The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics.

"Transcription factor Nrf2 regulates genes encoding drug-metabolising enzymes and drug transporters, as well as enzymes involved in the glutathione, thioredoxin and peroxiredoxin antioxidant pathways......."

Read more: CiteULike: The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics

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

Understanding Gut Health -- Implications for MCS and Other EI Illnesses!

There is alot more than just oxidative stress involved in MCS and environmental illness and includes as research is showing more and more, epigenetic changes. In addition, the pathology of the intestines directly impacts the liver where elevations in cytokines including TNF-a and Il-1b lead to changes in gene expression and neuroinflammation in the brain. It is important to understand these interactions and how conditions in the gut can influence it to really get the whole picture of environmental illness including MCS.

Son, G., Kremer, M., and Hines, I. N. Contribution of gut bacteria to liver pathobiology. Gastroenterology Research and Practice, 2010.
http://www.citeulike.org/user/HEIRS/article/7550873

Ammonia and Its Relationship To Environmental Illness

Background: The build-up of excess ammonia has been implicated in environmental conditions such as autism and may contribute to physiological effects of others as well. In recent days, we have discussed how homocysteinemia may impair the urea cycle which may lead to excess ammonia levels and that some common treatments used for environmental illness also are used as treatments to reduce physiological ammonia levels. Exogenous environmental factors may also lead to elevations in ammonia. Interestingly, in fish, exposure to ammonia leads to symptoms one may conclude typical of sickness syndrome which includes loss of appetite. While it is difficult to extrapolate behavior in these animals to similar behaviors in humans, we have mentioned previously that sickness syndrome is not exclusive to the human organism and has been observed in other animals (ie domesticated dogs). In the recent study of fish, ammonia activates the stress regulator corticotropin releasing factor and other stress systems including the one that controls dopamine and leads to elevations in this stress hormone also. The activation of this system has also been implicated in psychological effects associated with PTSD in humans and addictive behaviors such as alcohol abuse.

Taken these studies into account, one would suggest that ammonia which also contributes to mitochondrial dysfunction may contribute to a number of environmental illnesses by activating different systems during the stress response and may exacerbate the complications associated with injury or down-regulation in function from toxic exposures to the liver.  In addition, there are several negative psychological and physical effects in environmental illnesses that can be attributed to abherrant signaling by GSK-3b which is modulated through the Wnt pathway.   As Burke writes, "The liver contains two systems for the removal of ammonia - the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/-c:atenin pathway[]." Experts admit there is a lot to learn about this relatively unexplored molecular pathway. However, the most recent evidence suggests it is an important pathway that interacts with other pathways in inflammation and acts as a crucial regulator of functions of different biological systems. Recent studies associate Wnt signaling in inflammation in adipocytes which is the major site for bioaccumulation of toxicants in the body.  This fact elevates the significance of this pathway in environmental health studies. Of course, further research is needed to identify the level of the role it plays on the physical and mental effects of exposures from environmental contaminants.

The Wnt/β-catenin pathway: master regulator of liver zonation?. Zoë D. Burke. 2006; BioEssays - Wiley InterScience

Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866. http://www.citeulike.org/user/HEIRS/article/6594636
Castelo-Branco, G., Rawal, N., and Arenas, E. (2004). Gsk-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci, 117(24):5731-5737. http://www.citeulike.org/user/HEIRS/article/6582306

ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

ImmunoGenetics in Autism, MCS and Cancer --
What Has Food Got To Do With It

Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.

B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.

Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.

To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)

The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!

Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.

An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.

Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.

Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.

New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).

In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.

It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.




Original document and citations

How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.

Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.

We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.

Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)

Click to view original document and citations.

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Nrf2 and Environmental Pollutants

Summary: The Nrf2 has an important role in detoxification of environmental pollutants. Alterations in Nrf2 function can influence environmentally-induced disease.

Rubio, V., Valverde, M., and Rojas, E. (2009). Effects of atmospheric pollutants on the nrf2 survival pathway. Environmental Science and Pollution Research. http://www.citeulike.org/user/HEIRS/article/4330390

Cigarette Smoking and Invasive Pneumococcal Disease - Implications for Severity of H1N1

Cigarette smoking is the strongest risk factor for pneumococcal disease among immunocompetant non-elderly people. (Nuorti) As we have noted, cigarette also disrupts the major antioxidant system Nrf2. A recent report has shown that pneumococcal disease makes complications from H1N1 much more severe. Because of the relationship of Nrf2 and its important influence on modulation of inflammatory processes. It is worth suggesting that the dysruption of Nrf2 may contribute to H1N1 infection complications and because there have been polymorphs in Nrf2 identified - these polymorphs may make a person either more at risk or less at risk for complications related to H1N1. The implications of this includes that unless a person understands these risk factors related to their own genetic makeup it is advisable to take a physician's advice that is based on recent knowledge and understanding instead of those who claim to be "experts" in environmental disease.


CiteULike: Cigarette Smoking and Invasive Pneumococcal Disease: "Nuorti, J. P., Butler, J. C., Farley, M. M., Harrison, L. H., McGeer, A., Kolczak, M. S., Breiman, R. F., and Team, T. A. B. C. S. (2000). Cigarette smoking and invasive pneumococcal disease. N Engl J Med, 342(10):681-689."


Tokairin, Y., Shibata, Y., Sata, M., Abe, S., Takabatake, N., Igarashi, A., Ishikawa, T., Inoue, S., and Kubota, I. (2008). Enhanced immediate inflammatory response to streptococcus pneumoniae in the lungs of mice with pulmonary emphysema. Respirology (Carlton, Vic.), 13(3):324-332. http://www.citeulike.org/user/HEIRS/article/2651950

Nuorti, J. P., Butler, J. C., Farley, M. M., Harrison, L. H., McGeer, A., Kolczak, M. S., Breiman, R. F., and Team, T. A. B. C. S. (2000). Cigarette smoking and invasive pneumococcal disease. N Engl J Med, 342(10):681-689. http://www.citeulike.org/user/HEIRS/article/6462894

Reddy, N. M., Suryanarayana, V., Kalvakolanu, D. V., Yamamoto, M., Kensler, T. W., Hassoun, P. M., Kleeberger, S. R., and Reddy, S. P. (2009). Innate immunity against bacterial infection following hyperoxia exposure is impaired in nrf2-deficient mice. J Immunol, 183(7):4601-4608.

Severity of H1N1 influenza linked to presence of Streptococcus pneumoniae. EurekAlert. December 31, 2009. http://www.eurekalert.org/pub_releases/2009-12/cums-soh123009.php

High Fat Diets Make One More Susceptible to Oxidative Stress and Environmental Illness!

Background:

• Obesity is also an important risk factor for a number of health conditions including diabetes and cardiovascular disease.
• Fatty liver disease is a condition where large amounts of fat accumulate in liver cells and is characteristic of metabolic syndrome. (Wipedia)

High fat diets decrease PGC-1a which is important for metabolic cellular processes, mitochondrial biogenesis and mitochondrial DNA synthesis. In addition, it decreases the expression of Nrf2 which is the master gene promoter that upregulates expression of genes important for the same process. The PGC-1a complex also controls another protein called Foxo3a which is an important modulator of aging. (Dong)

In addition to playing a role in redox homeostasis, Nrf2 modulates inflammatory mediators such as Tnf-a and MCP-1 and prevents lipid accumulation. Nrf2 is activated in response to toxicant injury and oxidative stress and is important for the detoxification of xenobiotics.
Tanaka's studies have shown the absence of Nrf2 increases susceptibility to toxicants including acetaminophen, hyperoxia, benzopyrene (found in smoke). He demonstrated that Nrf2 has important lipid metabolism and that feeding a high fat diet in the short term reduces Nrf2. He notes, other studies have shown long-term feeding of high fat diets increases Nrf2 and suggests this is an adapative response to oxidative stress induced by chronic fat accumulation. Generally, animals with lower Nrf2 present with elevated cholesterol levels and lower levels of Nrf2 results in the inability to prevent lipid accumulation, absence leads to greater retention of lipids in the liver (fatty liver disease) and greater oxidative stress including, oxidative stress in the mitochondria and the endoplasmic reticulum. Interestingly, Tanaka found that PGC-1a is reduced in high-fat diets but not in Nrf2 null mice which indicates the down-regulation of PGC-1a is dependant on Nrf2.

Summary: High fat diets reduce mitochondrial biogenesis, increases the likelihood for toxicant bioaccumulation and their overall toxic effects, increases oxidative stress, contributes to fat accumulation and obesity and impairs liver function which is an important organ for detoxification.

Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., and Ren, J. (2007). Metallothionein prevents high-fat diet–induced cardiac contractile dysfunction role of peroxisome proliferator–activated receptor
coactivator 1 and mitochondrial biogenesis. 56(9):2201-2212. http://www.citeulike.org/user/HEIRS/article/5724999
Tanaka, Y., Aleksunes, L. M., Yeager, R. L., Gyamfi, M. A., Esterly, N., Guo, G. L., and Klaassen, C. D. (2008). Nf-e2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther, 325(2):655-664. http://www.citeulike.org/user/HEIRS/article/4788030