Higher Levels of Pain Intensity in Multiple Chemical Sensitvity -Says Study

"this is the first study to show facilitated pain processing in MCS and EC patients with the most abnormal responses in MCS"

The Clinical journal of pain, Vol. 27, No. 2. (February 2011), pp. 156-162. Key: citeulike:8774097


Read more: CiteULike: Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity.:

Recommended: Chemical Sensitivity: A Guide to Coping With Hypersensitivity Syndrome, Sick Building Syndrome and Other Environmental Illnesses

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

Chemical Sensivity and Asthma -- Systems Theory and The Idea of Loss of Tolerance in Different Tissues!

In the last few years, environmental illness researchers have suggested that chemical sensitivity is related to a general loss of tolerance that may occur after an event such as bacterial or viral event. Of course, this would make sense given that an inflammatory event may lead to loss of tolerance through alterations in immune function and some experts believe a similar process is responsible for autoimmune-type reactions and a loss of T regulatory cells (Tregs). In general, Treg serve as a type of mediator for inflammatory conditions and modulates the type and severity of the immune reaction. In MCS, there is a loss of tolerance to chemicals in the environment at levels that normally do not effect a healthy individual. Interestingly, a recent study of asthma has shown that hypersensitivity airway responsiveness can be improved by boosting immunity in the gut. The fact that airway responsiveness can be improved through gut improvement helps to support the possibility that MCS immune dysfunction may begin in the intestinal tract or the lungs even though symptoms may not necessarily be respiratory or gut related. It has been known for two decades, the intestinal tract is an important regulator of immune and brain function but admittedly, little is known about the pathways or the process involved that makes the connections of the intestinal tract, the brain and the CNS. However, studies published last year identified inflammatory brain processes that effect gene regulation and neurotransmission can be the result of the activities of inflammatory mediators or cytokines in the gut and the liver.

Individuals with MCS often present with abnormal respiratory function and many that suffer from MCS propose they are more sensitive to carbon monoxide and hydrogen sulfide than others. I would suggest through observation this is also true of nitrous oxide and possibly other greenhouse gases and note here there have been reports of mood and behavior changes from exposures to higher levels of these gases. These reports are similar to many with MCS when they describe their reported reactive symptoms. Therefore these reactions could be the result from elevations in greenhouse gases in addition to other pollutants that combine to form explained additional "triggers".   Previously, I have suggested the loss of Nrf2 and its associated proteins such as HO-1 that regulate the gasotransmitters may be to blame and could lead to loss of tolerance or heightened reaction even to lower levels of "perceived" pollutants or chemicals in the environment.  Considering the levels of greenhouse gases are steadily increasing on the average in the environment with each decade-- the constant exposure to one may be reducing the tolerance to the cumulative total of the others or "potentiating" the effects. This brings to light an important health and policy concern since the "jury" is still out on how to reduce greenhouse gases with our present dependance on fossil fuels. Interestingly, you never really hear about the increases in greenhouse gases in relation to the causes and implications of MCS, even though it should be considered...

In any case, there is recent evidence the proteins that make up the xenobiotic detoxification system such as the Nrf2, AhR, and HO-1 may influence Treg regulation. For this reason, the effects of Treg deficiency and dysfunction should be considered why addressing the possible causes for increased sensitivities that are observed in those effected with environmental illness and why boosting gut immunity of systemic immunity may influence more than one organ system. In addition, it has been demonstrated that endotoxin a component of bacteria may lead to a heightened response from allergans. It could be endotoxic exposure leads to a heightened response to chemicals or contaminants whether endogenous or not and alterations in methylation from endotoxin may augment conditions of the "loss of tolerance" that that lead to and occur with environmental illness. Unfortunately, this "loss of tolerance" may also be the consequence of pathogens and contaminants that normally reside at low levels in different tissue and are present in the environment.




Strickland, D. H., Judd, S., Thomas, J. A., Larcombe, A. N., Sly, P. D., and Holt, P. G. (2010). Boosting airway t-regulatory cells by gastrointestinal stimulation as a strategy for asthma control. Mucosal immunology. http://www.citeulike.org/user/HEIRS/article/7560150
Chapman, J. T., Otterbein, L. E., Elias, J. A., and Choi, A. M. K. (2001). Carbon monoxide attenuates aeroallergen-induced inflammation in mice. Am J Physiol Lung Cell Mol Physiol, 281(1):L209-216. http://www.citeulike.org/user/HEIRS/article/7560177
Zhou, X., Kong, N., Zou, H., Brand, D., Li, X., Liu, Z., and Zheng, S. G. G. (2010). Therapeutic potential of tgf-beta-induced cd4(+) foxp3(+) regulatory t cells in autoimmune diseases. Autoimmunity. http://www.citeulike.org/user/HEIRS/article/7560254
Fousteri, G., Dave, A., Bot, A., Juntti, T., Omid, S., and von Herrath, M. (2010). Subcutaneous insulin b:9-23/ifa immunisation induces tregs that control late-stage prediabetes in nod mice through il-10 and ifngamma. Diabetologia, 53(9):1958-1970. http://www.citeulike.org/user/HEIRS/article/7299083

Elevating Tregs and Heat Shock Proteins in EI - The Role of Food and Exercise

Background: In a recent blog, we expressed an interest in a recent study that showed alterations in the distributions of suppressive T cells called Tregs which may influence environmental illness.(Micovic) According to the author, these cells are normally upregulated upon chronic inhalation of pollutants but in this case, the researcher noted a decrease in these suppressive cells. In other studies, a decrease in Foxp3 Tregs are often associated with autoimmune-like conditions. In addition, we also discussed a study the showed that particulate matter may alter "immunological footprints" and may lead to a autoimmune-like presentation. Also, regulatory Treg suppression plays a role in protection of striatal neurons and reductions of microglial neuroinflammation and alpha-synuclein and therefore, Tregs may play an important protective role in Parkinson's disease. It also suggests an explanation of how environmental exposures may contribute to PD and other neurodegenerative diseases. Catecholamines have been shown to downregulate the expression of Tregs and this is dependant on the expression of the dopamine D1-like receptors.

Other studies have revealed some insights into the relationship of Tregs and other proteing called heat shock proteins. Heat shock proteins are normally considered protective and often chaperone proteins during specific metabolic processes. De Zoeten recently showed that Tregs with HSP70 had more suppressive effects than those without. It was concluded that at least for this study of colitis, there was an important interaction with HSP70 and FoxP3+. Interestingly, a recent CFS study which is often co-morbid with colitis, demonstrated altered profiles of a number of heat shock proteins including HSP70 (Jammes) and suggested these proteins may be used as a biomarker for CFS. Wieten describes heat shock proteins as proteins that are normally upregulated in response to stress, including thermal and oxidative stress and inflammation and help prevent cellular damage by increasing the expression of anti-inflammatory T cells.

Weiten explains that by elevating the levels of heat shock proteins, an individual may be able to restore or increase their resistance to cellular stress. Weiten provides evidence that dietary phytonutrients can elevate levels of heat shock proteins. In his study, he found that several compounds found in food elevated HSP70 that elevated the expression of T cells. One such compound called carvacol is found in thyme and oregano. In other blogs, we have noted that the latter is associated with expression of PPAR-gamma which has anti-inflammatory properties. Hontecillas demonstrates in his research that PPAR-gamma can influence the activity of Tregs against inflammation. This seems to entail down-regulation of certain other T cells (Konturek) and as we have noted numerous times before, PPAR-gamma expression can be influenced by the expression of Nrf2.

Different studies have shown positive and negative consequences of exercise on environmental illnesses and this may be dependant on the levels of expression of a number of different proteins. In any case, it has been demonstrated that exercise positively influences the expression of HSP70.(Milne)Researchers from University of Alabama at Birmingham recently demonstrated that Treg cells in exercised mice increased cells with FoxP3+ and were better able to fascilitate suppression of inflammatory cytokines in an experimental model of murine asthama. In contrast, increasing age may negatively influence the expression of both Tregs and HSP70. Also, exposure to paraquat decreases expression of both HO-1 and HSP70 and increases oxidation of proteins. (Nakanishi) Muscle atrophy is often associated with aging and serious illness; the prevention of which can be influenced by the expression of HSP70. (Senf) Other studies show HSP are regulated through exercise-induced SIRT1 but interactions with HSP regulation is not the only way SIRT1 is involved in immune regulation. Reports now show that the dysregulation of SIRT1 leads to abnormal T cells responses and loss of tolerance and the development of autoimmunity. Zhang explains that while SIRT1 regulation is required for normal T cell activity, this responsibility does not involve maintaining Treg function or Th17 but does involve control of autoreactive T cells. In contrast, van Loosdregt mentions that use of HDAC inhibitors may be an alternative method for modulating FoxP3+ in Tregs. So it seems, the level of involvement of SIRT1 of Treg function is not at all clear and needs further study. In any case, the findings of the studies above, definitively demonstrate the importance of both Nrf2 and SIRT1 in regulation/dysregulation of immune function in a number of environmental illnesses.


Mićović, V., Vojniković, B., Bulog, A., Coklo, M., Malatestinić, D., and Mrakovcić-Sutić, I. (2009). Regulatory t cells (tregs) monitoring in environmental diseases. Collegium antropologicum, 33(3):743-746. http://www.citeulike.org/user/HEIRS/article/6090770
De Zoeten, E. F., Wang, L., Sai, H., Dillmann, W. H., and Hancock, W. W. (2009). Expression of hdac9 by t regulatory cells prevents colitis in mice. Gastroenterology. http://www.citeulike.org/user/HEIRS/article/6553713
Wieten, L., van der Zee, R., Goedemans, R., Sijtsma, J., Serafini, M., Lubsen, N. H., van Eden, W., and Broere, F. (2010). Hsp70 expression and induction as a readout for detection of immune modulatory components in food. Cell stress & chaperones, 15(1):25-37.
http://www.citeulike.org/user/HEIRS/article/4675555
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1).
http://www.citeulike.org/user/HEIRS/article/6553728
Nakanishi, Y. and Yasumoto, K. (1997). Induction after administering paraquat of heme oxygenase-1 and heat shock protein 70 in the liver of senescence-accelerated mice. Bioscience, biotechnology, and biochemistry, 61(8):1302-1306.
http://www.citeulike.org/group/7833/article/6553731
Konturek, P. C., Dembinski, A., Warzecha, Z., Burnat, G., Ceranowicz, P., Hahn, E. G., Dembinski, M., Tomaszewska, R., and Konturek, S. J. (2005). Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World journal of gastroenterology : WJG, 11(40):6322-6329.
http://www.citeulike.org/user/HEIRS/article/6553866
Hontecillas, R. and Bassaganya-Riera, J. (2007). Peroxisome proliferator-activated receptor gamma is required for regulatory cd4+ t cell-mediated protection against colitis. Journal of immunology (Baltimore, Md. : 1950), 178(5):2940-2949.
Milne, K. J. and Noble, E. G. (2002). Exercise-induced elevation of hsp70 is intensity dependent. Journal of applied physiology (Bethesda, Md. : 1985), 93(2):561-568.
http://www.citeulike.org/user/HEIRS/article/6553732
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1). http://www.citeulike.org/user/HEIRS/article/6553728
Lowder, T., Dugger, K., Deshane, J., Estell, K., and Schwiebert, L. M. (2010). Repeated bouts of aerobic exercise enhance regulatory t cell responses in a murine asthma model. Brain, behavior, and immunity, 24(1):153-159. http://www.citeulike.org/user/HEIRS/article/5842541
Reynolds, A. D., Banerjee, R., Liu, J., Gendelman, H. E., and Mosley, R. L. (2007). Neuroprotective activities of cd4+cd25+ regulatory t cells in an animal model of parkinson's disease. Journal of leukocyte biology, 82(5):1083-1094. http://www.citeulike.org/user/HEIRS/article/6554146
Cosentino, M., Fietta, A. M., Ferrari, M., Rasini, E., Bombelli, R., Carcano, E., Saporiti, F., Meloni, F., Marino, F., and Lecchini, S. (2007). Human cd4+cd25+ regulatory t cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood, 109(2):632-642. http://www.citeulike.org/user/HEIRS/article/6554165
Iwata, S., Shimizu, T., Nomoto, M., and Fukuda, T. (1996). Characteristic upregulation of dopamine d1-receptor in rat striatum after 6-hydroxydopamine treatment. Japanese journal of pharmacology, 71(3):255-258.
http://www.citeulike.org/user/HEIRS/article/6554215
It is Hot in Here, or is it Just SIRT1. SIRT1 Activate Heat Shock Transcription. Retrieved on January 16, 2010.
Zhang, J., Lee, S.-M. M., Shannon, S., Gao, B., Chen, W., Chen, A., Divekar, R., McBurney, M. W., Braley-Mullen, H., Zaghouani, H., and Fang, D. (2009). The type iii histone deacetylase sirt1 is essential for maintenance of t cell tolerance in mice. The Journal of clinical investigation, 119(10):3048-3058.
http://www.citeulike.org/user/HEIRS/article/6554270
Jammes, Y., Steinberg, J. G., Delliaux, S., and Brégeon, F. (2009). Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and hsp responses. Journal of internal medicine, 266(2):196-206. http://www.citeulike.org/user/HEIRS/article/4695048

Chemica Pollutants and Itching: What Does Nerve Growth Factor Have to Do With It?

Background: Nerve growth factor (NGF) is a neurotropin that is important for the growth and survival of neurons and is believed to be important to preventing neural degeneration (in some cases and not others) and is present in larger amounts in inflamed tissue. (Wipedia, Pehar) On the other hand, it upregulates nociceptors and may play a role in neuropathic pain.  Altered nociception and ASICs signaling have both been implicated as a factors in multiple chemical sensitivity (Pall) and other environmentally-induced health conditions. In certain studies it has also been shown that the level of NGF is correlated to the severity of itching in atopy. Toluene is an air pollutant and is found in low or high amounts in homes and commercial buildings.

Two studies may shed more light on understanding the "itch" that is commonly associated with some cases of environmental illness. The first study provides an explanation of how air pollutants, in this case, toluene effects physiological systems. According to the first study findings, low-level toluene induced a significant increase in CCL2 (MCP-1) and CCL3 and cells positive for nerve growth factor while showing insignificant markers for oxidative stress and HO-1 in controls and immunized mice. Immunized mice were treated to model allergic animals. The findings of this study show that volatile organic compounds (ie toluene) enhance nerve growth factor production and airway inflammation is more severe in allergic animals.(Fujiama) Interestingly, another study, shows that dioxin, an activator of the AhR, caused itching when the experiment animal was exposed to another generally inocuous stimulus. In the study, it was demonstrated that the itching of this type was alleviated with pharmaceuticals that reduce skin levels of NGF. (Ono)

HEIRS Library Tags: nerve growth factor

Notes:

• There is an important relationship of Nrf2 and HO-1 in the consequences of activity by nerve growth factor which may include reduction of ROS and protection against endogenous environmental insults including dopamine toxicity. (Salinas)

Fujimaki, H., Tin-Tin-Win-Shwe, Yamamoto, S., Nakajima, D., and Goto, S. (2009). The expression of nerve growth factor in mice lung following low-level toluene exposure. Toxicology letters, 191(2-3):240-245. http://www.citeulike.org/user/HEIRS/article/5808711#
Pall, M. L. and Anderson, J. H. (2004). The vanilloid receptor as a putative target of diverse chemicals in multiple chemical sensitivity. Archives of environmental health, 59(7):363-375. http://www.citeulike.org/user/HEIRS/article/5911051
Diogenes, A., Akopian, A. N., and Hargreaves, K. M. (2007). Ngf up-regulates trpa1: Implications for orofacial pain. J Dent Res, 86(6):550-555. http://www.citeulike.org/user/HEIRS/article/3682087
Yamaguchi, J., Aihara, M., Kobayashi, Y., Kambara, T., and Ikezawa, Z. (2009). Quantitative analysis of nerve growth factor (ngf) in the atopic dermatitis and psoriasis horny layer and effect of treatment on ngf in atopic dermatitis. Journal of dermatological science, 53(1):48-54. http://www.citeulike.org/user/HEIRS/article/6453209
Ono, R., Kagawa, Y., Takahashi, Y., Akagi, M., and Kamei, C. (2009). Effect of 2,3,7,8- tetrachlorodibenzo-p-dioxin on scratching behavior in mice. International immunopharmacology. http://www.citeulike.org/user/HEIRS/article/6409196
Pehar, M., Vargas, M. R., Robinson, K. M., Cassina, P., Diaz-Amarilla, P. J., Hagen, T. M., Radi, R., Barbeito, L., and Beckman, J. S. (2007). Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J. Neurosci., 27(29):7777-7785. http://www.citeulike.org/user/HEIRS/article/3733200?updated=1262024743
Salinas, M., Diaz, R., Abraham, N. G., Ruiz de Galarreta, C. M., and Cuadrado, A. (2003). Nerve growth factor protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner. Journal of Biological Chemistry, 278(16):13898-13904. http://www.citeulike.org/user/HEIRS/article/6456500

General and Applied Toxicology - Includes a section written by MCS researcher Dr. Pall, Ph.D.

Multiple Chemical Sensitivity, Altered Brain Responses and Ups and Downs Of BDNF

 Multiple Chemical Sensitivity, Altered Brain Responses

and Up and Down Regulation of Proteins

 

Multiple chemical sensitivity is characterized by a heightened physical and emotional sensitivity to "agents" such as fragrance and chemicals in the environment.  A recent study that was posted on The Canary Report documents new research that supports the fact that MCS has neurogenic origins. While the idea is not new, this study provides SPECT imaging results that show abnormalities in MCS patients.  According to the author, the findings show neurocognitive impairment and disfunction in the areas of odor-processing. (Orriols) A past study showed similar alterations in odor processing without neural sensitization and suggests MCS hypersensitivity is a result of alterations in the top-down regulation of the odor-response. (Hillert) I suggest that some of the effects of MCS may be a consequence of alterations in the production of BDNF which plays a role in the regulation of olfactory bulb neurogenesis.
 

In past blogs, we have mentioned a neuropeptide brain-derived neutrophic factor. BDNF is important for long-term survival of neurons including those involved with learning and memory and control of downstream targets including neurotransmitters such as dopamine and glutamate. (Paredes) It also is important for olfactory neurogenesis and fine odor discrimination and function and its functions suggests critical importance for detecting and processing of changes in the environment, ie. odors. (Yuan) In recent years, research had identified certain functions of BDNF although there is still much to be learned. These findings include important roles in glucose and cognitive function regulation. More importantly it increases NAD+ levels which would suggests it elevates SIRT1 and protects against excitoxicity. (Liu) SIRT1 is an important regulating protein that upregulates regulatory proteins and acts through PGC-1a which is necessary for  mitochondrial biogenesis. In addition, it interacts with Nrf2 and other proteins to maintain cellular homeostasis. One study showed women with impaired insulin function such as insulin resistance and diabetes had lower BDNF levels than controls. Women with higher BDNF has poorer explicit memory and this suggests higher levels of BDNF may not always be indicative of good health but is probably a mechanism to respond to damage. (Arentoft) Markham shows that neutrophins like BDNF can not only modify neuronal plasticity but also modifies brain metabolism and increases mitochondrial function which can have both positive and negative tissue-specific effects.

 

Parkinson's disease is neurodegenerative condition that has been linked to environmental toxin exposure and in one study it was demonstrated that carnosis acid (CA) in rosemary can reduce the down-regulation of BDNF from the pesticide dieldrin which is no longer used but may be present in the environment and tissue because it is bioaccumulative.  This author explains that CA "safeguards dopaminergic neuronal cells from environmental neurotoxins by enhancing brain-derived neurotrophic factor and repressing apoptotic molecules."  Many have noted that pesticides can mediate the development of MCS and alteractions in gene regulation, such as BDNF, provides one explanation of why these exposures have a long-term impact on cognitive function. (Park) This study demonstrates that BDNF protects dopamine cells and might suggest  lower levels of BDNF may produce aberrant behaviors controlled by dopamine including changes in mood and addictive behavior. A just published study has also implicated a decrease in glutaminergic neurotransmission may also be a factor in learning and memory deficits from dieldrin.  Other environmental factors such as high-fat diets significantly reduces BDNF levels enough to alter cognitive function regulation and aggravates effects of brain injury. (Wu) One author is quoted as saying, "when you have adquate levels of BDNF, then memories do not come back to haunt you...which
seems reminiscent of the more behavior-influencing effects of PTSD.
 

In addition, it has been demonstrated the stress response including the secretion of cortisone has an impact on the production of BDNF and if stress persists for too long this can lead to atrophy of the hippocampus. Zhou proposes cortisone inhibits long-term potentiation. This, he says, is mediated by a presynaptic mechanism and this mechanism may involve the decrease in BDNF expression. BDNF has been implicated as a factor in a number of mental health conditions including depression and schizophrenia. Behavioral factors such as exercise, calorie restriction and antidepressants increase levels of BDNF and as numerous studies have demonstrated, these factors can also reduce mental health symptoms including those for depression. (Daney)
 

For several years, researchers have studied drugs in a class of AMPAkines for treating a variety of conditions such as schizophrenia, problems with attention span and alertness and memory problems associated with dementia and Alzheimer's. Interestingly, this class of drugs also significantly elevate BDNF and also LTP which is an indicator for memory formation. (Daney) Alterations in BDNF levels have been associated with fear-induced olfactory learning which suggests a possible connection to MCS and the behavioral changes that may occur when a person with MCS is confronted with an offending "odor". However, Jones argues that a stressor and odor exposure must occur together for fear-induced olfactory learning and one might suggest that the stressor may come from the immune response itself. In any case, it again provides proof that BDNF influences the olfactory system and very well could intensify the behavioral aspects of MCS.  In other blogs, I have mentioned odors activate the TRP receptors and consistent and long-term activation can lead to endoplasmic reticulum stress, cellular dysfunction and possible alterations of the "adaptive pathway" Nrf2 through PERK and subsequently negatively impact subsequent immune responses to offensive and hazardous stimuli. Activation of Nrf2 can be dependant or independant of oxidative stress. (Ho)      
 

Imbalances in cellular homeostasis can lead to overexpression of BDNF and pain generation. Norman explains neuropathic pain and depression are often co-morbid and demonstrated how nerve injury produces inflammation resulting in both allodynia and depression-like symptoms and Il-1b. (This of course sounds a lot like sickness syndrome even though the author does not mention it.) The study also demonstrated that chronic stress exacerbated the levels of neuropathic pain, depression, Il-1b and elevated BDNF levels may be compensatory like it was suggested in the paragraph above. Application of a corticosteroid inhibitor prevented the effects of the stress and an inhibitor of Il-1 prevented the depression and the neuropathic pain. (Norman)

Numerous studies have suggested environmental illnesses may be due to the dysregulation of insulin and glucose homeostasis on specific receptors that regulate inflammation and cellular function and it is my belief this is true of MCS.  Several studies have shown that cyokines can influence the regulation of gene expression and there is no reason this is not also true of MCS. As the author suggests, MCS may be the result of abnormal odor processing after chemical exposure and the effects include cognitive impairments. TRPV1 has been implicated as an important factor in the development of MCS (Pall) and also in neuropathic pain (Wipedia) and recently, it has been demonstrated altered TRPV1 function may play a role in diabetes. (Pabiddi) BDNF have been shown to be elevated in fibromyalgia and as Martin-Lavin explains it has been suggested fibromyalgia is in part, neuropathic pain and suspected to be a consequence of abnormal summation of pain and spinal-cord reflexes. (Martinez-Lavin) Other studies have demonstrated that insulin and IGF-1 potentiates the activity of TRPV1 through PKC (Van Burnen)  and several reports suggest chemical exposure causes inflammatory responses that induce insulin resistance and hyperglycemia which can impair mitochondrial function. In addition, a growing body of evidence links obesity and diabetes and the "removal" of TRPV1 fibers improve pain decreases weight gain and improves glucose tolerance both in high-fat diets and diabetic models. As we have noted, chemical bioaccumulation mimic the effects and are exacerbated by high-fat diet models and therefore, these findings are of importance to studies of the impact toxic injury on metabolism.  Experiments changing TRPV1 function prevents pancreatic beta cell destruction and autoimmune diabetes and (Suri) hyperglycemia can elevate reactive species which activates TRPV1 expression and at higher levels cause cell death. Earlier we mentioned that insulin function can regulate BDNF and alterations in levels are associated with insulin resistance and diabetes. Exercise increases levels of BDNF but excess energy production from exercise or a high-calorie diet can increase ROS and cause cellular overload and reductions in BDNF and cognitive function. (Go'mez-Pinilla) Recent findings have shown that both BDNF and GDNF (another neural factor) can regulate the expression of TRPV1 and TRPA1 (in a slightly different manner) leading to enhanced neuronal sensitivity to stimuli and elevations in other receptors.  (Ciobanu)

 

Next Research Blog:

• What the Light Study on Chronic Fatigue Syndrome Says and What It Does Not Say!

Library Resources:

• BDNF

Citations and References:

 

Video Report Posted By The Canary Report - Watch and then read our thoughts.....

Here is a blog from The Canary Report about a woman suffering from chemical sensitivy. Watch the video and then read our thoughts....

We have discussed before that we believe the Nrf2 system may be an important route or root (whichever way one looks at it) to environmental illness and chemical sensitivity and have noted in other blogs just a few of the factors that can impair the Nrf2 system. In this video, one sees how people suffer from this condition..and as the author of The Canary Report notes it is sloppy reporting...and somewhat offensive use of language.




*After viewing the video, check out the reference link below...and then the one to our page on HEIRS homepage.


Related references:

Potential Protection Against Aflotoxin-Induced Tumorigenesis Through The Induction of Nrf2 Pathway by CDDO-IM.
New Science: Toxicity Testing in the 21st Century: A Vision and A Strategy (2007)
Expression of the aflatoxin b1-8,9-epoxide-metabolizing murine glutathione s-transferase a3 subunit is regulated by the nrf2 transcription factor through an antioxidant response element
More about Nrf2: HEIRS Blog, HEIRS Library, HEIRS-online Website. Yahoo access has been blocked from the library. Sorry.







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The Ahr and Nrf2 in White Adipose Tissue

Background: There is interaction between the AhR and the Nrf2. The latter decreases as a consequence of aging as well as other factors including insulin resistance/IGF resistance from oxidative stress as a result of ROS which may occur from toxicant exposure. Recent information provides evidence that Nrf2 plays a homeostatic function in adipose tissue and obesity. The AhR has been demonstrated to play a role in fatty liver disease. The Nrf2 plays a role in the expression of the AhR and its downstream targets and inhibits adipogenesis through AhR signaling. Shin explains that "tighter coupling between the AhR and the Nrf2 may result in the attuation of health risks by xenobiotics." He further explains that Nrf2 upregulated cytoprotective enzymes and CYPs through AhR.


Yoshinari writes, "The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues......both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.


Yoshinari, K., Okino, N., Sato, T., Sugatani, J., and Miwa, M. (2006). Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants. Drug Metab Dispos, 34(7):1081-1089. http://www.citeulike.org/group/7376/article/783432
Beyer, T. A., Xu, W., Teupser, D., auf dem Keller, U., Bugnon, P., Hildt, E., Thiery, J., Kan, Y. W. W., and Werner, S. (2008). Impaired liver regeneration in nrf2 knockout mice: role of ros-mediated insulin/igf-1 resistance. The EMBO journal, 27(1):212-223. http://www.citeulike.org/user/HEIRS/article/2067919
Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G. H., Agoston, E. S., Yamamoto, M., and Kensler, T. W. (2007). Nrf2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. Mol. Cell. Biol., 27(20):7188-7197. http://www.citeulike.org/user/HEIRS/article/3787182

Dysregulation of Vascular Neutrophic Factors May Promote Nasal Inflammation, MCS, etc. Study Says!

Neutrophic factors modulate a number of processes during inflammation including those that regulate nociceptive behavior. For this reason, alterations in neutrophic factors may "provide a rational basis for responses to odorants in conditions such as MCS, hyposmia and rhinitis" according to Baraniuk. BDNF is a neutrophic factor that regulates neurons in the striatum and is produced in endothelial cells in vessels. Alterations in BDNF synthesis ie. from vascular damage or down-regulation may impair neuron generation in the striatum which is a structure new neuronals cells pass en route to the olfactory bulb. Overexpression of HO-1 protects dopaminergic neurons by upregulating BDNF/GDNF and reducing the synthesis of Tnf-a and Il-1b in substantia nigra and inhibited the reduction of striatal dopamine content.

Watch how neurons migrate along blood vessels. A video post by the Neurophysiology Blogger. See source citation below.


In 2006, Nakason demonstrated that deprenyl, a therapeutic drug used for Parkinson's disease, shows a cytoprotective effect by mediating the induction of HO-1 through Nrf2 and other antioxidants and included upstream activation of neurotrophin TrkB.


Baraniuk, J. N. and Merck, S. J. (2009). New concepts of neural regulation in human nasal mucosa. Acta clinica Croatica, 48(1):65-73. http://www.citeulike.org/user/HEIRS/article/5770471
Hung, S.-Y., Liou, H.-C., Kang, K.-H., Wu, R.-M., Wen, C.-C., and Fu, W.-M. (2008). Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl-4-phenylpyridinium-induced neurotoxicity. Mol Pharmacol, 74(6):1564-1575. http://www.citeulike.org/user/HEIRS/article/5770649
Nakaso, K., Nakamura, C., Sato, H., Imamura, K., Takeshima, T., and Nakashima, K. (2006). Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: Pi3k and nrf2-derived induction of antioxidative proteins☆. Biochemical and Biophysical Research Communications, 339(3):915-922. http://www.citeulike.org/user/HEIRS/article/5770676
Author Unknown. New cells in the adult brain migrate long distances by crawling along blood vessels. Neurophysiology Blogger. Retrieved on September 9, 2009.

Hydrogen Sulfide, Cigarette Smoke, Endotoxin and Particulate Matter -- The Toxic Effects They Have In Common!

Different chemicals have different modes of toxicity which can reduce, be additive or potentiate the effects of the others and alter other metabolic processes such as insulin release and activities of Nrf2 cell signaling.  Take four example, the four toxicants endotoxin, hydrogen sulfide (H2S), cigarette smoke and particulate matter. These pollutants are all common in the environment and can cause negative health effects in those that are susceptible, have certain chronic illnesses and/or multiple chemical sensitivity. Interestingly, one will note that all four are found in tobacco smoke and therefore, this probably makes cigarette more toxic at lower levels than each of the different agents on their own.

First of all, lets review a few important details about each of these toxicants. Cigarette smoke contains acrolein which is an aldehyde that has been implicated in the development of neurogenic inflammation. Cigarette smoke also has hundreds of chemicals. Some that have been identified and some that have not. The toxicity of many of the toxicants that have been identified are still unknown. Particulate matter (PM)are particles that are present in air pollution and reduce air quality. Their presence at higher levels are an irritant to almost anyone but at lower levels they may become irritants to individuals with special health conditions such as those patients with asthma and COPD. For PM, size matters! Finer particles are better able to travel down the windpipe and absorb into the lower lung tissue's protective layer and induce inflammation. Ultra-fine particles also have more surface area to bind chemicals which can elevate inflammatory responses even further. Exposures to hydrogen sulfide can be from endogenous sources such as intestinal bacteria or from production in the different cells. As we have noted, major sources of exogenous sources of H2S are from bacteria in contaminated drinking water from wells and groundwater and the waste of large animals feeding operations (CAFOS) that end up in rivers and streams. Of course, the source of endotoxin can be from those same sources but other sources include bacteria on food, smoke from wood and tobacco smoke, water-damaged buildings, animals, and from indoor contaminants like dust in the home and commercial and occupational settings. Contrary to popular belief, endotoxin is one of the most common pollutants in the environments because it can be found almost anywhere especially where there is water and is so small, that there is little, if any technology that is available to get rid of it. For instance, very few models of air filtration units have the ability to filter gram-negative bacteria which is the source of most endotoxin. 

Hydrogen sulfide has the ability to cause any number of health effects including death at high levels. As we noted above, it is produced endogenously by bacteria in the gut in addition to other cellulars sources including adipocytes (Fang) and the pancreas (Harrison). It has been shown that long-term exposure to endogenous hydrogen sulfide can impair the function of beta cells in the pancreas which may lead to insulin resistance and diabetes. Researcher's now believe that one way this occurs is through the generation of inflammatory processes from Il-1b that is produced by the liver may drive the inflammatory processes that effect the beta cells. Endotoxin has been associated with liver inflammation and inflammation in the liver has been associated with activation of neuroinflammation and sickness syndrome. Changes in Nrf2 signaling have been associated with insulin resistance and may be due to reductions in insulin secretion by damaged beta cells (Harrison) from H2S produced by pancreatic cells altering KATP channels and also from Il-1 production in the liver exerting a peripheral effect on pancreatic beta cells. Insulin has been shown to be an important signaler for HO-1 and Nrf2 under normal conditions. Harrison describes a five-fold increase in heme oxygenase -1 mRNA and a 4-fold increase expression in kidney epithelial cells by insulin induction. Long-term exposure to intestinal bacteria or other processes that produce copious amounts of H2S that activate cellular signal like nociceptors when detoxification is overwhelmed and cause pain, alter the microbiota and interact immunologically to cause inflammation that may contribute to autoimmune-type reactions. Also, the initiation of inflammatory processes in the liver and impaired insulin and Nrf2/HO-1 signaling and diabetes can generate long-lasting inflammatory processes in the brain and other peripheral complications may even be more detrimental. (Ehses)

It is interesting to note that both high levels and low levels of H2S are associated with diabetes. Dr. Whiteman from the Northcott Devon Medical Foundation reports reduced levels of H2S in the blood of patients with diabetes. Lower levels of H2S were found to be important clinical markers for microvessel functioning which is an important complication of diabetes (ScienceDaily). Considering that Nrf2 modulates the effects of H2S from HO-1,this has important implications for the role of Nrf2. Maybe homeostasis becomes unbalanced at both high and low H2S levels which may be a consequence of impaired Nrf2 signaling. Oh describes that H2S and Ho-1 can inhibit the damaging effects of NO and NF-kappaB from LPS endotoxin and that down-regulation of H2S/CSE in lung injury pathology includes down-regulation of NO/iNOS and upregulation of CO/HO-1 (Zhou). (Jee whiz, I feel like I am on a roller coaster ride - up, down, up, down! Just kidding!) The point here is how we see the modulation of two neurogasotransmitters.

Recently it has been reported that antagonizing TRPA1 channels for a prolonged period reduces some of the symptoms associated with diabetic hypersensitivity (Wei). Hyperglycemia is an important consequence of insulin resistance and diabetes which produces alterations in mitochondrial function and as Bonnard shows from his findings the mitochondrial dysfunction is a consequence of insulin resistance and result of ROS generation in diet-induced diabetic mice. Diet is an important source for the ingestion and propagation of intestinal bacteria in the intestinal tract. Mitochondrial dysfunction generates reactive species especially H2O2 from NADPH which can alter cell signaling and cause further damage to cells.

Fibromyalgia is suspected to be at least in part, a condition associated with neuropathic pain in which nociception plays an important role. Ro presents evidence that both TRPV1 and TRPA1 contribute to muscle nociception and hyperalgesia and elevations inflammatory mediators, H2O2 and other ROS increase their expression as well as, sensitize them. In addtion, chronic and consistent activation of TRP channels may lead to endoplasmic reticulum stress and the effects of ER stress are usually attenuated through HO-1 (Liu) but Fallahi shows in his presentation that Nrf2 signal decline following activation of the ER stress response. Andre explains aldehydes, which acrolein is one in cigarette smoke and also present in cooking oil and combustive products, are the main cause of neurogenic inflammation mediated through TRPA1 and suggests this channel may add to smoking pathologies. Acrolein also triggers endoplasmic reticulum stress. Haberzetti writes acrolein is also produced from the metabolism of numerous drugs, in addition to be a major irritant in cigarette smoke and through his observations, he determined that exposure to acrolein induces ER stress including the unfolding response and implicates NF-kappaB and production of cytokines as important factors in the process. Zhang demonstrated that acrolein up-regulates HO-1 through the gene promoter Nrf2 and silencing Nrf2 attenuated significantly the response of HO-1 to acrolein. The result of which could include an increase in the toxic effects of smoking. From this study one can see that Nrf2 knock-out would increase sensitivity in the respiratory tract to cigarette smoke.  Roy reveals further details in showing that acrolein can either lead to an adaptive response at low doses, presumably through the up-regulation of HO-1 through Nrf2 or lead to death processes. At higher doses, mitochondrial-induced apoptotic processes are more apt to ensue. This is also the case if the adaptive process can not mitigate the effects of the toxicant.

Nociceptive behavior seems to be an important part of many of the environmental illnesses including fibromyalgia, airway hypersensitivity and other lung disease, degenerative diseases and multiple chemical sensitivity(MCS), just to name a few. One symptom often reported by those who suffer from MCS is a chronic and annoying cough from cigarette smoke and air pollution. Birrell recently showed that activation of TRPA1 by its agonists can lead to chronic cough and incidentally the "agent" he used in his experiment was acrolein which activated both TRPA1 and vagal nerves. The author points out that current cold remedy treatments are usually not effective for this kind of cough and there a number of TRPA1 ligands, and therefore are number of TRPA1 triggers that can generate a cough. This study might help to explain the persistant cough in many MCS patients. Of course, many chemicals can bind to particulate matter and therefore activate TRPA1 receptor and stimulate chronic cough. Caterina notes that TRPA1 can be activated in a different manner than just binding and this is achieved by TRPA1 ligands attaching themselves to cysteine residues on the channel which may change the structure and lengthen the time of activation. Bang explains that activators of TRPA1 are reactive eletrophile species. Meaning they are all able to effect gene expression by reacting with nucleic acids, proteins and other small molecules (Farmer) and include acrolein, mustard oil, iodoacetamide etc.  In addition, there are also non-electrophile activators which include menthol, THC, camphor and others. (Bang) TRPA1 also reacts to the ROS, H2O2. In addition, these compounds induce the expression of the enzymes of the Nrf2 detoxification system. Caterina explains, "there may be a so-far unexplained mechanism of cooperation between Nrf2 and TRPA1 that has not been identified". He could be referring to the now understood role of nociception and the ER stress response which involves PERK/Nrf2 or may be referring to some other mechanism. Madeira demonstrates that H2S is protective against gastic damage and in a similar study this is achieved by the down-regulation of NO and the up-regulation of CO/HO-1. He also suggests that TRPV1, at least in this case, plays some part in this protection. The similarities between Caterina's and Madiera's study are worth noting and may suggest interaction between TRP receptors and Nrf2 is important for the protective benefits of the gasoneurotransmitters.

The aryl hydrocarbon (AhR) may be another important factor in multiple chemical sensitivity. In addition to smoke mediated COX-2 and prostaglandin production and contributing to inflammation induced lung disease, the AhR is involved in the detoxification of polyaromatic and polyhalogenic hydrocarbons. Both classes include a number of chemicals that are present in the environment and used in manufacturing and agriculture. Also, abherrant functioning of the AhR is believed to be responsible for mediating the toxicity of dioxins which is also in cigarette smoke. In addition, to the ER stress response activation from cigarette smoke. Cigarette smokes also activates the AhR and also alters adipocyte differentiation and down-regulated the expression of adiponectin, PPAR-gamma and other markers and elevated MCP-1(Shimada) . There may be some negative control of the Nrf2/HO-1 pathway by cigarette smoke which can elevate levels of adiponectin and suppress levels cytokine levels (Kim). The absence of the aryl hydrocarbon is responsible for toxicities of other chemicals as well. It was reported last week that endotoxin which has been shown to be a trigger for chronic fatigue syndrome, is detoxified by the activities of the aryl hydrocarbon. Any dysfunction in this protein could lead to unexpected consequences and an increased sensitivity to endotoxin. It is important to remember here that Nrf2 is both modulated and modulates the AhR. Abnormal signaling by either one could lead to consequences related to toxicity. In addition, the beneficial activities of the AhR are inhibited by Tnf-a. Impaired Nrf2 which modulates the inflammatory mediator will only add to toxic effects in a negative way. Recent studies show endotoxin  causes endoplasmic reticulum failure "possibly by actions of the mitochondria" which would lead again, to reduction of Nrf2 (Koslov).   Endotoxin is extremely common in the environment in air and water pollution and therefore, it should be of particular concern for those with multiple chemical sensitivities as well as other conditions including those with dysfunction in immune regulation.

Related Reference:

• Slide Presentation: Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress.

Citations and Original Document

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

Biological and Behavioral Factors: Increasing the Risk for Environmental Disease Development!

Background: Chen explains, "GSK3b is like an on/off switch for the detoxification system Nrf2. Endoplasmic reticulum stress can be caused by consistent and long-term activation of nociceptors as well as, abnormal dopamine flux by genetic alterations or environmental insults like the abuse or use of certain drugs. Dopamine-generated ER stress can activate the GSK3b response through PP2A that leads to neuronal death. This is the type of neuronal death that has been implicated in the neural degeneration seen in Parkinson's disease. Indications of ER dysfunction include unfolded protein response and may also activate the NF-kappa B inflammatory pathway. Other studies have shown it may be important in acute brain injury and other chronic degenerative diseases including Alzheimer's. GSK3b activity has been shown to be regulated by ER stress, oxidative stress, heat shock and and hyperosmosis."

• GDNF and BDNF provide protection against GSK3b but may be down-regulated in some instances of environmental illness.
• Inhibition of PP2a result in the inhibition of GSK3b activation leading to apoptosis (programmed cell death).
• Ceramide-dependant activation of PP2a leads to the downregulation of Nrf2. (Hagan)
• (R)-alpha-lipoic acid (LA) has been shown to positively regulate the gene expression of Nrf2 which is the basis of Tory Hagan's research, in addition to PP2A activity, at the Linus Pauling Institute at Oregon State University. Nrf2 up-regulates heat shock protein HO-1.
• PP2a increases parallel increases in a-synuclein. (Peng)

Conclusions: Nrf2 is a modulator of the effects of gasoneurotransmitters through HO-1. Its impairment can not only result in susceptability to the effects of CO, NO and H2S but also the effects of catecholamines (ie. dopamine) that are activated by stress as part of the stress response. Long-term continuous activation of endoplasmic reticulum stress with impairments in Nrf2 can lead to environmentally induced conditions such as neurodegenerative conditions and brain injury as well as other inflammatory consequences including mitochondrial deficiency. Muscarinic receptors upregulate Nrf2 and Chaudhuri demonstrates the increase or decrease of binding of pesticides to the muscarinic receptor depends on the type of pesticide and greatly influences the toxicity of the pesticide. In his study, he showed paraquat's toxicity was greater. In addition, agricultural products may be contaminated with other agents or include "inert" ingredients that increase their toxicity by negatively influencing the expression of Nrf2 and/or its downstream targets. Other environmental influences may include nutrition (ie. obesity, malnutrition and high fat diets), mitochondrial disease, genetic mutations in the dopamine transporter (DAT) or DJ-1, or those in Nrf2, contaminants like dioxin and endotoxin that activate the AhR all enhance toxicity and risk for environmental disease.

Click for a more detailed list:

• biological factors that are directly related to Nrf2 signaling are may be mentioned within the body of blog text

Citations: Original Document

Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses

Title: Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses

Summary: The author writes, "The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6."


Kimura, A., Naka, T., Nakahama, T., Chinen, I., Masuda, K., Nohara, K., Fujii-Kuriyama, Y., and Kishimoto, T. (2009). Aryl hydrocarbon receptor in combination with stat1 regulates lps-induced inflammatory responses. J. Exp. Med., 206(9):2027-2035. http://www.citeulike.org/user/HEIRS/article/5700353

Mitochondrial Bioenergetics, CFS, Muscle Fatigue, PGC-1a, CAMKII and Nrf2.

Chronic fatigue syndrome is a condition that includes overwhelming fatigue even with rest that lasts for a period of six months or longer. It has been 3 decades since research on the condition began and there is no definitive answer on what causes it. However, they are making research strides and have an idea of at least some things that may contribute to it. SIRT1 activity regulates most of its activity through PGC-1a which an important regulator of metabolic homeotstasis, cellular function and mitochondrial biogenesis. Generally, cells that are lacking in PGC-1a are more insulin resistant and also have less eNOS.

In chronic fatigue syndrome, patients have a slow to fast twitch muscular presentation and altered muscle metabolism. (Pietrangelo) CAMKII is also important in fast-twitch muscle for sustaining contraction during exercise and it has been demonstrated that lower levels of CAMKII which are common in mitochondrial respiratory deficiencies may effect muscle performance. (Tanaka) AMPK is also another important regulator of this pathway through phosporylation of PGC-1a (Jager). AMPK also improves fatty acid metabolism in muscle and that activity is partially dependant on CAMKII (Rose). Again, a decrease in CAMKII would surely lead to changes in muscle metabolism. In this case, poor fatty acid metabolism causes higher fat in the muscle and is associated with insulin resistance and obesity and potentially, diabetes. (Adams) Interestingly, 89% of the muscles around the eyes and certain other areas of the face are fast-twitch muscles which may contribute to certain types of facial pain. Fast twitch muscle have less PGC-1a and as a result mitochondrial content is decreased and muscle activity is “energetically less efficient and expensive”(Schaffer). Cells with higher levels of PGC-1a have a better recovery of mitochondrial function to oxidant stress than those with lower levels of PGC-1a. (Rasbach) This would suggest a down-regulation or inhibition of SIRT1 activity which can be inhibited by many factors including nutrition including excessive calorie intake, Tnf-a or overproduction of H2O2. Many exposures including those to dioxin can increase levels of the pro-inflammatory Tnf-a (Frigo). Overall, cells with negative alterations in PGC-1a have demonstrated metabolic abnormalities, are more sensitive to cold, have more degenerative lesions and when expoxed to H2O2 are more apt to become damaged.

Because Nrf2 regulates NRF1 which is intricately tied and necessary for PGC-1a cellular function, Nrf2 becomes an important part of the pathway of SIRT1 and PGC-1a. Piantadosi describes the process as ”Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3 (GSK3b), which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter.” (Piantadosi) In simple terms, GSK3b can become an on/off switch for Nrf2 and you got to have the promoter nuclear respiratory factor NRF-1 and Nrf2. In terms of mitochondrial function, it seems like the NRF-1/Nrf2 complex would be an important place where future therapies target. One already in existence that provides some of this action is metformin which is used as a diabetes treatment. Exercise may increase levels of PGC-1a but this is inhibited in insulin resistant muscle.(Filippis) Resveratrol and quercetin may improve mitochondrial function.


Notes:
****Nrf2 SNPS can be ethnically-derived which would make people with more (or less) susceptible to oxidative stress and possibly a decrease in mitochondrial biogenesis. (Marzec)
****SNPs or mutations may make Nrf2 less responsive or overly responsive to cell signals.
****Friedrich's Ataxia is a condition caused by an alteration in coding for Nrf2 which leads to poor induction of the antioxidant system. It is not the only form of ataxia. Read more about ataxia here. Other SNPs may cause one to be more sensitive to lung injury. Some of the symptoms may seem similar to those with some symptoms related to chemical sensitivity.

****The Nrf2 regulates a number of proteins including the aryl hydrocarbon which may be an important initiator and factor in multiple chemical sensitivity. The AhR is responsible for mediating the detoxification of PAHs and HAHs in addition to other xenobiotics. It has also been determined it mediates most of the toxicity associated with dioxins.


This is a list of common symptoms associated with CFS:
*cognitive dysfunction, including impaired memory or concentration
*postexertional malaise lasting more than 24 hours (exhaustion and increased symptoms) following physical or mental exercise
*unrefreshing sleep
*joint pain (without redness or swelling)
*persistent muscle pain
*headaches of a new type or severity
*tender cervical or axillary lymph nodes
*sore throat

Other Common Conditions:
*irritable bowel, abdominal pain, nausea, diarrhea or bloating
*chills and night sweats
*brain fog
*chest pain
*shortness of breath
*chronic cough
*visual disturbances (blurring, sensitivity to light, eye pain or dry eyes)
*allergies or sensitivities to foods, alcohol, odors, chemicals, medications or noise
*difficulty maintaining upright position (orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting)
*psychological problems (depression, irritability, mood swings, anxiety, panic attacks)
*jaw pain
*weight loss or gain

Source: CDC

Citations: Original Post Source
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