"Asian dust particles can exert toxicological effects on human skin through the activation of the cellular detoxification system, the production of pro-inflammatory and immunomodulatory cytokines, and changes in the expression of proteins essential in normal epidermal differentiation."
Read more: Asian Dust Storm Particles Induce a Broad Toxicolo... [Toxicol Lett. 2010] - PubMed result:
Showing posts with label AhR. Show all posts
Showing posts with label AhR. Show all posts
Sunday, November 14, 2010
Friday, October 29, 2010
Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Hepatocytes is Required for Aryl Hydrocarbon Receptor-Mediated Adaptive and Toxic Responses in Liver
CiteULike: Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Hepatocytes is Required for Aryl Hydrocarbon Receptor-Mediated Adaptive and Toxic Responses in Liver: "AHR-ARNT dimers within the hepatocyte direct the toxic and adaptive and developmental functions associated with the AHR and that developmental vascular events arise due to signaling in a distinct cell type expressing this dimeric pair"
Thursday, October 7, 2010
IDENTIFICATION OF THE ARYL HYDROCARBON RECEPTOR TA... [J Biol Chem. 2010] - PubMed result
IDENTIFICATION OF THE ARYL HYDROCARBON RECEPTOR TA... [J Biol Chem. 2010] - PubMed result: "The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD(+), and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD(+) levels and suppression of AHR target gene induction."
Tuesday, October 5, 2010
Cellular Immune Processes in IBD Activated By Smoke, Burning and More!
"Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD."
Arsenescu, R., Arsenescu, V., Zhong, J., Nasser, M., Melinte, R., Dingle, C. W., Swanson, H., and de Villiers, W. J. (2010). Role of the xenobiotic receptor in inflammatory bowel disease. Inflammatory bowel diseases.
http://www.citeulike.org/user/HEIRS/article/7950224
Arsenescu, R., Arsenescu, V., Zhong, J., Nasser, M., Melinte, R., Dingle, C. W., Swanson, H., and de Villiers, W. J. (2010). Role of the xenobiotic receptor in inflammatory bowel disease. Inflammatory bowel diseases.
http://www.citeulike.org/user/HEIRS/article/7950224
Monday, October 4, 2010
Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET — Toxicol Sci
"common pollutants, such as the polycyclic aromatic hydrocarbon benzo(a)pyrene, can have a direct, negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes."
Read more: Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET — Toxicol Sci:
Read more: Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET — Toxicol Sci:
Saturday, September 4, 2010
Contaminants in Air Pollution Including Endotoxin and Dioxin May Increase Insulin Resistance~!
Complications associated with insulin resistance may play a significant role in environmental diseases including obesity, sleep apneas and potentially Gulf War Syndrome and chemical sensitivity just for examples. Other studies show that sustained endotoxin, a potential consideration in CFS and other environmental illnesses, is a common component of particulate matter and environmental pollutants may alter insuling signalling in muscle especially under sustained stress such as malnutrition. These conditions may potentiate one another if they occur at the same time.....
"TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance."
Read more: CiteULike: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.:
For further understanding: IRS-1
McCowen, K. C., Ling, P. R., Ciccarone, A., Mao, Y., Chow, J. C., Bistrian, B. R., and Smith, R. J. (2001). Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade. Critical care medicine, 29(4):839-846. http://www.citeulike.org/user/HEIRS/article/7782376
"TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance."
Read more: CiteULike: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.:
For further understanding: IRS-1
McCowen, K. C., Ling, P. R., Ciccarone, A., Mao, Y., Chow, J. C., Bistrian, B. R., and Smith, R. J. (2001). Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade. Critical care medicine, 29(4):839-846. http://www.citeulike.org/user/HEIRS/article/7782376
Wednesday, August 4, 2010
Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.
"induction of functional Foxp3(+) iT(reg) cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT(reg) cells could be induced in human autoimmune disorders."Read more: CiteULike: Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.
:"Gandhi, R., Kumar, D., Burns, E. J., Nadeau, M., Dake, B., Laroni, A., Kozoriz, D., Weiner, H. L., and Quintana, F. J. (2010). Activation of the aryl hydrocarbon receptor induces human type 1 regulatory t cell-like and foxp3(+) regulatory t cells. Nature immunology."
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
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
Thursday, July 15, 2010
Coffee induces expression of glucuronosyltransferases via the aryl hydrocarbon receptor and Nrf2 in liver and stomach.
Glucuronidation: phase II detoxification pathway occurring in the liver in which glucuronic acid is conjugated with toxins. Effectively detoxifies the majority of commonly prescribed drugs. (Source Link: glucuronidation )
"UGT1A genes are induced in vitro and in vivo by coffee, independent of caffeine content, cafestol, or kahweol. Coffee upregulates glucuronidation via AhR signaling and Nrf2 binding to the ARE/XRE. Glucuronidation could mediate the protective and antioxidant effects of coffee."
CiteULike: Coffee induces expression of glucuronosyltransferases via the aryl hydrocarbon receptor and Nrf2 in liver and stomach.:
"UGT1A genes are induced in vitro and in vivo by coffee, independent of caffeine content, cafestol, or kahweol. Coffee upregulates glucuronidation via AhR signaling and Nrf2 binding to the ARE/XRE. Glucuronidation could mediate the protective and antioxidant effects of coffee."
CiteULike: Coffee induces expression of glucuronosyltransferases via the aryl hydrocarbon receptor and Nrf2 in liver and stomach.:
Tuesday, June 29, 2010
The Unexpected Role for the Aryl Hydrocarbon Receptor on Susceptibility to Experimental Toxoplasmosis
Toxoplasmosis is caused by infection with Toxoplasma gondii, an obligate intracellular parasite. The infection produces a wide range of clinical syndromes in humans, land and sea mammals, and various bird species.
The Unexpected Role for the Aryl Hydrocarbon Receptor on Susceptibility to Experimental Toxoplasmosis: "The Unexpected Role for the Aryl Hydrocarbon Receptor on Susceptibility to Experimental Toxoplasmosis"
Toxoplasmosis. eMedicine. Retrieved on June 30, 2010. http://emedicine.medscape.com/article/229969-overview
Friday, June 18, 2010
Dioxin Causes Changes in Blood Vessels Through AhR in Developing Zebrafish!
Dioxins: bioaccumulatives chemical compounds formed through combustion and manufacturing. Incidents include backyard burning, applications of herbicides, wastewater treatment, coal-fires, diesel trucks, cigarette smoke, etc(Wipedia)
A recent study shows "activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish." Past studies have demonstrated a significant impact of AhR signaling on the immune system that may also alter the Nrf2 antioxidant system. For this reason, we have suggested an important relationship of AhR and Nrf2 signaling in environmental illness and alterations of blood flow may be a factor in environmental illness symptoms. Dinatale showed AhR signaling initiates an inflammatory cascade that includes Il-6 via Il-1 and NF-kappaB and present in autoimmune and chronic proliferative diseases.
CiteULike: Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.:
Teraoka, H., Ogawa, A., Kubota, A., Stegeman, J. J., Peterson, R. E., and Hiraga, T. (2010). Malformation of certain brain blood vessels caused by tcdd activation of ahr2/arnt1 signaling in developing zebrafish. Aquatic toxicology (Amsterdam, Netherlands).
http://www.citeulike.org/user/HEIRS/article/7149860
Dinatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A., and Perdew, G. H. (2010). Mechanistic insights into the events that lead to synergistic induction of il6 transcription upon activation of the ah receptor and inflammatory signaling. The Journal of biological chemistry.
http://www.citeulike.org/user/HEIRS/article/7339715
A recent study shows "activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish." Past studies have demonstrated a significant impact of AhR signaling on the immune system that may also alter the Nrf2 antioxidant system. For this reason, we have suggested an important relationship of AhR and Nrf2 signaling in environmental illness and alterations of blood flow may be a factor in environmental illness symptoms. Dinatale showed AhR signaling initiates an inflammatory cascade that includes Il-6 via Il-1 and NF-kappaB and present in autoimmune and chronic proliferative diseases.
CiteULike: Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.:
Teraoka, H., Ogawa, A., Kubota, A., Stegeman, J. J., Peterson, R. E., and Hiraga, T. (2010). Malformation of certain brain blood vessels caused by tcdd activation of ahr2/arnt1 signaling in developing zebrafish. Aquatic toxicology (Amsterdam, Netherlands).
http://www.citeulike.org/user/HEIRS/article/7149860
Dinatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A., and Perdew, G. H. (2010). Mechanistic insights into the events that lead to synergistic induction of il6 transcription upon activation of the ah receptor and inflammatory signaling. The Journal of biological chemistry.
http://www.citeulike.org/user/HEIRS/article/7339715
Thursday, June 17, 2010
AhR and NF-E2-related factor 2 are key regulators of human MRP4 expression
Our findings indicate that AhR and Nrf2 play important roles in regulating MRP4 expression and suggest that agents that activate their activity may be of therapeutic benefit for cholestasis.
CiteULike: Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression: "Xu, S., Weerachayaphorn, J., Cai, S.-Y., Soroka, C. J., and Boyer, J. L. (2010). Aryl hydrocarbon receptor and nf-e2-related factor 2 are key regulators of human mrp4 expression. Am J Physiol Gastrointest Liver Physiol, 299(1):G126-135."
Wednesday, June 16, 2010
Dioxin downregulation folate carrier transport through the AhR.
deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptorCiteULike: Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway.: "Halwachs, S., Lakoma, C., Gebhardt, R., Schäfer, I., Seibel, P., and Honscha, W. (2010). Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway. Toxicology and applied pharmacology, 246(1-2):100-106."
Wednesday, January 13, 2010
ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!
ImmunoGenetics in Autism, MCS and Cancer --
What Has Food Got To Do With It
Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.
B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.
Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.
To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)
The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!
Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.
An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.
Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.
Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.
New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).
In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.
It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.
Original document and citations
What Has Food Got To Do With It
Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.
B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.
Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.
To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)
The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!
Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.
An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.
Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.
Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.
New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).
In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.
It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.
Original document and citations
Monday, January 11, 2010
Interaction between oxidative stress sensor NRF2 and AhR in the regulation of the phase II detoxification UDP- GST1A10
In the past, we have noted that both the proper function of the AhR and Nrf2 may coordinate detoxification activities. This new study provides evidence that evidence that both are necessary for the induction of enzymes necessary for detoxification of substance including "steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites." KalthoffWipedia As we have noted, EGCG has been demonstrated to have beneficial properties. The chemical EGCG found in green tea has been demonstrated to increase both UGT1A8 and UGT1A10 and has been shown to be dependant on Nrf2 expression. (Yang)
CiteULike: Interaction between oxidative stress sensor nuclear factor erythroid 2-related factor 2 (NRF2) and xenobiotic activated aryl hydrocarbon receptor (AHR) in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10.: "Kalthoff, S., Ehmer, U., Freiberg, N., Manns, M. P., and Strassburg, C. P. (2010). Interaction between oxidative stress sensor nuclear factor erythroid 2-related factor 2 (nrf2) and xenobiotic activated aryl hydrocarbon receptor (ahr) in the regulation of the human phase ii detoxifying udp-glucuronosyltransferase 1a10. The Journal of biological chemistry."
Yang, X.-y. Y., Zhao, W.-p. P., Li, Y.-q. Q., Sun, Z.-y. Y., Zhang, Y., Guo, Y.-t. T., Yuan, J.-h. H., Zhu, Q., and Wang, M. (2006). [the role of nf-e2-related factor 2 in the induction of uridine 5'-diphosphate-glucuronosyltransferase 1a and its isoforms by epigallocatechin gallate in colon cancer cells]. Zhonghua yi xue za zhi, 86(2):82-87.
http://www.citeulike.org/user/HEIRS/article/6525255
CiteULike: Interaction between oxidative stress sensor nuclear factor erythroid 2-related factor 2 (NRF2) and xenobiotic activated aryl hydrocarbon receptor (AHR) in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10.: "Kalthoff, S., Ehmer, U., Freiberg, N., Manns, M. P., and Strassburg, C. P. (2010). Interaction between oxidative stress sensor nuclear factor erythroid 2-related factor 2 (nrf2) and xenobiotic activated aryl hydrocarbon receptor (ahr) in the regulation of the human phase ii detoxifying udp-glucuronosyltransferase 1a10. The Journal of biological chemistry."
Yang, X.-y. Y., Zhao, W.-p. P., Li, Y.-q. Q., Sun, Z.-y. Y., Zhang, Y., Guo, Y.-t. T., Yuan, J.-h. H., Zhu, Q., and Wang, M. (2006). [the role of nf-e2-related factor 2 in the induction of uridine 5'-diphosphate-glucuronosyltransferase 1a and its isoforms by epigallocatechin gallate in colon cancer cells]. Zhonghua yi xue za zhi, 86(2):82-87.
http://www.citeulike.org/user/HEIRS/article/6525255
Wednesday, December 30, 2009
Etiological and biological aspects (ie AhR,Th-17) of cigarette smoking in rheumatoid arthritis.
One would suspect that pollutants are a major factor considering involvement with the AhR and this author makes some interesting points that RA started in the New World in the N American population and spread to Europe suggesting a vector-born disease.....??
TENNESSEE ORIGINS OF RHEUMATOID ARTHRITIS by Bruce M. Rothschild
Etiological and biological aspects of cigarette smoking in rheumatoid arthritis.: "Onozaki, K. (2009). Etiological and biological aspects of cigarette smoking in rheumatoid arthritis. Inflammation & allergy drug targets, 8(5):364-368"
TENNESSEE ORIGINS OF RHEUMATOID ARTHRITIS by Bruce M. Rothschild
Etiological and biological aspects of cigarette smoking in rheumatoid arthritis.: "Onozaki, K. (2009). Etiological and biological aspects of cigarette smoking in rheumatoid arthritis. Inflammation & allergy drug targets, 8(5):364-368"
Monday, October 19, 2009
Hypersensitivity of ahr-deficient mice to lps-induced septic shock
Background: Recent studies suggest endotoxin may be a pathway to chronic fatigue syndrome and the associated inflammtory processes associated with it may contribute to a number of other acute, chronic and environmental diseases as well.
Title: Hypersensitivity of ahr-deficient mice to lps-induced septic shock.
Summary: This study suggests that absence of AhR expression results in increased expression of Il-1b and are hypersensitive to shock after exposure to LPS endotoxin.
Citation: Sekine, H., Mimura, J., Oshima, M., Okawa, H., Kanno, J., Igarashi, K., Gonzalez, F. J., Ikuta, T., Kawajiri, K., and Fujii-Kuriyama, Y. (2009). Hypersensitivity of ahr-deficient mice to lps-induced septic shock. Molecular and cellular biology. http://www.citeulike.org/user/HEIRS/article/5971045
Title: Hypersensitivity of ahr-deficient mice to lps-induced septic shock.
Summary: This study suggests that absence of AhR expression results in increased expression of Il-1b and are hypersensitive to shock after exposure to LPS endotoxin.
Citation: Sekine, H., Mimura, J., Oshima, M., Okawa, H., Kanno, J., Igarashi, K., Gonzalez, F. J., Ikuta, T., Kawajiri, K., and Fujii-Kuriyama, Y. (2009). Hypersensitivity of ahr-deficient mice to lps-induced septic shock. Molecular and cellular biology. http://www.citeulike.org/user/HEIRS/article/5971045
Monday, September 21, 2009
AhR and Excitoxicity
Lin, C.-H. H., Chen, C.-C. C., Chou, C.-M. M., Wang, C.-Y. Y., Hung, C.-C. C., Chen, J. Y., Chang, H.-W. W., Chen, Y.-C. C., Yeh, G. C. C., and Lee, Y.-H. H. (2009). Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances nmda-induced bdnf expression in cortical neurons. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5817355
Monday, September 14, 2009
Effects of acute and prolonged naphthalene exposure on brain monoaminergic neurotransmitters in rainbow trout (oncorhynchus mykiss).
"levels of NA were increased in hypothalamus and telencephalon after acute treatment and in hypothalamus and preoptic area after several days of exposure to naphthalene. These data suggest that brain neurotransmitter systems are sensitive to polycyclic aromatic hydrocarbons and could represent a target of the naphthalene-induced neuroendocrine disruption."
Gesto, M., Tintos, A., Soengas, J. L., and Míguez, J. M. (2006). Effects of acute and prolonged naphthalene exposure on brain monoaminergic neurotransmitters in rainbow trout (oncorhynchus mykiss). Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 144(2):173-183. http://www.citeulike.org/user/HEIRS/article/5784797
Gesto, M., Tintos, A., Soengas, J. L., and Míguez, J. M. (2006). Effects of acute and prolonged naphthalene exposure on brain monoaminergic neurotransmitters in rainbow trout (oncorhynchus mykiss). Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 144(2):173-183. http://www.citeulike.org/user/HEIRS/article/5784797
Saturday, September 12, 2009
PPAR-gamma Ligands Can Induce HO-1 with/without Nrf2
Background: Dioxins and other environmental contaminants can lead to the bioaccumulation and the production of Tnf-a which can lead to activation of other cellular signal and inflammatory mediators. In addition, its expression can inhibit the expression of cellular proteins that are necessary for cellular functions and protection from inflammation. Some of these proteins can have both positive and negative effects. One such proteins is PPAR-gamma which is an important player in adipogenesis which if uncontrolled can lead to obesity. On the other hand, it has powerful cellular anti-inflammatory properties and regulates insulin sensitivity and fatty acid metabolism. Nrf2’s role in cells is to help modulate the expression of chemokines like Tnf-a. Its decrease may lead to overexpression of inflammatory proteins that alter cellular homeostasis. Nrf2 levels can fall due to aging, nutritional factors such as high-fat diets, interaction with other proteins etc. The AhR is one protein that interacts with Nrf2 to provide protective effects. The AhR also mediates toxicity from dioxin and other compounds similar to dioxins and can inhibit the activities of PPAR-gamma which may lead to weight loss and abnormal fatty acid metabolism. Other studies have shown this inhibition is not direct but acts through the activities of other proteins. Nrf2 also controls the levels of HO-1 which is an important anti-inflammatory, antioxidant and anti-apoptotic properties by acting through bilirubin/biliverdin and CO. Ho-1 has the ability to mediate adiponectin which can decrease fat content and inflammatory cytokines in diabetic rats. (Kim, Abraham) Cao’s findings show that HO-1 combined with increases in adiponectin in diabetes decreased oxidative stress and improved endothelial function and hypertension and also prevented apoptosis.
Fergusen demonstrates in fibroblasts that PPAR-gamma ligands can elevate the levels of HO-1 which as one author showed is independent, in this case, of Nrf2. In this study it was shown that two ligands of PPAR-gamma, CDDO and 15-PJG2 have potent anti-fibrotic effects in-vitro, also has the ability to upregulate HO-1 in lung fibroblasts. Ligands that do not have an electrophilic center did not elevate HO-1 in this study and the results show that these ligands induce HO-1 through a GSH-dependant mechanism. The author concludes from this study that electrophilic PPAR-gamma ligands have a clinical potential as anti-fibrotic agents by their activities on fibroblast function and indirectly activating antioxidant defenses. In this experiment, NAC prevented the upregulation of HO-1. Past studies have shown that PJG2 has the ability to enhance the expression of GSTA2 through Nrf2 and that PPAR-gamma can enhance this expression further. (Park)
Note:
Hanlon, P. (2003). Ahr- and erk-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicology and Applied Pharmacology, 189(1):11-27. http://www.citeulike.org/user/HEIRS/article/5778106
Ferguson, H. E., Thatcher, T. H., Olsen, K. C., Garcia-Bates, T. M., Baglole, C. J., Kottmann, R. M., Strong, E. R., Phipps, R. P., and Sime, P. J. (2009). Peroxisome proliferator activated receptor-gamma (ppargamma) ligands induce heme oxygenase-1 in lung fibroblasts by a ppargamma-independent, glutathione-dependent mechanism. American journal of physiology. Lung cellular and molecular physiology. http://www.citeulike.org/user/HEIRS/article/5778124
Park, E. Y. Y., Cho, I. J. J., and Kim, S. G. G. (2004). Transactivation of the ppar-responsive enhancer module in chemopreventive glutathione s-transferase gene by the peroxisome proliferator-activated receptor-gamma and retinoid x receptor heterodimer. Cancer research, 64(10):3701-3713. http://www.citeulike.org/user/HEIRS/article/5775526
Kim, D. H., Burgess, A. P., Li, M., Tsenovoy, P. L., Addabbo, F., McClung, J. A., Puri, N., and Abraham, N. G. (2008). Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in zucker rats and reduce adipogenesis in human mesenchymal stem cells. J Pharmacol Exp Ther, 325(3):833-840. http://www.citeulike.org/user/HEIRS/article/5127284
Cao, J., Drummond, G., Inoue, K., Sodhi, K., Li, X. Y. Y., and Omura, S. (2008). Upregulation of heme oxygenase-1 combined with increased adiponectin lowers blood pressure in diabetic spontaneously hypertensive rats through a reduction in endothelial cell dysfunction, apoptosis and oxidative stress. International journal of molecular sciences, 9(12):2388-2406. http://www.citeulike.org/user/HEIRS/article/5778162
Abraham, N. G., Kushida, T., McClung, J., Weiss, M., Quan, S., Lafaro, R., Darzynkiewicz, Z., and Wolin, M. (2003). Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res, 93(6):507-514. http://www.citeulike.org/user/HEIRS/article/5743474
Mueller, M., Lukas, B., Novak, J., Simoncini, T., Genazzani, A. R., and Jungbauer, A. (2008). Oregano: A source for peroxisome proliferator-activated receptor γ antagonists. Journal of Agricultural and Food Chemistry. http://www.citeulike.org/group/7086/article/3647240
Yao, P., Hao, L., Nussler, N., Lehmann, A., Song, F., Zhao, J., Neuhaus, P., Liu, L., and Nussler, A. (2009). The protective role of ho-1 and its generated products (co, bilirubin, and fe) in ethanol-induced human hepatocyte damage. Am J Physiol Gastrointest Liver Physiol, 296(6):G1318-1323. http://www.citeulike.org/user/HEIRS/article/5778434
Note:
- Oregano has the potential for preventing or reducing the effects of the metabolic syndrome which includes obesity, high blood sugar, high blood pressure and alteractions in lipid levels. Oregano binds but does not transactivate PPAR-gamma and contain a number of different chemicals that have been shown in studies to be of nutritional benefit. According to one author, "there may be a use for oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARα agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis. The results warrant further investigation of oregano extract for its potential to prevent and ameliorate metabolic syndrome and its complications."
- Quercetin (which is in oregano extract) can counteract ethanol-induced liver damage by upregulating HO-1. (Yao)
Hanlon, P. (2003). Ahr- and erk-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicology and Applied Pharmacology, 189(1):11-27. http://www.citeulike.org/user/HEIRS/article/5778106
Ferguson, H. E., Thatcher, T. H., Olsen, K. C., Garcia-Bates, T. M., Baglole, C. J., Kottmann, R. M., Strong, E. R., Phipps, R. P., and Sime, P. J. (2009). Peroxisome proliferator activated receptor-gamma (ppargamma) ligands induce heme oxygenase-1 in lung fibroblasts by a ppargamma-independent, glutathione-dependent mechanism. American journal of physiology. Lung cellular and molecular physiology. http://www.citeulike.org/user/HEIRS/article/5778124
Park, E. Y. Y., Cho, I. J. J., and Kim, S. G. G. (2004). Transactivation of the ppar-responsive enhancer module in chemopreventive glutathione s-transferase gene by the peroxisome proliferator-activated receptor-gamma and retinoid x receptor heterodimer. Cancer research, 64(10):3701-3713. http://www.citeulike.org/user/HEIRS/article/5775526
Kim, D. H., Burgess, A. P., Li, M., Tsenovoy, P. L., Addabbo, F., McClung, J. A., Puri, N., and Abraham, N. G. (2008). Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in zucker rats and reduce adipogenesis in human mesenchymal stem cells. J Pharmacol Exp Ther, 325(3):833-840. http://www.citeulike.org/user/HEIRS/article/5127284
Cao, J., Drummond, G., Inoue, K., Sodhi, K., Li, X. Y. Y., and Omura, S. (2008). Upregulation of heme oxygenase-1 combined with increased adiponectin lowers blood pressure in diabetic spontaneously hypertensive rats through a reduction in endothelial cell dysfunction, apoptosis and oxidative stress. International journal of molecular sciences, 9(12):2388-2406. http://www.citeulike.org/user/HEIRS/article/5778162
Abraham, N. G., Kushida, T., McClung, J., Weiss, M., Quan, S., Lafaro, R., Darzynkiewicz, Z., and Wolin, M. (2003). Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res, 93(6):507-514. http://www.citeulike.org/user/HEIRS/article/5743474
Mueller, M., Lukas, B., Novak, J., Simoncini, T., Genazzani, A. R., and Jungbauer, A. (2008). Oregano: A source for peroxisome proliferator-activated receptor γ antagonists. Journal of Agricultural and Food Chemistry. http://www.citeulike.org/group/7086/article/3647240
Yao, P., Hao, L., Nussler, N., Lehmann, A., Song, F., Zhao, J., Neuhaus, P., Liu, L., and Nussler, A. (2009). The protective role of ho-1 and its generated products (co, bilirubin, and fe) in ethanol-induced human hepatocyte damage. Am J Physiol Gastrointest Liver Physiol, 296(6):G1318-1323. http://www.citeulike.org/user/HEIRS/article/5778434
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