is modulated by Nrf2.

Alterations in cortico-releasing factors (CRF), a key regulator of cortisol in the brain have been associated with IBS, depression and anxiety. I recently wrote how hyperammonemia is associated with negative effects of cortico-releasing hormone(CRF) on mood and how high ammonia levels cause a number physiological effects in trout that are comparable to symptoms in sickness syndrome. These changes may include changes in dopamine and serotonin and the latter, may influence ammonia-mediated appetite suppression. While I hesitate to compare health conditions in humans to those in animals such as fish, these finding are interesting never-the-less. (Ortega) In mice, CRF effects similar behaviors including feeding, anxiety and activation of the sympathetic nervous system. Hyperammonemia alters the circadian rhythym of corticosteroids and motor activity in rats while not producing anxiety (Ahabrach) while flavanoids such as quercetin, can reduce CRF's activation of the HPA axis. (Kawabata)

Therer are any number of genes and polymorphisms that can effect metabolism that may lead to diseases of the intestinal tract or any organ for that matter and ammonia is just one of many. At present, scientists have only just begun to discover with the use of genetic studies to discover how these polymorphisms may differently effect the health of individuals and populations. There are many yet to be discovered. Genetic counselors can be a tremendous help in this respect, sometimes just by noting and being familiar with "patterns".  Dr. Yasko supplies a pretty good break-down of genetic conditions that may alter and contribute to high ammonia levels in one posted article but it is not all inclusive.  A genetic counselor I am not going to discuss each of the genes SNPs because the article is long and detailed but quite informative. She does note that ammonia regimines need to be monitored and sometimes changed and therefore, any therapeutic program that addresses genetic influences needs to be done in consultation with a physician. I have explained how different genetic conditions can impair proper ammonia excretion and much of that is explained in this paper. I am not a doctor and therefore will not comment on her treatments but have read about her practice in the literature. She points out a few things I found interesting including hazards associated with some "alternative" therapeutics including epsom salts, MSM and the consequence they can be metabolically be converted to ammonia and may effect the function of another enzyme. I have researched this enzyme and indeed, there may be some concerns with this enzyme in some people with environmental illnesses. This article in this respect and as a whole provides an interesting read and more importantly possibly warrants a discussion with your doctor. (Yasko) Because ammonia levels may influence autism and other conditions as mentioned above, I believe this discussion may be an important priority.

It is difficult to predict how endogenous and exogenous chemicals are going to react to produce health effects including increasing the tendency for chronic conditions like IBS and autoimmune-type inflammatory disease. A recent study demonstrated different mouse strains have different before and after levels of antioxidant genes including glutathione, Nrf2 and HO-1 and also have higher levels of oxidative stress upon exposure to cigarette smoke. It also demonstrates variations exist between individual organisms (mice) which may be comparable to differences in the immune response that might occur in individuals in different populations. From a population health standpoint, different populations may be more or less susceptible to exposures and consequently certain diseases. This potentially becomes more of a concern when there is a poor quality of health care system and disparities already exist in those populations. To support this idea, a study was released in 2007 that identified population differences exist in the Nrf2 gene and concluded they may make them more or less resistent to oxidative stress and lead to an increased prevalence of disease and lower quality of life. (Marzec) Conditions of mixed and chronic environmental stress where there is a reduction in the ability to activate and control the adaptive response has important and broad implications for the health status and adaptive ability of a population as a whole. Several years ago, one researcher found hydrazine, an agricultural product, had a negative effect on the B12-dependant methionine synthase pathway and as a consequence from homocysteine elevations impaired the urea cycle and sulphur amino acid detoxification. (Kenyon) Exposure to nitrous oxide (laughing gas) can deactivate B12 and potentiate impairments in the cyles that eliminate ammonia and in recent weeks, it was reported that exposure to the greenhouse gas nitrous oxide from home maintainance of lawns can be as significant as the amount produced by agriculture and therefore ubiquitous in the environment. With this in mind and in a mixed environment, the study on cigarette smoke mentioned earlier becomes more significant because in the past cigarettes have added ammonia to make themmaking them more addictive. In addition to the hundreds of contaminants in cigarette smoke, it also contains bacteria that may have the potential to cause infectious disease and contains endotoxin that elicits inflammatory responses. Interestingly, the absence of GSK-3b, the on and off switch for Nrf2, eliminates Tnf-a and NF-kappaB signaling from both endotoxin and cigarette smoke. (Takada) This suggests ammonia in cigarette smoke has the potential to down-regulate the Nrf2 system and may help explain the variety of health effects from these exposures and increased sensitivity to them in some individuals. In support the research by Hubner reported that Nrf2 plays "important roles in cellular defenses against smoking in the epithelium and there is variability within populations of oxidant burden. (Hubner) All of this, can lead one to assume that variants in the exposures to agricultural products, alterations in nutritional status and genetic variants may increase the likelihood of any number of diseases including irritable bowel syndrome and inflammatory bowel disease.

Finally, it is important to review some important general health consequences of high ammonia levels. As we have noted, hyperammonemia can be caused by enzyme deficiencies or liver disease and because liver damage and impairment of antioxidant systems are concerns upon exposures, high ammonia levels should be considered as a factor in patients with environmental illnesses. "Hyperammonemia does cause astrocyte swelling (acute hyperammonemia) to astrocytosis (chronic hyperammonemia) and when the urea cycle is impaired, changes to allow for the excretion of ammonia occur in the brain. Some of these changes include changes in glutamate regulation and drug receptors (benzodiazipine) in the mitochondria. Acute changes include activation of NMDA receptors (although some may argue this) and chronic hyperammonemia may cause increases in tryptophan metabolites including serotonin. As one author stresses, current therapies for hyperammonemia are mediated through reduction of ammonia levels through the gastrointestinal tract and increased ammomia in the muscle." (Butterworth) Further studies show that IDO, an enzyme involved in the catabolism of tryptophan, has protective qualities against certain immune reactions and this is achieved through T cell suppression. These findings may lead to more supportive evidence of a loss of T cell suppression and an increase in autoimmune responses in MCS reactions. Other studies show oxidative stress plays a role in the neuropathology of ammonia toxicity and cause derangements in the cerebellum and cerebral cortex that lead to both increasing or decreasing antioxidant levels in both of these areas in acute and chronic ammonia toxicity.(Singh)

For further emphasis:

• Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.

For Clinical Professionals:

Citations located here.

Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!

It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.

In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin)  While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.

To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation."  Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to  treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS."  If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.

Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain  fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP .  We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)

In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease.  (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)

Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown,  "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels  in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well.  (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)

I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl)  and supports that the AhR modulates Treg production (Mezrich) and they may  be a factor at least in some types of reactions to certain toxins.  It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.

As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis.  Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS.  Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue.  He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires".  This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff)  They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.

Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment.  The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis.  Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular."  In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)

Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan)  This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).

An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and  suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of  pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity.  The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)

I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of  GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so!  One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.





Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438.  http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168.  http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000.  http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191.  http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745