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
Showing posts sorted by relevance for query loss of tolerance. Sort by date Show all posts
Showing posts sorted by relevance for query loss of tolerance. Sort by date Show all posts
Monday, August 2, 2010
Tuesday, January 5, 2010
T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.
Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.
One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.
Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.
Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)
It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.
Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.
For original document and citations.
null
One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.
Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.
Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)
It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.
Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.
For original document and citations.
null
Sunday, August 8, 2010
Endotoxin and Loss of Tolerance via Reduced HO-1: Potential Mechanism in CFS and MCS?
It has been suggested that chemical sensitivity and possibly other environmental illness conditions can be the result of a "loss of tolerance". Notably, this "loss of tolerance" may be the result of altered signaling of the immune response and contrbuting factors may include the presence of endotoxin which can 1) activate inflammatory responses, 2) reduce the threshold of reactions to allergens and 3) alter gene expression from ROS and alterations in methylation. In addition, endotoxin through activtion of GSK3b provides a mechanism to "deactivate" the antioxidant system, Nrf2. High fat diets and hyperglycemia may also promote the translocation of bacteria in the respiratory and intestinal tract. This may further increase inflammation and promote neuroinflammation in the brain as a consequence of cytokine activity in the intestinal tract and liver. At some point, the break down of the blood brain barrier may increase the likelihood of brain inflammation and changes in behavior and neurotransmission.
A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification. Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome. There is debate on the benefits and potential harmful effects of exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.
Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057. http://www.citeulike.org/user/HEIRS/article/7586285
A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification. Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome. There is debate on the benefits and potential harmful effects of exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.
Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057. http://www.citeulike.org/user/HEIRS/article/7586285
Thursday, January 7, 2010
Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!
I recently discussed how IL-10 determines the severity and length of sickness syndrome. At that time, I suggested chemical sensitivity is a loss of tolerance caused by an imbalance of T regulator cells and dysfunction of Nrf2 and based this assumption on a recent study showing environmental pollutants may lead to a decrease in the expression of Tregs whereas, normally chronic exposure increases them. In previous animal studies, the loss of Tregs results in the development of "immediate autoimmune-type disease."
This is how he classifies the autoimmune diseases:
Th1 Autoimmune Disease
For further reading:
Williams, M. A., Rangasamy, T., Bauer, S. M., Killedar, S., Karp, M., Kensler, T. W., Yamamoto, M., Breysse, P., Biswal, S., and Georas, S. N. (2008). Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol, 181(7):4545-4559. http://www.citeulike.org/user/HEIRS/article/3716629?show_msg=already_posted
Vojdani, A. and Lambert, J. (2009). A gut feeling for immune dysregulation & neuroinflammation in autism. http://www.citeulike.org/user/HEIRS/article/6498182
Definition of Dendritic Cell. MedicineNet.com. Retrieved January 7, 2009.
George, J. F., Braun, A., Brusko, T. M., Joseph, R., Bolisetty, S., Wasserfall, C. H., Atkinson, M. A., Agarwal, A., and Kapturczak, M. H. (2008). Suppression by cd4+cd25+ regulatory t cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol, 173(1):154-160 http://www.citeulike.org/user/HEIRS/article/6477829?show_msg=already_posted
Ibrahim, S. A. and Khalifa, N. A. (2009). Interleukin-18 correlates with disease severity in chronic autoimmune urticaria. Egyptian Dermatology Online Journal, 5(1). http://www.citeulike.org/user/HEIRS/article/6509891
Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529. http://www.citeulike.org/group/6096/article/6496762
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H. L. (2008). Control of treg and th17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191):65-71. http://www.citeulike.org/group/5070/article/2578286
The paragraphs below will provide more support for the idea that Nrf2 does indeed play a role in environmental illness including MCS in particular. First of all, it is important to review that environmental illnesses usually include allergy, asthma, inflammatory bowel disease, diabetes, lyme disease, heavy metal disease, chemical sensitivity, just to name a few. Generally, environmental illnesses may be categorized as Th1 or Th2 according to their T cell pathway subset which is either considered to be cell-mediated or humoral , respectively. Vodjani provides a graphical representation of environmental illnesses in relation to autism in his article and classifies them as Th1 or Th2. He classifies chemical sensitivity as a Th2 humorally- regulated autoimmune disease along with allergy and asthma. Tregs, as he describes, are cells that try to negotiate a balance between cells that suppress and ones that maintain homeostasis. More simply, they are T cells with specific markers. Personally, I have dubbed them to be immune cell referees!
- mulptiple sclerosis
- diabetes
- arthritis
- uveitis
- lyme disease
- mercury-induced autoimmunity
- atopic dermatitis (initiation phase)
- inflammatory bowel disease
- bacterial infection
- mold infection
- lupus erythematosis
- lead-induced autoimmune disease
- allergy
- asthma
- chemical sensitivity
- parasitic infection
- atopic dermatitis (acute phase)
- inflammatory bowel disease
- bacterial infection
- malignancy
- mucosal immune abnormalities
- imbalanced gut flora
- intestinal barrier diysfunction
- systemic inflammation
- neuroinflammation
- neuroinvasion
- neurodegeneration
In support of the idea of chemical sensitivity as an autoimmune disease one needs to understand the concept of loss of tolerance which include loss of Tregs and loss of suppression of inflammatory initiators. This loss may depend on other proteins such as Il-10 and HO-1 which are ultimately directed or indirectly regulated by Nrf2. For instance, it has been demonstrated Nrf2 -/- cells express lower HO-1 which is necessary for Treg suppression. Tregs levels also are negatively influenced by high-fat (Ma), age, mental stress, are differentially regulated by different AhR ligands (Quintana) and vitamin D levels. The last of which also decreases with age.
Williams and his team provides more insight into how the expression of Nrf2 is different with exposure to environmental pollutants. This article is long and the author makes several points worth discussion that support the notion of the possible involvement of Nrf2 in chemical intolerance. Initially the researcher describes how Nrf2 deficiency may stimulate a Th2 response according to the type of pollutant such as particulate matter. He admits even after presenting his findings, exposures to mixed pollutants are hard to analyze but he believes he uses an approach to match a "real-world" setting. His findings provide a mechanism for how certain environments tend to be more reactive to certain people and why these reactions do not always "appear" to be allergenically-mediated. Through this study, the researcher demonstrates Nrf2 positive and Nrf2 deficient animals show different immune profiles when exposed to different pollutants. For example, he found IL-18 was increased in Nrf2 positive but decreased in Nrf2 deficiency. This suggests Nrf2 regulates Il-18 which plays a role in inhibiting IgE in B cells. Typically, IL-18 is associated with some types of allergy, most often bacterial or viral and curiously, it is elevated in chronic autoimmune urticaria (itchy rash). (Ibrahim) Also, Nrf2-/- show lower protein CD40 that regulate IgE response which may include mild allergy-type responses like in hay fever to life threatening symptoms of anaphylactic shock. Nrf2 levels can fluctuate and if alterations of CD40 and IgE reflect this, it may explain why IgE profiles are often "scewed" in MCS patients. Williams also demonstrated that NAC, a common antioxidant used in MCS therapy has both positive and negative immune effects depending on the type of exposure to the point it may influence the Th1 or Th2 subtypes and may explain why some patients have good luck with NAC therapy and others do not. It also makes it evident that MCS treatments need to be medically-focused and individualized, why control of environmental stressors are critical and at least for the present, no "recipe" is going to be a "fix" for every MCS patient.
Williams and his team provides more insight into how the expression of Nrf2 is different with exposure to environmental pollutants. This article is long and the author makes several points worth discussion that support the notion of the possible involvement of Nrf2 in chemical intolerance. Initially the researcher describes how Nrf2 deficiency may stimulate a Th2 response according to the type of pollutant such as particulate matter. He admits even after presenting his findings, exposures to mixed pollutants are hard to analyze but he believes he uses an approach to match a "real-world" setting. His findings provide a mechanism for how certain environments tend to be more reactive to certain people and why these reactions do not always "appear" to be allergenically-mediated. Through this study, the researcher demonstrates Nrf2 positive and Nrf2 deficient animals show different immune profiles when exposed to different pollutants. For example, he found IL-18 was increased in Nrf2 positive but decreased in Nrf2 deficiency. This suggests Nrf2 regulates Il-18 which plays a role in inhibiting IgE in B cells. Typically, IL-18 is associated with some types of allergy, most often bacterial or viral and curiously, it is elevated in chronic autoimmune urticaria (itchy rash). (Ibrahim) Also, Nrf2-/- show lower protein CD40 that regulate IgE response which may include mild allergy-type responses like in hay fever to life threatening symptoms of anaphylactic shock. Nrf2 levels can fluctuate and if alterations of CD40 and IgE reflect this, it may explain why IgE profiles are often "scewed" in MCS patients. Williams also demonstrated that NAC, a common antioxidant used in MCS therapy has both positive and negative immune effects depending on the type of exposure to the point it may influence the Th1 or Th2 subtypes and may explain why some patients have good luck with NAC therapy and others do not. It also makes it evident that MCS treatments need to be medically-focused and individualized, why control of environmental stressors are critical and at least for the present, no "recipe" is going to be a "fix" for every MCS patient.
Williams states "oxidative stress is an important determinant of what path Th1 or Th2 autoimmunity takes and Nrf2 dysfunction may determine whether disease presentation is more of a Th1 or Th2 pattern." (This is an explanation for why patients with MCS have a long list of co-morbid health conditions and why they experience such a wide spectrum of symptoms.) Most importantly his findings demonstrate as he explains, "In this elegant study it was shown that a change in the intracellular redox status of DCs upon activation by particulates such as diesel exhaust particulates disrupt the normal ability of TLR agonists to mature DCs and this perturbation of DC function was associated with dampened IFN- and augmented IL-10 secretion in Ag-specific T cells, agreeing with these Nrf2 findings. Our data supports the idea that restoring the oxidant/antioxidant balance in DCs may have a therapeutic benefit in Th2-dominant allergic diseases. Also, enhanced activation in Nrf2-/- exposure to PM may result from decreased expression of HO-1 which is a powerful immunosuppressive" which provides evidence of loss of Treg involvement. George et al findings indeed demonstrated that Treg suppression is dependant on HO-1. HO-1 defiency leads to abolished Treg cell suppression activity normally necessary for keeping the Th1 and Th2 immune balance responses "in check" . Interestingly it seems, the contaminant and how effective the immune response to it ultimately may determine the development of MCS and how severe the symptoms if this author and the concept of "loss of tolerance" is attributable to the condition. As we have noted, HO-1 regulates Il-10 which is involved in Treg regulation and with the loss of IL-10 and lower levels of Tregs, heightened reactions and inflammatory responses could occur. Supportively, the author explains, "Nrf2-disrupted DCs exhibit a heightened and constitutively proinflammatory state. These observations indicate an important role for Nrf2 in gauging an appropriate pattern of inflammatory activation of DCs, key regulators of the immune response, to danger signals such as environmental particulate matter or other allergens. Disruption of the Nrf2 gene may potentially enhance host susceptibility to various allergic or infectious diseases" and this he admits, "warrants further study."
For further reading:
- Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
- T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.
Vojdani, A. and Lambert, J. (2009). A gut feeling for immune dysregulation & neuroinflammation in autism. http://www.citeulike.org/user/HEIRS/article/6498182
Definition of Dendritic Cell. MedicineNet.com. Retrieved January 7, 2009.
George, J. F., Braun, A., Brusko, T. M., Joseph, R., Bolisetty, S., Wasserfall, C. H., Atkinson, M. A., Agarwal, A., and Kapturczak, M. H. (2008). Suppression by cd4+cd25+ regulatory t cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol, 173(1):154-160 http://www.citeulike.org/user/HEIRS/article/6477829?show_msg=already_posted
Ibrahim, S. A. and Khalifa, N. A. (2009). Interleukin-18 correlates with disease severity in chronic autoimmune urticaria. Egyptian Dermatology Online Journal, 5(1). http://www.citeulike.org/user/HEIRS/article/6509891
Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529. http://www.citeulike.org/group/6096/article/6496762
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H. L. (2008). Control of treg and th17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191):65-71. http://www.citeulike.org/group/5070/article/2578286
Wednesday, January 6, 2010
Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
A number of researchers now believe endotoxin from bacterial contaminants may be a pathway that leads to the development of chronic fatigue syndrome. In addition it has been determined that high-fat diets exacerbate inflammatory conditions by altering the TLR signaling pathway which contributes to the loss of suppression of inflammatory responses by regulatory T cells (tregs) after endotoxin injury. Many experts believe this loss of tolerance may play an important role in MCS which is a condition that exhibits symptoms that often appear autoimmune in nature. In the lungs, TLR signaling and other proteins induced by endotoxin lead to the increased expression of inflammatory mediators including IL-6 which suppress Treg expression resulting in loss of tolerance in the airway and increase inflammation. Incidentally, a very small amount of endotoxin can lower the threshold of immune reactions in some people and since humans do not live in sterile environments, we are consistantly exposed to endogenous and exogenous bacteria (and endotoxin) in the air we breath, the food we eat, the things we touch, etc.
EGCG, the compound in green tea, has been shown to provide relief in animal models of chronic fatigue syndrome and several studies show it may have several modes of action. Currently Tufts University is performing an in-depth analysis of EGCG and the preliminary results show EGCG has the capacity to regulate different subsets of T cells including those responsible for playing a role in the development of autoimmune-type disease such as tregs. In support of these preliminary findings, a few years ago, Yoneyama demonstrated EGCG can regulate IL-10 and does have substantial immunosuppressive properties.
Over the past few months I have written how humans and animals demonstrate sickness behavior and the related behavioral changes are consistent with many of the symptoms in CFS and may include fatigue, malaise, mood changes, decreased appetite, etc. Also, the severity of sickness syndrome is dependant on the production or absence of Il-10 which is necessary for Treg production. One inflammatory cytokine produced by endotoxin is Il-6 which has the ability to suppress Treg expression and is most often responsible for sickness syndrome behavior and the polyphenols in green tea inhibit the expression of it. Considering all of this, it makes sense the loss of Treg through abherrant signaling is a causal factor in the loss of tolerance and MCS, sickness syndrome and chronic fatigue syndrome. Lastly, Nrf2 along may influence and regulate Treg expression through HO-1 and Il-10.
CiteULike: A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.: "Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529." http://www.citeulike.org/user/HEIRS/article/6496762
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. J Immunol, 181(12):8650-8659.
http://www.citeulike.org/user/HEIRS/article/3752381?show_msg=already_posted
Wu, D. Green tea egcg and t cell function in autoimmune inflammation.
http://www.citeulike.org/user/HEIRS/article/6496862
Yoneyama, S., Kawai, K., Tsuno, N., Okaji, Y., Asakage, M., Tsuchiya, T., Yamada, J., Sunami, E., Osada, T., and Kitayama, J. (2008). Epigallocatechin gallate affects human dendritic cell differentiation and maturation. Journal of Allergy and Clinical Immunology, 121(1):209-214. http://www.citeulike.org/user/HEIRS/article/6496680
Singal, A., Tirkey, N., Pilkhwal, S., and Chopra, K. (2006). Green tea (camellia sinensis) extract ameliorates endotoxin induced sickness behavior and liver damage in rats. Phytotherapy Research, 20(2):125-129.
http://www.citeulike.org/user/HEIRS/article/6496875
EGCG, the compound in green tea, has been shown to provide relief in animal models of chronic fatigue syndrome and several studies show it may have several modes of action. Currently Tufts University is performing an in-depth analysis of EGCG and the preliminary results show EGCG has the capacity to regulate different subsets of T cells including those responsible for playing a role in the development of autoimmune-type disease such as tregs. In support of these preliminary findings, a few years ago, Yoneyama demonstrated EGCG can regulate IL-10 and does have substantial immunosuppressive properties.
Over the past few months I have written how humans and animals demonstrate sickness behavior and the related behavioral changes are consistent with many of the symptoms in CFS and may include fatigue, malaise, mood changes, decreased appetite, etc. Also, the severity of sickness syndrome is dependant on the production or absence of Il-10 which is necessary for Treg production. One inflammatory cytokine produced by endotoxin is Il-6 which has the ability to suppress Treg expression and is most often responsible for sickness syndrome behavior and the polyphenols in green tea inhibit the expression of it. Considering all of this, it makes sense the loss of Treg through abherrant signaling is a causal factor in the loss of tolerance and MCS, sickness syndrome and chronic fatigue syndrome. Lastly, Nrf2 along may influence and regulate Treg expression through HO-1 and Il-10.
CiteULike: A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.: "Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529." http://www.citeulike.org/user/HEIRS/article/6496762
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. J Immunol, 181(12):8650-8659.
http://www.citeulike.org/user/HEIRS/article/3752381?show_msg=already_posted
Wu, D. Green tea egcg and t cell function in autoimmune inflammation.
http://www.citeulike.org/user/HEIRS/article/6496862
Yoneyama, S., Kawai, K., Tsuno, N., Okaji, Y., Asakage, M., Tsuchiya, T., Yamada, J., Sunami, E., Osada, T., and Kitayama, J. (2008). Epigallocatechin gallate affects human dendritic cell differentiation and maturation. Journal of Allergy and Clinical Immunology, 121(1):209-214. http://www.citeulike.org/user/HEIRS/article/6496680
Singal, A., Tirkey, N., Pilkhwal, S., and Chopra, K. (2006). Green tea (camellia sinensis) extract ameliorates endotoxin induced sickness behavior and liver damage in rats. Phytotherapy Research, 20(2):125-129.
http://www.citeulike.org/user/HEIRS/article/6496875
Thursday, September 2, 2010
Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!
It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.
In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin) While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.
To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation." Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS." If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.
Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP . We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)
In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease. (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)
Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown, "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well. (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)
I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl) and supports that the AhR modulates Treg production (Mezrich) and they may be a factor at least in some types of reactions to certain toxins. It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.
As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis. Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS. Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue. He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires". This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff) They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.
Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment. The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis. Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular." In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)
Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan) This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).
An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity. The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)
I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so! One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.
Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438. http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168. http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000. http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191. http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745
In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin) While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.
To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation." Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS." If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.
Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP . We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)
In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease. (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)
Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown, "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well. (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)
I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl) and supports that the AhR modulates Treg production (Mezrich) and they may be a factor at least in some types of reactions to certain toxins. It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.
As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis. Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS. Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue. He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires". This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff) They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.
Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment. The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis. Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular." In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)
Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan) This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).
An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity. The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)
I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so! One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.
Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438. http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168. http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000. http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191. http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745
Thursday, June 24, 2010
CRH and Tregs in Autoimmunity: Possible Connections to Chemical Sensitivity~!
Background: In earlier posts we described how commensal bacteria in the gut regulates the induction of T regulatory cells called Tregs that are important for immune functions. The loss of which may include autoimmune-type expressions and may be influential in MCS by loss of tolerance. In addition, we have also discussed how cortico-releasing hormone (CRH or CRF) has many effects and tissue targets, can be influenced by odors, may influence addictive-type behaviors and abherrant signaling may lead to altered signaling that can lead to mood disorders and have other negative influences on behaviors. The activation of CRH is part of the stress response and therefore, become an important part of the response to environmental cues. This same response activates the inflammatory cascade and therefore, the existence of one may coincide with the activation of the other. In addition, inflammatory cascades include activation of immune cells including mast cells.
Christy and Brown explain that Tregs are important in autoimmune disease and have the potential upon induction to prevent and reverse these conditions including diabetes and multiple sclerosis. Both of which are now considered to have an environmental connection. In addition the author notes that lupus, another condition with possible environmental triggers, and other autoimmune conditions are not just a loss of Tregs but a condition where other immune cells called Ag-effector cells become resistent to Treg suppression. At this point, one would suggest that other physiological pathways may be involved and this potentiates the non-adaptive conditions that lead to MCS. In other blogs, we have discussed a number of these conditions including nutrition and expression of cytokines, as well as, the expression of Nrf2.
Christy and Brown also present another important factor that very well may influence the development of MCS by contributing to loss of tolerance and that is the production of CRH from mast cells. These cells are often produced from inflammatory reactions such as those conditions that produced and reported from environmental toxin exposure. The authors discuss how the role of CRH produced from these inflammatory cells in basically an uptapped area of immune science. On the other hand, Soderholm does note that mast cells and CRH are implicated in disruptions of barrier function in irritable bowel syndrome and to a degree, it it now understood they are produced in inflamed tissue and increase inflammation. This protein has been implicated in reactions in rheumatoid arthritis and other inflammatory conditions during stress. For this reason, one can suggest that inflammatory conditions and production of mast cells which can produce this protein may contribute to the response and long-term activation can have important effects on downstream targets and participate in autoimmune-type response such as those observed in chemical sensitivities.
Past HEIRS Blogs: Related Tags: CRF , CRH , Nrf2
Christy, A. L. and Brown, M. A. (2007). The multitasking mast cell: Positive and negative roles in the progression of autoimmunity. J Immunol, 179(5):2673-2679.
http://www.citeulike.org/user/HEIRS/article/7357936
McKay, D. M. (2005). Good bug, bad bug: in the case of enteric inflammatory disease does the epithelium decide? Memórias do Instituto Oswaldo Cruz, 100(s1):205-210.
http://www.citeulike.org/user/HEIRS/article/7357955
Teitelbaum, A. A., Gareau, M. G., Jury, J., Yang, P. C., and Perdue, M. H. (2008). Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol Gastrointest Liver Physiol, 295(3):G452-459. http://www.citeulike.org/user/HEIRS/article/7357961
Christy and Brown explain that Tregs are important in autoimmune disease and have the potential upon induction to prevent and reverse these conditions including diabetes and multiple sclerosis. Both of which are now considered to have an environmental connection. In addition the author notes that lupus, another condition with possible environmental triggers, and other autoimmune conditions are not just a loss of Tregs but a condition where other immune cells called Ag-effector cells become resistent to Treg suppression. At this point, one would suggest that other physiological pathways may be involved and this potentiates the non-adaptive conditions that lead to MCS. In other blogs, we have discussed a number of these conditions including nutrition and expression of cytokines, as well as, the expression of Nrf2.
Christy and Brown also present another important factor that very well may influence the development of MCS by contributing to loss of tolerance and that is the production of CRH from mast cells. These cells are often produced from inflammatory reactions such as those conditions that produced and reported from environmental toxin exposure. The authors discuss how the role of CRH produced from these inflammatory cells in basically an uptapped area of immune science. On the other hand, Soderholm does note that mast cells and CRH are implicated in disruptions of barrier function in irritable bowel syndrome and to a degree, it it now understood they are produced in inflamed tissue and increase inflammation. This protein has been implicated in reactions in rheumatoid arthritis and other inflammatory conditions during stress. For this reason, one can suggest that inflammatory conditions and production of mast cells which can produce this protein may contribute to the response and long-term activation can have important effects on downstream targets and participate in autoimmune-type response such as those observed in chemical sensitivities.
Past HEIRS Blogs: Related Tags: CRF , CRH , Nrf2
Christy, A. L. and Brown, M. A. (2007). The multitasking mast cell: Positive and negative roles in the progression of autoimmunity. J Immunol, 179(5):2673-2679.
http://www.citeulike.org/user/HEIRS/article/7357936
McKay, D. M. (2005). Good bug, bad bug: in the case of enteric inflammatory disease does the epithelium decide? Memórias do Instituto Oswaldo Cruz, 100(s1):205-210.
http://www.citeulike.org/user/HEIRS/article/7357955
Teitelbaum, A. A., Gareau, M. G., Jury, J., Yang, P. C., and Perdue, M. H. (2008). Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol Gastrointest Liver Physiol, 295(3):G452-459. http://www.citeulike.org/user/HEIRS/article/7357961
Thursday, May 6, 2010
Ammonia, Smoking,Insulin Resistance and Protein Dysfunction in MCS
Background: Manufacturers of cigarettes have admitted to adding ammonia since the 1960s to make them more addictive by boosting the absorption of nicotine significantly. This may make cigarette smoke more toxic to some including people that are more vulnerable such as young children with immature immune systems, the elderly or other individuals that have urinary impairments or genetic factors that alter excretory metabolism. Below are some examples of why adding ammonia to cigarettes may be indirectly responsible, at least in part, for the rise in cardiovascular and other diseases from smoking because of its toxic effects on genes and different tissues in the body.
In cells, chemical toxins effect metabolic pathways which may run parallel, are independant and/or interact, potentiate or possibly minimize the effects of each another. For this reason, it is difficult to predict the severity and the consequences of them on the health of an organism. Exposure to cigarette smoke is no different and has been shown to act differently in different people and on more than one molecular pathway at the same time. Through the years, hundreds of studies have demonstrated the health hazards associated with the toxic effects of smoking and one of these effects includes the dysregulation of metabolism including altering blood sugar homeostasis. Personally, I have suspected this to be the case for some time. Over the past several years, scientists have discovered smoking not only increases the risk for diabetes which includes higher glucose levels, higher insulin levels and increased blood pressure it may also contribute to episodes of hypoglycemia in diabetes. As one article state, "this may be due to an effect of smoking on insulin clearance, leading to hyperinsulinemia, increasing hypoglycemia, and worsening metabolic control. In addition, smoking has been shown to increase the secretion of hormones (i.e., growth hormone, vasopressin, and cortisol) that counteract insulin action, leading to an increased insulin requirement. Smokers have been found to require more insulin than nonsmokers to achieve the same level of glycemic control in some, but not all, studies." (Hirai)
In addition to ammonia making cigarettes more addictive, ammonia can act on the cortico-releasing factor (CRF) system which regulates behavior including feeding and increases serotonin and dopamine levels. As a consequence, it can influence mood and alter homeostasis leading the conditions like the weight loss and weight gain from smoking and cessation, respectively. Activation of this pathway, in fact, mediates psychological effects of nicotine withdrawal. (Grunberg) I recently mentioned that because ammonia activates the CRF pathway that regulates neuroendocrine, drug abuse responses and aversion one could relate MCS behaviors to a scewed form of addictive behavior. (Kreibich, Sahuque) More simply, its activation leads to changes in hormone production and alter behaviors, it is possible that abherrant signaling in this system may be responsible for some of the symptoms of MCS and similar to those from chemical withdrawal but modified into aversive response. It is also possible the addictive nature of smoking from ammonia or other volatiles on the CRF from smoke exposure could be a sensitizing factor, stimulate the immune system and also initiate a "loss of tolerance" which has been suggested as an explanation of multiple chemical sensitivity and sensitivities in autism. An interesting research study could be designed to determine wether a potential correlation of MCS sensitization and smoking could exist.
To support this idea further, researchers have demonstrated the addictive nature of smoking involves a cellular pathway called CREB that involves the relationship of reward to smoking behaviors and their association with environmental cues. Also, recent research findings show a strong association of CREB and CRF in stress-induced drug reward behavior. It is not beyond reason to suggest that alterations in signals that lead to physical and psychological symptoms of drug withdrawal may also influence physical and emotional aversive behaviors of MCS and argues against the notion of that symptoms of MCS are "psychosomatic". The high levels of cadmium may further disrupt the CREB pathway and normal cell functions. Both of these discoveries provide an important mechanism to explain activation of MCS by environmental cues and suggests that insulin resistance may play a part in some of its reactions. "Previously,it has been shown the CREB pathway keeps blood sugar in balance under certain metabolic conditions and excessive CREB activity in diabetes contributes to high blood sugar and insulin resistance. New findings show CREB encourages insulin resistance by lowering adiponectin and the insulin-sensitive glucose transporter 4 (GLUT4)." (US Health News) CREB is a mediator of inflammation and both of these findings demonstrate that overactive CREB may contribute to endothelial dysfunction and impair cognitive function by mediating inflammation and insulin resistance. (Ishiki) On the other hand, downregulation of the cGMP/NO/CREB by amyloid or hyperammonemia may contribute to neurodegenerative diseases and Alzheimer's. (Copper Mountain, CO, Puzzo) This has important implications not only for cigarette smoke but persistent organic pollutants considering they both may contribute to diabetes complications.Other environmental factors such as other exposures to heavy metals implicated in contributing to diabetes and altered methylation may also contribute to these conditions. (Pozharny)
Along those same lines, cigarette smoking also contributes to weight loss through activation of the aryl hydrocarbon and endoplasmic reticulum stress. In other blogs, I have suggested this process also is involved in MCS. A recent study agrees with findings that cigarette smoke and dioxin does lower adiponectin but also demonstrated that PPAR-gamma and c/EPB were also decreased. In another study, ornithine impairments in c/EPB knock-outs from hypoglycemia presented with significantly higher levels of ammonia. Further, it has been shown ornithine enzymes interact with C/EPB and is important for ammonia detoxification. Without it, you get impaired excretion of urea and gluconeogenesis. As one can see, metabolically cigarette smoke may cause severe alterations in metabolism. This may include alterations of ammonia which may potentially sensitize an individual towards development and contribute to multiple chemical sensitivity.
Citations and other documents available here.
In cells, chemical toxins effect metabolic pathways which may run parallel, are independant and/or interact, potentiate or possibly minimize the effects of each another. For this reason, it is difficult to predict the severity and the consequences of them on the health of an organism. Exposure to cigarette smoke is no different and has been shown to act differently in different people and on more than one molecular pathway at the same time. Through the years, hundreds of studies have demonstrated the health hazards associated with the toxic effects of smoking and one of these effects includes the dysregulation of metabolism including altering blood sugar homeostasis. Personally, I have suspected this to be the case for some time. Over the past several years, scientists have discovered smoking not only increases the risk for diabetes which includes higher glucose levels, higher insulin levels and increased blood pressure it may also contribute to episodes of hypoglycemia in diabetes. As one article state, "this may be due to an effect of smoking on insulin clearance, leading to hyperinsulinemia, increasing hypoglycemia, and worsening metabolic control. In addition, smoking has been shown to increase the secretion of hormones (i.e., growth hormone, vasopressin, and cortisol) that counteract insulin action, leading to an increased insulin requirement. Smokers have been found to require more insulin than nonsmokers to achieve the same level of glycemic control in some, but not all, studies." (Hirai)
In addition to ammonia making cigarettes more addictive, ammonia can act on the cortico-releasing factor (CRF) system which regulates behavior including feeding and increases serotonin and dopamine levels. As a consequence, it can influence mood and alter homeostasis leading the conditions like the weight loss and weight gain from smoking and cessation, respectively. Activation of this pathway, in fact, mediates psychological effects of nicotine withdrawal. (Grunberg) I recently mentioned that because ammonia activates the CRF pathway that regulates neuroendocrine, drug abuse responses and aversion one could relate MCS behaviors to a scewed form of addictive behavior. (Kreibich, Sahuque) More simply, its activation leads to changes in hormone production and alter behaviors, it is possible that abherrant signaling in this system may be responsible for some of the symptoms of MCS and similar to those from chemical withdrawal but modified into aversive response. It is also possible the addictive nature of smoking from ammonia or other volatiles on the CRF from smoke exposure could be a sensitizing factor, stimulate the immune system and also initiate a "loss of tolerance" which has been suggested as an explanation of multiple chemical sensitivity and sensitivities in autism. An interesting research study could be designed to determine wether a potential correlation of MCS sensitization and smoking could exist.
To support this idea further, researchers have demonstrated the addictive nature of smoking involves a cellular pathway called CREB that involves the relationship of reward to smoking behaviors and their association with environmental cues. Also, recent research findings show a strong association of CREB and CRF in stress-induced drug reward behavior. It is not beyond reason to suggest that alterations in signals that lead to physical and psychological symptoms of drug withdrawal may also influence physical and emotional aversive behaviors of MCS and argues against the notion of that symptoms of MCS are "psychosomatic". The high levels of cadmium may further disrupt the CREB pathway and normal cell functions. Both of these discoveries provide an important mechanism to explain activation of MCS by environmental cues and suggests that insulin resistance may play a part in some of its reactions. "Previously,it has been shown the CREB pathway keeps blood sugar in balance under certain metabolic conditions and excessive CREB activity in diabetes contributes to high blood sugar and insulin resistance. New findings show CREB encourages insulin resistance by lowering adiponectin and the insulin-sensitive glucose transporter 4 (GLUT4)." (US Health News) CREB is a mediator of inflammation and both of these findings demonstrate that overactive CREB may contribute to endothelial dysfunction and impair cognitive function by mediating inflammation and insulin resistance. (Ishiki) On the other hand, downregulation of the cGMP/NO/CREB by amyloid or hyperammonemia may contribute to neurodegenerative diseases and Alzheimer's. (Copper Mountain, CO, Puzzo) This has important implications not only for cigarette smoke but persistent organic pollutants considering they both may contribute to diabetes complications.Other environmental factors such as other exposures to heavy metals implicated in contributing to diabetes and altered methylation may also contribute to these conditions. (Pozharny)
Along those same lines, cigarette smoking also contributes to weight loss through activation of the aryl hydrocarbon and endoplasmic reticulum stress. In other blogs, I have suggested this process also is involved in MCS. A recent study agrees with findings that cigarette smoke and dioxin does lower adiponectin but also demonstrated that PPAR-gamma and c/EPB were also decreased. In another study, ornithine impairments in c/EPB knock-outs from hypoglycemia presented with significantly higher levels of ammonia. Further, it has been shown ornithine enzymes interact with C/EPB and is important for ammonia detoxification. Without it, you get impaired excretion of urea and gluconeogenesis. As one can see, metabolically cigarette smoke may cause severe alterations in metabolism. This may include alterations of ammonia which may potentially sensitize an individual towards development and contribute to multiple chemical sensitivity.
Citations and other documents available here.
Sunday, January 17, 2010
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
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
Thursday, August 26, 2010
Vitamin D may treat and prevent allergic reaction to mold in cystic fibrosis patients
Comment: The following study helps support the HEIRS and others' hypothesis that MCS and other environmental illnesses are a "loss of tolerance" which involves impaired Treg production.
"PITTSBURGH, Aug. 25 – Vitamin D may be an effective therapy to treat and even prevent allergy to a common mold that can cause severe complications for patients with cystic fibrosis and asthma, according to researchers from Children's Hospital of Pittsburgh of UPMC, the University of Pittsburgh School of Medicine and Louisiana State University School of Medicine."
Read more: Vitamin D may treat and prevent allergic reaction to mold in cystic fibrosis patients:
For further reading: Tregs, loss of tolerance, FoxP3
**********You can also search the HEIRS Citation database for related citations.
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. Journal of immunology (Baltimore, Md. : 1950), 181(12):8650-8659. http://www.citeulike.org/user/HEIRS/article/3752381
"PITTSBURGH, Aug. 25 – Vitamin D may be an effective therapy to treat and even prevent allergy to a common mold that can cause severe complications for patients with cystic fibrosis and asthma, according to researchers from Children's Hospital of Pittsburgh of UPMC, the University of Pittsburgh School of Medicine and Louisiana State University School of Medicine."
Read more: Vitamin D may treat and prevent allergic reaction to mold in cystic fibrosis patients:
For further reading: Tregs, loss of tolerance, FoxP3
**********You can also search the HEIRS Citation database for related citations.
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. Journal of immunology (Baltimore, Md. : 1950), 181(12):8650-8659. http://www.citeulike.org/user/HEIRS/article/3752381
Saturday, August 14, 2010
Green Tea Compound, Hypermethylation and Tregs In Allergy and Chemical Sensitivity!
Recent studies propose that environmental illnesses are caused from "loss of tolerance" and that alterations in T regulatory cells (Tregs) may be a important factor. A number of studies demonstrate health benefits from epigallocatechin gallate (EGCG) which is a compound found in green tea. Yun shows EGCG can enhance Tregs production and enhance expression of histone deacetylases while decreasing expression of NF-kappaB. It also has been shown to reactivate genes that have been silenced by hypermethylation and prevent these changes to subsequent passage to daughter cells by DNA methyltransferases. (Fang) Interestingly, CCL18 is a chemokine that is elevated in allergic patients and may contribute to the "loss of tolerance" because in normal patients it promotes the generation of normal normal Tregs but in allergic patients it does not and may
an increased prevalence for symptoms that are common with chemical sensitivity in allergic patients. In addition, other factors including the proper expression of the Nrf2 system and other pathways for antioxidant expression may mitigate the effects while impairments may exacerbate them. EGCG has been shown to act through Nrf2, although this may not be its only mode of action. In any event, EGCG may provide some therapeutic effects for these kinds of conditions.
Yun, J.-M. and Jialal, I. Effects of epigallocatechin gallate on regulatory t cell number and function in obese versus lean volunteers. FASEB.http://www.citeulike.org/user/HEIRS/article/7651808
Fang, M. Z. Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., Welsh, W., and Yang, C. S. (2003). Tea polyphenol (-)-epigallocatechin-3-gallate inhibits dna methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer research, 63(22):7563-7570.
http://www.citeulike.org/user/HEIRS/article/3326104
Chang, Y., de Nadai, P., Azzaoui, I., Morales, O., Delhem, N., Vorng, H., Tomavo, S., Ait Yahia, S., Zhang, G., Wallaert, B., Chenivesse, C., and Tsicopoulos, A. (2010). The chemokine ccl18 generates adaptive regulatory t cells from memory cd4+ t cells of healthy but not allergic subjects. The FASEB journal. http://www.citeulike.org/user/HEIRS/article/7651843
an increased prevalence for symptoms that are common with chemical sensitivity in allergic patients. In addition, other factors including the proper expression of the Nrf2 system and other pathways for antioxidant expression may mitigate the effects while impairments may exacerbate them. EGCG has been shown to act through Nrf2, although this may not be its only mode of action. In any event, EGCG may provide some therapeutic effects for these kinds of conditions.
Yun, J.-M. and Jialal, I. Effects of epigallocatechin gallate on regulatory t cell number and function in obese versus lean volunteers. FASEB.http://www.citeulike.org/user/HEIRS/article/7651808
Fang, M. Z. Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., Welsh, W., and Yang, C. S. (2003). Tea polyphenol (-)-epigallocatechin-3-gallate inhibits dna methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer research, 63(22):7563-7570.
http://www.citeulike.org/user/HEIRS/article/3326104
Chang, Y., de Nadai, P., Azzaoui, I., Morales, O., Delhem, N., Vorng, H., Tomavo, S., Ait Yahia, S., Zhang, G., Wallaert, B., Chenivesse, C., and Tsicopoulos, A. (2010). The chemokine ccl18 generates adaptive regulatory t cells from memory cd4+ t cells of healthy but not allergic subjects. The FASEB journal. http://www.citeulike.org/user/HEIRS/article/7651843
Friday, June 25, 2010
Regulatory T Cell (Tregs) Production Dependant on Methylation Modifications~!
Background: New report support that the balance of Tregs need to be maintained for suppression of immune functions that lead to autoimmune-type reactions including those that may be seen in diabetes, colitis and lupus. In previous blogs, I suggest that loss of Tregs may influence the development of chemical sensitivity through the loss of Treg suppression and "loss of tolerance" and has been suggested by other authors. In the past, I have also reviewed several research studies that identify how recent findings of aberrant methylation influence environmental disease including autism, endometriosis and PTSD.
Interesting the following study by Floess shows that epigenetic modifications must occur with immune cells for cells to develop into "suppressor-type" lineages of Tregs. Therefore, alterations in methylation may negatively influence the development of Treg cells and could cause or augment environmental disease. This also provides a mechanism for what appears an inheritability of environmental disease.
Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.-D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., and Huehn, J. (2007). Epigenetic control of the foxp3 locus in regulatory t cells. PLoS Biol, 5(2):e38+.
http://www.citeulike.org/user/HEIRS/article/1080288
Interesting the following study by Floess shows that epigenetic modifications must occur with immune cells for cells to develop into "suppressor-type" lineages of Tregs. Therefore, alterations in methylation may negatively influence the development of Treg cells and could cause or augment environmental disease. This also provides a mechanism for what appears an inheritability of environmental disease.
Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.-D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., and Huehn, J. (2007). Epigenetic control of the foxp3 locus in regulatory t cells. PLoS Biol, 5(2):e38+.
http://www.citeulike.org/user/HEIRS/article/1080288
Saturday, July 24, 2010
Inflammation, Insulin Resistance and Decreased PPARs-- A Pathway to CFS?
I thought today I would review some points that I have made over the last several months about environmental illness specifically chronic fatigue syndrome. I do this today, because of recent research news that supports some of what I have been saying all along and that is that CFS is probably the result of stresses that alter cellular functioning and disrupt cellular metabolism. This is not a new thing but believe that many researchers have failed to notice that many of the symptoms may be caused by alterations in glucose metabolism and insulin activity and include some influences like what occur in
sickness syndrome even though CFS and sickness syndrome are not the same thing. Sickness syndrome is a variety of changes that occur in the body as a response to sickness and provides a mechanism to fight whatever is causing the sickness. Personally, I can recognize it more in animals because humans have been taught that we "must" overcome --- and that goes for being ill too that usually leads to more sickness.
Michael Maes has probably been the leader in the idea of sickness syndrome in relation to CFS. In his last report, he definitely makes the distinction and I have to agree with him. CFS is not sickness syndrome and is more due to inflammation and oxidative and nitrosative stress and pathogenic conditions and permeability can be to blame. Again, I agree and am critical of some that try to base everything about CFS on oxidative stress because it does not really explain how one "gets there"! In my view, it all comes down to and the problem with labels and this always has been my issue..... IN this case, how can we understand where one illness like CFS starts and another one ends such as sickness syndrome if noone really has defined the former CFS well in the first place? It is my belief that sickness syndrome may be a prelude to CFS or maybe the beginning point of it, and different factors can inhibit or lead to a "full-blown" case of CFS and recognizing the biological factors that play a part may in fact, help to prevent CFS in its most severe form. As far as oxidative and nitrosative stress in CFS, I think if you just leave it at..then it is doing a disservice not only to the condition but to those who suffer from it. The reason I say this is because of the nature of oxidative/nitrosative stress --- it is a natural result of cellular processes. Just saying that CFS is caused from too much of these stresses does nothing to answer what is causing the overwhelming oxidative stress in the first place in CFS. Maes has implied that endotoxin may be a pathway to CFS and bacterial infection has potential for causing oxidative stress and changing environments and altered methylation. But the possibility that other environmental factors such as hyperglycemia and high-fat diets which promote bacterial translocation and consequently activate certain immune responses leadin to CFS also, can not be dismissed. I have suggested that the failure of the antioxidant system to adequately meet the needs of oxidative stress or maybe even at all to any real level may play a very important role. In other blogs, we have noted that oxidative and nitrosative stress is needed to activate this system and nutritional and genetic factors may influence the speed and level of activation. So if we have overwhelming oxidative stress -- it makes sense that something like underactivation of the antioxidant system may be at fault or is just not working. So in essence, it should be a no-brainer to look at the Nrf2-Keap1 and other proteins it controls to get a better handle on what may be causing the failure of an adaptive immune response and elevations in inflammatory markers and oxidative stress that are obviously maladaptive.
Several new studies some evidence that a failure in the antioxidant system could contribute to CFS. It is not a direct road I admit, but considering I have been following these paths for 3 years now. They make sense to me, mainly because I look for the CFS from a more holistic and systems theory perspective. For someone that has been trained both in anthropology and biology, this perspective works better for me when I need to find out the answers to different questions that need to be investigated. In addition, one could ask what is a direct road or pathway in reference to disease anyway....to me, it is all relative and most always depends on personal interpretation. Several months ago, I blogged that environmental pollutants may contribute to diabetes and insulin resistance. Since then several other reports conclude this may be the case and many studies have provided evidence how inflammation can lead to insulin resistance and diabetes through the down-regulation of genes and up-regulation of inflammatory cytokines. Several inflammatory markers, not just one, can contribute and can be produced as a consequence of the stress response including TNF-a, Il-1, Il-6. Some of these activate other responses that lead to neuroinflammation and also alteration of neurotransmitters and have other effects on brain chemistry which could be characteristic of the cognitive dysfunction associated with CFS.
It has been suspected that pollutants lead to the alteration of a class of class of genes. I refer to them most often as PARRs and may include PPAR-gamma, PARR-delta and PARR-alpha. I have discussed both PPAR-gamma and PPAR-alpha at length in different discussions and most notably, PPAR-gamma is an important anti-inflammatory which helps prevent the development of insulin resistance in addition to other functions and may help repress autoimmunity. (Klotz) Recently, a study of the combination of pioglitizone and caffeic acid, demonstrated significant improvement in a mouse model of chronic fatigue. In this study, the results showed improvements in running wheel activity, locomotor activity and anxiety. Other improvements included reductions in oxidative damage including lipid peroxidation and nitrite concentration and increased glutatione and catalase levels in addition to altering mitochondrial function. When one digs a little deeper, interesting things appear related to the actions of these compounds. Caffeic acid is an antioxidant and anti-inflammatory that while having potential hazard qualities, also demonstrates the ability to " suppress MMP-9 enzyme activity and down-regulate NF-κB through inhibition of protein IKK and activation of Nrf2 (Lee) and other studies provide in vitro evidence it may effect DNA methylation.(Wipedia)" In contrast, pioglitizone is an anti-hyperglycemic medication and "stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. Both of these compounds act through PARR-gamma directly or indirectly via Nrf which may explain why their benefits in the CFS model is synergistic compared to when they were used alone. (Kumar) Generally, PARRs modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. (Wipedia)" What this says to me is that CFS very well could be considered a condition that is a consequence of significantly disrupted normal glucose uptake and cellular and energy metabolism and altered immune function in different tissues.
I have also postulated that the aryl hydrocarbon may play an important role in both CFS and MCS and there are several "conditions" that lead me to make this assumption and the hypothesis but unfortunately, how this interaction occurs is quite "muddy". First, it has been demonstrated that there is a close connection in the actions of the AhR and the Nrf2 in response to environmental pollutants and their "gene batteries". Second, I have suggested that abnormal signalling from the AhR may influence the functioning of several proteins including the Nrf2 even though the specific mechanismin of how this is achieved is not entirely understood. Third, dioxin which persists in the environment, albeit at lower levels in the last decade in many locales but still present in food, has been associated with diabetes and activates the AhR. Four, for some time it has been believed the AhR may inhibit PPAR-gamma and therefore leads us to environmental conditions, at least physiologically, of elevated inflammation and an increased risk for diabetes. (Remillard) Arguably, the role of the AhR on PPAR-gamma depends on the tissue. (Kitchner, Shin) However, dioxins are bioaccumulative and activation of the AhR and its effects on PPAR-gamma may spill over to surrounding tissues. Lastly, a new study has shown that Nrf2 drives PPAR-gamma in protecting against oxidant injury at least in the respiratory system. Taking all this into account, it is safe to at least suggest that CFS may be influenced by fluctuations in PPAR-gamma and the proteins that regulate it and factors that upregulate it may be beneficial or preventative against CFS. Because PPAR-gamma demonstrates inhibitory properties on autoimmune responses, its absence may play significantly in the "loss of tolerance" responses of chemical sensitivity and inflammatory bowel disease. Other studies show PPAR-gamma has as an important regulatory function with HO-1 and may be neuroprotective against Parkinson's (Lui, Schintu) and influences mitochondrial biogenesis through PGC-1a (Miglio). In other blogs, I discuss how certain nutritional compounds such as resveratrol and EGCG in different foods have shown some benefit and their modes of actions address some of the issues that are discussed in the paragraphs above. IN addition, because these proteins can be effected by methylation this explains the inheritabilty factor that exists with CFS that is not explained just by the presence of oxidative stress.
Notes:
Cho, H.-Y. Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S. P., and Kleeberger, S. R. (2010). Nrf2-regulated ppargamma expression is critical to protection against acute lung injury in mice. American journal of respiratory and critical care medicine, 182(2):170-182. http://www.citeulike.org/user/HEIRS/article/6854883?show_msg=already_posted
Kumar, A., Vashist, A., and Kumar, P. (2010). Potential role of pioglitazone, caffeic acid and their combination against fatigue syndrome-induced behavioural, biochemical and mitochondrial alterations in mice. Inflammopharmacology. http://www.citeulike.org/user/HEIRS/article/7474822
Yang, J.-Y. Y., Della-Fera, M. A. A., Rayalam, S., Ambati, S., Hartzell, D. L., Park, H. J. J., and Baile, C. A. (2008). Enhanced inhibition of adipogenesis and induction of apoptosis in 3t3-l1 adipocytes with combinations of resveratrol and quercetin. Life sciences, 82(19-20):1032-1039. http://www.citeulike.org/user/HEIRS/article/7537205
Pioglitazone. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Pioglitazone
Caffeic Acid. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Caffeic_Acid
Zhou, M., Wu, R., Dong, W., Jacob, A., and Wang, P. (2008). Endotoxin downregulates peroxisome proliferator-activated receptor-gamma via the increase in tnf-alpha release. Am J Physiol Regul Integr Comp Physiol, 294(1):R84-92. http://www.citeulike.org/user/HEIRS/article/2439726
Remillard, R. B. and Bunce, N. J. (2002). Linking dioxins to diabetes: epidemiology and biologic plausibility. Environmental health perspectives, 110(9):853-858. http://www.ncbi.nlm.nih.gov/pubmed/12204817
Kintscher, U. and Law, R. E. (2005). Ppargamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab, 288(2):E287-291. http://www.citeulike.org/user/HEIRS/article/3824606
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
Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Novak, N., Beyer, M., Mayer, G., Langhans, B., Klockgether, T., Waisman, A., Eberl, G., Schultze, J., Famulok, M., Kolanus, W., Glass, C., Kurts, C., and Knolle, P. A. (2009). The nuclear receptor ppargamma selectively inhibits th17 differentiation in a t cell-intrinsic fashion and suppresses cns autoimmunity. J. Exp. Med., 206(10):2079-2089. http://www.citeulike.org/user/HEIRS/article/5778777
Liu, S. H. H., Yang, C. N. N., Pan, H. C. C., Sung, Y. J. J., Liao, K. K. K., Chen, W. B. B., Lin, W. Z. Z., and Sheu, M. L. L. (2010). Il-13 downregulates ppar-gamma/heme oxygenase-1 via er stress-stimulated calpain activation: aggravation of activated microglia death. Cellular and molecular life sciences : CMLS. http://www.citeulike.org/user/HEIRS/article/6826740
Schintu, N., Frau, L., Ibba, M., Caboni, P., Garau, A., Carboni, E., and Carta, A. R. (2009). Ppar-gamma-mediated neuroprotection in a chronic mouse model of parkinson's disease. The European journal of neuroscience, 29(5):954-963. http://www.citeulike.org/user/HEIRS/article/4136907
Miglio, G., Rosa, A. C., Rattazzi, L., Collino, M., Lombardi, G., and Fantozzi, R. (2009). Ppargamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochemistry international, 55(7):496-504. http://www.citeulike.org/user/HEIRS/article/5345204
Lee, Y., Shin, D.-H. H., Kim, J.-H. H., Hong, S., Choi, D., Kim, Y.-J. J., Kwak, M.-K. K., and Jung, Y. (2010). Caffeic acid phenethyl ester-mediated nrf2 activation and ikappab kinase inhibition are involved in nfkappab inhibitory effect: Structural analysis for nfkappab inhibition. European journal of pharmacology, 643(1):21-28. http://www.citeulike.org/user/HEIRS/article/7394789
sickness syndrome even though CFS and sickness syndrome are not the same thing. Sickness syndrome is a variety of changes that occur in the body as a response to sickness and provides a mechanism to fight whatever is causing the sickness. Personally, I can recognize it more in animals because humans have been taught that we "must" overcome --- and that goes for being ill too that usually leads to more sickness.
Michael Maes has probably been the leader in the idea of sickness syndrome in relation to CFS. In his last report, he definitely makes the distinction and I have to agree with him. CFS is not sickness syndrome and is more due to inflammation and oxidative and nitrosative stress and pathogenic conditions and permeability can be to blame. Again, I agree and am critical of some that try to base everything about CFS on oxidative stress because it does not really explain how one "gets there"! In my view, it all comes down to and the problem with labels and this always has been my issue..... IN this case, how can we understand where one illness like CFS starts and another one ends such as sickness syndrome if noone really has defined the former CFS well in the first place? It is my belief that sickness syndrome may be a prelude to CFS or maybe the beginning point of it, and different factors can inhibit or lead to a "full-blown" case of CFS and recognizing the biological factors that play a part may in fact, help to prevent CFS in its most severe form. As far as oxidative and nitrosative stress in CFS, I think if you just leave it at..then it is doing a disservice not only to the condition but to those who suffer from it. The reason I say this is because of the nature of oxidative/nitrosative stress --- it is a natural result of cellular processes. Just saying that CFS is caused from too much of these stresses does nothing to answer what is causing the overwhelming oxidative stress in the first place in CFS. Maes has implied that endotoxin may be a pathway to CFS and bacterial infection has potential for causing oxidative stress and changing environments and altered methylation. But the possibility that other environmental factors such as hyperglycemia and high-fat diets which promote bacterial translocation and consequently activate certain immune responses leadin to CFS also, can not be dismissed. I have suggested that the failure of the antioxidant system to adequately meet the needs of oxidative stress or maybe even at all to any real level may play a very important role. In other blogs, we have noted that oxidative and nitrosative stress is needed to activate this system and nutritional and genetic factors may influence the speed and level of activation. So if we have overwhelming oxidative stress -- it makes sense that something like underactivation of the antioxidant system may be at fault or is just not working. So in essence, it should be a no-brainer to look at the Nrf2-Keap1 and other proteins it controls to get a better handle on what may be causing the failure of an adaptive immune response and elevations in inflammatory markers and oxidative stress that are obviously maladaptive.
Several new studies some evidence that a failure in the antioxidant system could contribute to CFS. It is not a direct road I admit, but considering I have been following these paths for 3 years now. They make sense to me, mainly because I look for the CFS from a more holistic and systems theory perspective. For someone that has been trained both in anthropology and biology, this perspective works better for me when I need to find out the answers to different questions that need to be investigated. In addition, one could ask what is a direct road or pathway in reference to disease anyway....to me, it is all relative and most always depends on personal interpretation. Several months ago, I blogged that environmental pollutants may contribute to diabetes and insulin resistance. Since then several other reports conclude this may be the case and many studies have provided evidence how inflammation can lead to insulin resistance and diabetes through the down-regulation of genes and up-regulation of inflammatory cytokines. Several inflammatory markers, not just one, can contribute and can be produced as a consequence of the stress response including TNF-a, Il-1, Il-6. Some of these activate other responses that lead to neuroinflammation and also alteration of neurotransmitters and have other effects on brain chemistry which could be characteristic of the cognitive dysfunction associated with CFS.
It has been suspected that pollutants lead to the alteration of a class of class of genes. I refer to them most often as PARRs and may include PPAR-gamma, PARR-delta and PARR-alpha. I have discussed both PPAR-gamma and PPAR-alpha at length in different discussions and most notably, PPAR-gamma is an important anti-inflammatory which helps prevent the development of insulin resistance in addition to other functions and may help repress autoimmunity. (Klotz) Recently, a study of the combination of pioglitizone and caffeic acid, demonstrated significant improvement in a mouse model of chronic fatigue. In this study, the results showed improvements in running wheel activity, locomotor activity and anxiety. Other improvements included reductions in oxidative damage including lipid peroxidation and nitrite concentration and increased glutatione and catalase levels in addition to altering mitochondrial function. When one digs a little deeper, interesting things appear related to the actions of these compounds. Caffeic acid is an antioxidant and anti-inflammatory that while having potential hazard qualities, also demonstrates the ability to " suppress MMP-9 enzyme activity and down-regulate NF-κB through inhibition of protein IKK and activation of Nrf2 (Lee) and other studies provide in vitro evidence it may effect DNA methylation.(Wipedia)" In contrast, pioglitizone is an anti-hyperglycemic medication and "stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. Both of these compounds act through PARR-gamma directly or indirectly via Nrf which may explain why their benefits in the CFS model is synergistic compared to when they were used alone. (Kumar) Generally, PARRs modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. (Wipedia)" What this says to me is that CFS very well could be considered a condition that is a consequence of significantly disrupted normal glucose uptake and cellular and energy metabolism and altered immune function in different tissues.
I have also postulated that the aryl hydrocarbon may play an important role in both CFS and MCS and there are several "conditions" that lead me to make this assumption and the hypothesis but unfortunately, how this interaction occurs is quite "muddy". First, it has been demonstrated that there is a close connection in the actions of the AhR and the Nrf2 in response to environmental pollutants and their "gene batteries". Second, I have suggested that abnormal signalling from the AhR may influence the functioning of several proteins including the Nrf2 even though the specific mechanismin of how this is achieved is not entirely understood. Third, dioxin which persists in the environment, albeit at lower levels in the last decade in many locales but still present in food, has been associated with diabetes and activates the AhR. Four, for some time it has been believed the AhR may inhibit PPAR-gamma and therefore leads us to environmental conditions, at least physiologically, of elevated inflammation and an increased risk for diabetes. (Remillard) Arguably, the role of the AhR on PPAR-gamma depends on the tissue. (Kitchner, Shin) However, dioxins are bioaccumulative and activation of the AhR and its effects on PPAR-gamma may spill over to surrounding tissues. Lastly, a new study has shown that Nrf2 drives PPAR-gamma in protecting against oxidant injury at least in the respiratory system. Taking all this into account, it is safe to at least suggest that CFS may be influenced by fluctuations in PPAR-gamma and the proteins that regulate it and factors that upregulate it may be beneficial or preventative against CFS. Because PPAR-gamma demonstrates inhibitory properties on autoimmune responses, its absence may play significantly in the "loss of tolerance" responses of chemical sensitivity and inflammatory bowel disease. Other studies show PPAR-gamma has as an important regulatory function with HO-1 and may be neuroprotective against Parkinson's (Lui, Schintu) and influences mitochondrial biogenesis through PGC-1a (Miglio). In other blogs, I discuss how certain nutritional compounds such as resveratrol and EGCG in different foods have shown some benefit and their modes of actions address some of the issues that are discussed in the paragraphs above. IN addition, because these proteins can be effected by methylation this explains the inheritabilty factor that exists with CFS that is not explained just by the presence of oxidative stress.
Notes:
- Endotoxin is considered potential pathway to CFS and inhibits PPAR-gamma through Tnf-a (Zhou)
- It as been suggested that XMRV may play a role in CFS - I would suggest that while XMRV may be a piggy-back condition, any pathogen or infection or pollutant that inhibits PPARs and increase inflammatory mediators contribute to CFS.
Cho, H.-Y. Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S. P., and Kleeberger, S. R. (2010). Nrf2-regulated ppargamma expression is critical to protection against acute lung injury in mice. American journal of respiratory and critical care medicine, 182(2):170-182. http://www.citeulike.org/user/HEIRS/article/6854883?show_msg=already_posted
Kumar, A., Vashist, A., and Kumar, P. (2010). Potential role of pioglitazone, caffeic acid and their combination against fatigue syndrome-induced behavioural, biochemical and mitochondrial alterations in mice. Inflammopharmacology. http://www.citeulike.org/user/HEIRS/article/7474822
Yang, J.-Y. Y., Della-Fera, M. A. A., Rayalam, S., Ambati, S., Hartzell, D. L., Park, H. J. J., and Baile, C. A. (2008). Enhanced inhibition of adipogenesis and induction of apoptosis in 3t3-l1 adipocytes with combinations of resveratrol and quercetin. Life sciences, 82(19-20):1032-1039. http://www.citeulike.org/user/HEIRS/article/7537205
Pioglitazone. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Pioglitazone
Caffeic Acid. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Caffeic_Acid
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