Sunday, January 31, 2010
Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases.
Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases.: "URL: Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases.
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Tumor necrosis factor [alpha] blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells
Tumor necrosis factor [alpha] blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells: "URL: Tumor necrosis factor [alpha] blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells
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Oxidative stress in systemic lupus erythematosus: relationship to Th1 cytokine and disease activity.
CiteULike: Wnt/beta-Catenin Signaling Activates and Determines Hepatic Zonal Expression of Glutathione S-Transferases in Mouse Liver
CiteULike: Wnt/beta-Catenin Signaling Activates and Determines Hepatic Zonal Expression of Glutathione S-Transferases in Mouse Liver: "Giera, S., Braeuning, A., Kohle, C., Bursch, W., Metzger, U., Buchmann, A., and Schwarz, M. (2010). Wnt/beta-catenin signaling activates and determines hepatic zonal expression of glutathione s-transferases in mouse liver. Toxicol. Sci., pages kfq033+."
Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells.
CiteULike: Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells.: "Han, Y. S. S. and Lee, C. S. S. (2009). Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated pc12 cells. European journal of pharmacology, 604(1-3):36-44."
Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats
"In conclusion, LPS impairs hepatic ammonia detoxification by both downregulation of GS and its inactivation because of tyrosine nitration. The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis."Görg, B., Wettstein, M., Metzger, S., Schliess, F., and Häussinger, D. (2005). Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat. Hepatology (Baltimore, Md.), 41(5):1065-1073.
Saturday, January 30, 2010
Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6.
CiteULike: Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6.: "Tweedell, A., Mulligan, K. X., Martel, J. E., Chueh, F.-Y. Y., Santomango, T., and McGuinness, O. P. (2010). Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6. Metabolism: clinical and experimental."
Modeling human health risks of airborne endotoxin in homes during the winter and summer seasons.
CiteULike: Modeling human health risks of airborne endotoxin in homes during the winter and summer seasons.: "Liao, V. H.-C. H., Chio, C.-P. P., Chou, W.-C. C., Ju, Y.-R. R., and Liao, C.-M. M. (2010). Modeling human health risks of airborne endotoxin in homes during the winter and summer seasons. The Science of the total environment."
CiteULike: Exposure of Toll-like receptors 4 to bacterial lipopolysaccharide (LPS) impairs human colonic smooth muscle cell function.
CiteULike: Exposure of Toll-like receptors 4 to bacterial lipopolysaccharide (LPS) impairs human colonic smooth muscle cell function.: "Scirocco, A., Matarrese, P., Petitta, C., Cicenia, A., Ascione, B., Mannironi, C., Ammoscato, F., Cardi, M., Fanello, G., Guarino, M. P., Malorni, W., and Severi, C. (2010). Exposure of toll-like receptors 4 to bacterial lipopolysaccharide (lps) impairs human colonic smooth muscle cell function. Journal of cellular physiology."
Ammonia, ASIC Channels and Mental Health
We recently have been discussing how the biological accumulation of ammonia may be an important condition related to a number of environmental illnesses. In fact, several studies suggest that accumulation of ammonia may contribute to autism and others note it plays a very important role in hepatic failure. As we noted, elevated levels of homocysteinemia may impair the urea cycle - which helps the body get rid of excess ammonia and glutamine synthetase genes of the Wnt/Catenin pathway, also regulate ammonia concentrations in the body. Interestingly, several "so-called therapies" for MCS also have the capacity to reduce ammonia. Also, it is well-known that psychological disturbances are co-morbid with a number of environmental conditions, in addition to those mental effects associated with autism and liver disease.
In light of the potential for elevated ammonia levels to influence the psychological and physical effects of environmental disease, I thought I would point out two interesting studies. The first is a study that suggests that ASIC channels contribute to the health consequences where hyperammonemia becomes an issue. As the author points out, this may include hepatic encephalopathy, cirrhosis and neuronal disorders. This study discusses how these types of channels have been implicated in neuronal death after their activation. Incidentally, nociceptive behavior is associated with acidic environments that develop from injury and inflammation and therefore could play a role in the pain generation in environmental illnesses including MCS (Pall) and chronic fatigue syndrome (Light). Pidoplichko provides evidence the involvement of these channels may contribute to the loss of dopamine neurons in Parkinson's disease because these channels are associated with those neurons and "ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus." The second study seems to suggest that these same channels have an important role in the development of depression-related behavior by demonstrating genetically altered -/- mice presented with anti-depressant-like behaviors even while put under experiemental stress. In addition, the dysruption of these channels interfered with an important "biomarker of depression" which is a decrease of levels of BDNF in the hippocampus. In past blogs, we have explained how BDNF is important for "olfactory neurogenesis" and may be important consideration in the development of MCS. Coryell concludes by saying that his "findings of ASIC1 signaling in the amydala in mood regulation support others and that pharmaceutical approaches that target ASIC1 signaling may be therapeutic for this kind of depression. We might propose that investigating therapies that reduce ASIC signaling may be beneficial for a number of environmentally-related conditions may be of value.
Notes:
Coryell, M. W., Wunsch, A. M., Haenfler, J. M., Allen, J. E., Schnizler, M., Ziemann, A. E., Cook, M. N., Dunning, J. P., Price, M. P., Rainier, J. D., Liu, Z., Light, A. R., Langbehn, D. R., and Wemmie, J. A. (2009). Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci., 29(17):5381-5388. http://www.citeulike.org/user/HEIRS/article/6607146
Pidoplichko, V. I. and Dani, J. A. (2006). Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proceedings of the National Academy of Sciences of the United States of America, 103(30):11376-11380. http://www.citeulike.org/user/HEIRS/article/6607127
Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. http://www.citeulike.org/user/HEIRS/article/5370052
Ugawa, S., Ueda, T., Ishida, Y., Nishigaki, M., Shibata, Y., and Shimada, S. (2002). Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. The Journal of clinical investigation, 110(8):1185-1190. http://www.citeulike.org/user/HEIRS/article/2942104
Pall, Martin (2007). Explaining Ãœnexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479
Hung, S.-Y. Y., Liou, H.-C. C., and Fu, W.-M. M. (2010). The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology, 58(2):321-329. http://www.citeulike.org/user/HEIRS/article/6196852
In light of the potential for elevated ammonia levels to influence the psychological and physical effects of environmental disease, I thought I would point out two interesting studies. The first is a study that suggests that ASIC channels contribute to the health consequences where hyperammonemia becomes an issue. As the author points out, this may include hepatic encephalopathy, cirrhosis and neuronal disorders. This study discusses how these types of channels have been implicated in neuronal death after their activation. Incidentally, nociceptive behavior is associated with acidic environments that develop from injury and inflammation and therefore could play a role in the pain generation in environmental illnesses including MCS (Pall) and chronic fatigue syndrome (Light). Pidoplichko provides evidence the involvement of these channels may contribute to the loss of dopamine neurons in Parkinson's disease because these channels are associated with those neurons and "ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus." The second study seems to suggest that these same channels have an important role in the development of depression-related behavior by demonstrating genetically altered -/- mice presented with anti-depressant-like behaviors even while put under experiemental stress. In addition, the dysruption of these channels interfered with an important "biomarker of depression" which is a decrease of levels of BDNF in the hippocampus. In past blogs, we have explained how BDNF is important for "olfactory neurogenesis" and may be important consideration in the development of MCS. Coryell concludes by saying that his "findings of ASIC1 signaling in the amydala in mood regulation support others and that pharmaceutical approaches that target ASIC1 signaling may be therapeutic for this kind of depression. We might propose that investigating therapies that reduce ASIC signaling may be beneficial for a number of environmentally-related conditions may be of value.
Notes:
- A recent study shows that HO-1 activates bilirubin and CO to modulate BDNF/GDNF in neurons and astrocytes. This provides a protective effect on dopaminergic neurons.
Coryell, M. W., Wunsch, A. M., Haenfler, J. M., Allen, J. E., Schnizler, M., Ziemann, A. E., Cook, M. N., Dunning, J. P., Price, M. P., Rainier, J. D., Liu, Z., Light, A. R., Langbehn, D. R., and Wemmie, J. A. (2009). Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci., 29(17):5381-5388. http://www.citeulike.org/user/HEIRS/article/6607146
Pidoplichko, V. I. and Dani, J. A. (2006). Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proceedings of the National Academy of Sciences of the United States of America, 103(30):11376-11380. http://www.citeulike.org/user/HEIRS/article/6607127
Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. http://www.citeulike.org/user/HEIRS/article/5370052
Ugawa, S., Ueda, T., Ishida, Y., Nishigaki, M., Shibata, Y., and Shimada, S. (2002). Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. The Journal of clinical investigation, 110(8):1185-1190. http://www.citeulike.org/user/HEIRS/article/2942104
Pall, Martin (2007). Explaining Ãœnexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479
Hung, S.-Y. Y., Liou, H.-C. C., and Fu, W.-M. M. (2010). The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology, 58(2):321-329. http://www.citeulike.org/user/HEIRS/article/6196852
Friday, January 29, 2010
Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression.
CiteULike: Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression.: "Choi, H.-K. K., Pokharel, Y. R. R., Lim, S. C. C., Han, H.-K. K., Ryu, C. S. S., Kim, S. K. K., Kwak, M. K. K., and Kang, K. W. W. (2009). Inhibition of liver fibrosis by solubilized coenzyme q10: Role of nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicology and applied pharmacology, 240(3):377-384."
CiteULike: The protective role of Nrf2 in STZ-induced diabetic nephropathy.
CiteULike: The protective role of Nrf2 in STZ-induced diabetic nephropathy.: "Jiang, T., Huang, Z., Lin, Y., Zhang, Z., Fang, D., and Zhang, D. D. (2010). The protective role of nrf2 in stz-induced diabetic nephropathy. Diabetes."
CiteULike: The NRF2-heme oxygenase-1 system modulates cyclosporine A-induced epithelial-mesenchymal transition and renal fibrosis.
CiteULike: The NRF2-heme oxygenase-1 system modulates cyclosporine A-induced epithelial-mesenchymal transition and renal fibrosis.: "Shin, D.-H. H., Park, H.-M. M., Jung, K.-A. A., Choi, H.-G. G., Kim, J.-A. A., Kim, D.-D. D., Kim, S. G. G., Kang, K. W. W., Ku, S. K. K., Kensler, T. W., and Kwak, M.-K. K. (2010). The nrf2-heme oxygenase-1 system modulates cyclosporine a-induced epithelial-mesenchymal transition and renal fibrosis. Free radical biology & medicine."
Thursday, January 28, 2010
Wednesday, January 27, 2010
CiteULike: The Wnt/beta-catenin pathway: master regulator of liver zonation?
The Wnt/beta-catenin pathway: master regulator of liver zonation?: "Burke, Z. D. and Tosh, D. (2006). The wnt/beta-catenin pathway: master regulator of liver zonation? BioEssays, 28(11):1072-1077."
Arthritis: Environmental exposure to hairspray, lipstick, pollution, can trigger autoimmune diseases
Arthritis: Environmental exposure to hairspray, lipstick, pollution, can trigger autoimmune diseases
ScienceDaily (2010-01-27) -- Our immediate environment interacts with our genetic programming and can determine if we will succumb to an autoimmune disease, according to new research. ... > read full article
ScienceDaily (2010-01-27) -- Our immediate environment interacts with our genetic programming and can determine if we will succumb to an autoimmune disease, according to new research. ... > read full article
CiteULike: ENDOTOXIN-MEDIATED DISTURBANCE OF HEPATIC CYTOCHROME P450 FUNCTION AND DEVELOPMENT OF ENDOTOXIN TOLERANCE IN THE RAT MODEL OF DEXTRAN SULFATE SODIUM-INDUCED EXPERIMENTAL COLITIS
CiteULike: ENDOTOXIN-MEDIATED DISTURBANCE OF HEPATIC CYTOCHROME P450 FUNCTION AND DEVELOPMENT OF ENDOTOXIN TOLERANCE IN THE RAT MODEL OF DEXTRAN SULFATE SODIUM-INDUCED EXPERIMENTAL COLITIS: "Masubuchi, Y. and Horie, T. (2004). Endotoxin-mediated disturbance of hepatic cytochrome p450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metabolism and Disposition, 32(4):437-441."
Ammonia and Its Relationship To Environmental Illness
Background: The build-up of excess ammonia has been implicated in environmental conditions such as autism and may contribute to physiological effects of others as well. In recent days, we have discussed how homocysteinemia may impair the urea cycle which may lead to excess ammonia levels and that some common treatments used for environmental illness also are used as treatments to reduce physiological ammonia levels. Exogenous environmental factors may also lead to elevations in ammonia. Interestingly, in fish, exposure to ammonia leads to symptoms one may conclude typical of sickness syndrome which includes loss of appetite. While it is difficult to extrapolate behavior in these animals to similar behaviors in humans, we have mentioned previously that sickness syndrome is not exclusive to the human organism and has been observed in other animals (ie domesticated dogs). In the recent study of fish, ammonia activates the stress regulator corticotropin releasing factor and other stress systems including the one that controls dopamine and leads to elevations in this stress hormone also. The activation of this system has also been implicated in psychological effects associated with PTSD in humans and addictive behaviors such as alcohol abuse.
Taken these studies into account, one would suggest that ammonia which also contributes to mitochondrial dysfunction may contribute to a number of environmental illnesses by activating different systems during the stress response and may exacerbate the complications associated with injury or down-regulation in function from toxic exposures to the liver. In addition, there are several negative psychological and physical effects in environmental illnesses that can be attributed to abherrant signaling by GSK-3b which is modulated through the Wnt pathway. As Burke writes, "The liver contains two systems for the removal of ammonia - the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/-c:atenin pathway[]." Experts admit there is a lot to learn about this relatively unexplored molecular pathway. However, the most recent evidence suggests it is an important pathway that interacts with other pathways in inflammation and acts as a crucial regulator of functions of different biological systems. Recent studies associate Wnt signaling in inflammation in adipocytes which is the major site for bioaccumulation of toxicants in the body. This fact elevates the significance of this pathway in environmental health studies. Of course, further research is needed to identify the level of the role it plays on the physical and mental effects of exposures from environmental contaminants.
The Wnt/β-catenin pathway: master regulator of liver zonation?. Zoë D. Burke. 2006; BioEssays - Wiley InterScience
Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866. http://www.citeulike.org/user/HEIRS/article/6594636
Castelo-Branco, G., Rawal, N., and Arenas, E. (2004). Gsk-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci, 117(24):5731-5737. http://www.citeulike.org/user/HEIRS/article/6582306
Taken these studies into account, one would suggest that ammonia which also contributes to mitochondrial dysfunction may contribute to a number of environmental illnesses by activating different systems during the stress response and may exacerbate the complications associated with injury or down-regulation in function from toxic exposures to the liver. In addition, there are several negative psychological and physical effects in environmental illnesses that can be attributed to abherrant signaling by GSK-3b which is modulated through the Wnt pathway. As Burke writes, "The liver contains two systems for the removal of ammonia - the urea cycle and the enzyme glutamine synthetase. These systems are expressed in a complementary fashion in two distinct populations of hepatocytes, referred to as periportal and perivenous cells. One of the unresolved problems in hepatology has been to elucidate the molecular mechanisms responsible for induction and maintenance of the cellular heterogeneity for ammonia detoxification. There is now a potential molecular explanation for the zonation of the urea cycle and glutamine synthetase based on the Wnt/-c:atenin pathway[]." Experts admit there is a lot to learn about this relatively unexplored molecular pathway. However, the most recent evidence suggests it is an important pathway that interacts with other pathways in inflammation and acts as a crucial regulator of functions of different biological systems. Recent studies associate Wnt signaling in inflammation in adipocytes which is the major site for bioaccumulation of toxicants in the body. This fact elevates the significance of this pathway in environmental health studies. Of course, further research is needed to identify the level of the role it plays on the physical and mental effects of exposures from environmental contaminants.
The Wnt/β-catenin pathway: master regulator of liver zonation?. Zoë D. Burke. 2006; BioEssays - Wiley InterScience
Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866. http://www.citeulike.org/user/HEIRS/article/6594636
Castelo-Branco, G., Rawal, N., and Arenas, E. (2004). Gsk-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci, 117(24):5731-5737. http://www.citeulike.org/user/HEIRS/article/6582306
Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and CRF systems
CiteULike: Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and CRF systems: "Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866."
Tuesday, January 26, 2010
Reduced fertility linked to flame retardant exposure
Reduced fertility linked to flame retardant exposure
ScienceDaily (2010-01-26) -- A new study finds that women with higher blood levels of PBDEs, a common type of flame retardant, took longer to get pregnant. The flame retardants are used in foam furniture, electronics, fabrics, carpets, plastics and other common items in the home. ... > read full article
ScienceDaily (2010-01-26) -- A new study finds that women with higher blood levels of PBDEs, a common type of flame retardant, took longer to get pregnant. The flame retardants are used in foam furniture, electronics, fabrics, carpets, plastics and other common items in the home. ... > read full article
Antidepressants and Effects on Dopamine Receptors
"From our findings, we propose that the antidepressant drugs tested enhance dopamine function in the nucleus accumbens through either increased expression of postsynaptic D2 receptors (fluoxetine and desipramine) or increased dopamine release (tranylcypromine). "
SpringerLink - Journal Article: "Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat"
SpringerLink - Journal Article: "Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat"
Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop
CiteULike: Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop: "Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-beta by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-alpha or interferon-gamma."
GSK-3b and the Inflammatory Response in Environmental Illnesses
Some experts believe that Il-6 is an important cytokine in the activation of autoimmune and inflammatory diseases, some forms of cancer and present at high levels in PTSD. GSK-3b has been our recent topic of discussion and some important considerations for the actions of this protein is its overexpression may contribute to a number of mental and physical health conditions. Its activities provide a sort-of "on-off" switch for the antioxidant system Nrf2 and inhibits the expression of PGC-1 and for this reason is an important regulator of cellular homeostasis and energy metabolism. It has also been demonstrated GSK-3b inhibits heat shock factor which has important implications for studies of lifespan. Heat shock factor assists in the control of stress response activation through heat shock proteins which have protective properties that "aid in folding, transport, regulation, and degradation of cellular proteins under normal conditions, and their expression during stress is essential for cell survival." (Xavier) Heat shock factor has the ability to "repress" the expression of Il-1 through a transcription mechanism associated with Il-6 and thereby, limiting inflammatory responses. (Xie) These studies suggest that overexpression of GSK-3b (ie. that may occur from endotoxin-induced production of Tnf-a) may contribute to activation of immune responses that are "autoimmune or inflammatory" in nature. It also provides more evidence of the role of Nrf2 in autoimmune-type responses and that inhibition of PGC-1a may contribute to dysregulation of metabolism associated with environmental illness.
Notes:
Xavier et al. Glycogen Synthase Kinase 3B Negatively Regulates Both DNA-Binding and Transcriptional Activities of Heat Shock Factor 1. June 2000. http://www.citeulike.org/user/HEIRS/article/6590895
Ishihara, K. and Hirano, T. (2002). Il-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine & growth factor reviews, 13(4-5):357-368. http://www.citeulike.org/user/HEIRS/article/4365589
Maes, M. (1999). Elevated serum interleukin-6 (il-6) and il-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45(7):833-839. http://www.citeulike.org/user/HEIRS/article/4509997
Xie, Y., Chen, C., Stevenson, M. A., Auron, P. E., and Calderwood, S. K. (2002). Heat shock factor 1 represses transcription of theil-1β gene through physical interaction with the nuclear factor of interleukin 6. Journal of Biological Chemistry, 277(14):11802-11810. http://www.citeulike.org/user/HEIRS/article/6590793
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in pgc-1 alpha muscle-specific knock-out animals. The Journal of biological chemistry, 282(41):30014-30021. http://www.citeulike.org/user/HEIRS/article/1907765
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648
Notes:
Xavier et al. Glycogen Synthase Kinase 3B Negatively Regulates Both DNA-Binding and Transcriptional Activities of Heat Shock Factor 1. June 2000. http://www.citeulike.org/user/HEIRS/article/6590895
Ishihara, K. and Hirano, T. (2002). Il-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine & growth factor reviews, 13(4-5):357-368. http://www.citeulike.org/user/HEIRS/article/4365589
Maes, M. (1999). Elevated serum interleukin-6 (il-6) and il-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45(7):833-839. http://www.citeulike.org/user/HEIRS/article/4509997
Xie, Y., Chen, C., Stevenson, M. A., Auron, P. E., and Calderwood, S. K. (2002). Heat shock factor 1 represses transcription of theil-1β gene through physical interaction with the nuclear factor of interleukin 6. Journal of Biological Chemistry, 277(14):11802-11810. http://www.citeulike.org/user/HEIRS/article/6590793
Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in pgc-1 alpha muscle-specific knock-out animals. The Journal of biological chemistry, 282(41):30014-30021. http://www.citeulike.org/user/HEIRS/article/1907765
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648
Monday, January 25, 2010
Schizophrenia-Linked Gene Controls The Birth Of New Neurons
Background: Elevations in ammonia levels
CiteULike: Schizophrenia-Linked Gene Controls The Birth Of New Neurons: "2009). Schizophrenia-linked gene controls the birth of new neurons. MedPage Today."
CiteULike: Schizophrenia-Linked Gene Controls The Birth Of New Neurons: "2009). Schizophrenia-linked gene controls the birth of new neurons. MedPage Today."
Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals.
CiteULike: Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals.: "Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N. K., Yan, Z., and Spiegelman, B. M. (2007). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in pgc-1alpha muscle-specific knock-out animals. The Journal of biological chemistry, 282(41):30014-30021."
Sunday, January 24, 2010
Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses
Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.
Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others. Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)
Notes:
Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others. Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)
- EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
- Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
- Aging influences increased expression of GSK-3b. (Mercado-Gomez)
- GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
- Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness
Saturday, January 23, 2010
Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain.
CiteULike: Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain.: "Beurel, E. and Jope, R. S. (2009). Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and stat3 in the brain. Journal of neuroinflammation, 6:9+."
Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 beta activity.
CiteULike: Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 beta activity.: "Kuemmerle, J. F. (2005). Endogenous igf-i protects human intestinal smooth muscle cells from apoptosis by regulation of gsk-3 beta activity. American journal of physiology. Gastrointestinal and liver physiology, 288(1)."
GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
CiteULike: GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons: "Castelo-Branco, G., Rawal, N., and Arenas, E. (2004). Gsk-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci, 117(24):5731-5737."
IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10
CiteULike: IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10: "Lin, C.-F., Tsai, C.-C., Huang, W.-C., Wang, C.-Y., Tseng, H.-C., Wang, Y., Kai, J.-I., Wang, S.-W., and Cheng, Y.-L. (2008). Ifn-gamma synergizes with lps to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited il-10. Journal of Cellular Biochemistry, 105(3):746-755."
Friday, January 22, 2010
Inhibition of Glycogen Synthase Kinase 3beta (GSK3beta) Decreases Inflammatory Responses in Brain Endothelial Cells.
CiteULike: Inhibition of Glycogen Synthase Kinase 3beta (GSK3beta) Decreases Inflammatory Responses in Brain Endothelial Cells.: "Ramirez, S. H., Fan, S., Zhang, M., Papugani, A., Reichenbach, N., Dykstra, H., Mercer, A. J., Tuma, R. F., and Persidsky, Y. (2010). Inhibition of glycogen synthase kinase 3beta (gsk3beta) decreases inflammatory responses in brain endothelial cells. The American journal of pathology."
Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness
When you are talking about biological pathways there is never a linear path where one protein action only leads to another. It would make understanding these pathways alot simpler but it just does not work that way. Of course, if this were so, it would be so easy for everything to just stop working if something went wrong. When there are multiple pathways that intersect, run parallel or make feedback loops on proteins that ultimately activate other proteins, it results in a kind of "checks and balance system" inside a cell. This provides a safety mechanism so processes keep working or at least "keep chugging along" even if one protein or even a few proteins that make up a pathway are damaged, are lost or their signals get misdirected. It is easy to get confused when thinking about all those protein interactions at the same time. For me.... it is easier to break the activities down and focus on the processes individually. It makes it easier to understand how these pathways work and easier to remember just what they do! (If you would like to see a graphical depiction of the tangled mess these pathways make - click here!) Today's focus is on mostly on the PGC1a pathway and its relevance to the molecular biology of environmental illnesses.
In a recent blog, I wrote about my interest in nutrition as well as, a variety of other topics I have studied that impact health and wellness. In that blog, I discussed how a number of dietary excesses or deficiencies may influence environmental disease. Specifically dietary deficiencies include vitamin D, vitamin B and folate and also may include methionine(either too little or too much). I added changes in human dietary patterns and lifestyles over the last several decades or more may have contributed to this. There is debate on whether we get too much or too little methionine from our diet. The most recent articles provide evidence that methionine actually increases mitochondrial stress and lack of DNA repair even though others recommend supplementation of methionine. Generally, our bodies use methionine to make something called s-adenosyl methionine (SAM) which is used for biosynthesis of hormones like dopamine and serotonin. (Deth, Cully) It breaks down into homocysteine which can be toxic at excess amounts but with the help of B6, B12 and folate it recycles back into methionine or glutathione. (This means we have to have substantial amounts of these nutrients too!) Methionine can also be used to make cysteine, cartinine, taurine and lecithin. Excess levels of homocysteine (homocysteinemia) has been demonstrated to have negative effects on the cardiovascular system, impair the urea cycle and may produce problematic cognitive effects. It has recently been demonstrated that PGC-1a effects homocysteine metabolism and overexpression of the antioxidant may elevate levels of homocysteine and lower PGC-1a expression is associated with lower plasma homocysteine levels. Low levels of homocysteine can alter the normal metabolism of glutathione, taurine and sulfate and therefore can be a health concern. Because homocysteine is the intermediate in the production of methionine to cysteine, it may make one more susceptible to oxidative stress and certain toxic exposures. In these cases, NAC, methionine and taurine are often recommended.
Now that we have reviewed how PGC-1a interacts with the methionine synthase pathway, let us now discuss more about this protein and its importance for maintaining overall cellular metabolism and homestasis. Homeostasis inside cells can be severely impaired without proper expression of PGC-1a because its expression influences the regulation of a number of other proteins including the PPARS, estrogen, thyroid hormone, glucocorticoids and the pregnane X receptor, just to name a few. (Finck) To demonstrate this take for example how the pregnane X receptor interacts with PGC-1a in the synthesis of CYPA26 and CYPA34. These are two enzymes necessary for the metabolism and/or detoxification of certain anesthetics, antidepressants, nicotine and other contaminants like certain molds. Additional key targets for PGC-1a include NRF1 and NRF2 which regulate mitochondrial function. The former, NRF1, is regulated by Nrf2 and taken together, Nrf2 and PGC-1a are responsible for most of the activities that promote oxidative stress resistance and cellular survival in toxic environments. PGC-1a also interacts with vitamin D and "because the expression of PGC-1α is regulated by environmental stimuli, such as diet and lower temperatures, it follows that the function of VDR could be influenced in response to these external stimuli in the tissues that exhibit an overlap in the expression of PGC-1α." (Savkur)
The PGC-1a gene responds to a number of different environmental cues including diet like fasting, caffeine, exercise and cold exposure and is preferentially expressed in tissues with high oxidative capacity. (Finck) On the other hand, it is inhibited by obesity, lack of exercise and the exposure to endotoxin. These factors lead one to consider important policy and regulatory concerns for the elderly and vulnerable populations, those with access issues to proper nutrition or individuals living with unhospitable conditions like contaminated water supplies. In general, the inhibition of PGC-1a expression has a variety of physiological effects including lower cardiac function, lower mitochondrial function, endothelial and epithelial dysfunction, poor thermoregulation, lower protection against environmental toxins, reduced energy metabolism, alterations of muscle fiber type and numerous others. One will note, all of these contribute to a variety of complications indentified in patients with environmental illnesses. As Patti describes, one complication from reduced PGC-1a expression leading to oxidative stress and altered cellular metabolism is insulin resistance and diabetes. As we noted earlier, PGC-1a interacts with NRF-1 a nuclear respiratory factor. This author demonstrates that although NRF-1 is reduced in diabetics, a number of other proteins that interact with and including PGC-1a such as PGC-1b, PPAR-gamma and NRF1 are also reduced in members of their families. From this it is assumed that decreased expression of PGC-1a is responsible for a decrease in NRF genes and the associated disturbances of insulin resistance and diabetes.
At this point, it would be worth suggesting here that metabolic disturbances may not only be the result of a reduction in expression in PGC-1a but may also be due to a reduction in the expression or regulation of NRF1 by Nrf2 at least in some cell types. One protein that has been implicated in a number of mental and physical health disorders, GSK-3b, is like an off and on switch for the Nrf2 antioxidant system that allows for cellular stress resistance. Also, other proteins may participate and PGC-1a inhibition. Tnf-a from cigarette smoke inhibites PGC-1a and may be a "key step" to vascular and myocyte dysfunction. (Tang) Both NRF1 and NRF2 are involved in the generation of the respiratory chain and it seems NRF1's role includes inducing gene expression and maintaining cytochrome C levels. An interesting article explains that several pathways exist that inhibit PGC-1a which may be different in different tissues. In addition to possible inhibition of PGC-1a in hepatocytes by Akt/PKB, there is evidence expression of PGC-1a can be dependant on reduction of a ligase called Cdc4 or through the activation of GSK-3b which also contributes to neuroinflammation. GSK-3b increases in response to oxidative stress and can regulate the TH1/Th2 balance (Ohtani) and its inhibition according to one author may lead to "stabilization of PGC-1a". Cdc4 is elevated in Parkinson's disease and as one author mentions, "it will be interesting to see if Cdc4 is responsible for the reduction of PGC-1a in the brains of PD patients." (Olson) For GSK-3b, metallothionein which can be upregulated by Nrf2 is an effective inhibitor of GSK-3b and prevents a number of diabetic-induced changes in inflammation, nitrosative stress and energy metabolism. (Wang) In cardiac cells the presense of metallothionein "abrogates mitochondrial damage, loss of mitochondrial DNA and downregulation of PGC-1a and its downstream targets. In this article the author proposes eNOS uncoupling induces the down-regulation of PGC-1a, NRF1, NRF2 and other proteins which contributes to the loss of mitochondrial biogenesis while saying further the precise mechanism for loss of mitochondrial biogenesis under eNOS uncoupling is not known. It might be important to stress here that it is now understood that Nrf2 is an important protective component against eNOS uncoupling. (Heiss) Recent evidence provides evidence of an alternative mechanism involving elevations in CO and H2O2 activates mitochondrial biogenesis through PGC-1a independantly of eNOS. In any event, PGC-1a expression is vital for normal heart function, because reductions in expression of PGC-1a results in compromised function. Other important inducers of PGC-1a include cAMP, CAMKII, AMPK and NO.
Numerous studies demonstrate and as we mentioned earlier, exercise elevates both PGC-1a gene and protein expression. As Wright explains, "with this discovery it was initially believed that exercise-induced biogenesis was mediated by increases in PGC-1a but suggests that activation of PGC-1a mediates mitochondrial biogenesis rather than the increases in protein expression." His study provides support for this because a) PGC-1a regulates binding of NRF1 and NRF2 and he demonstrates that their binding increased after exercise but before there was an increase in PGC-1a protein expression and b) a number of mitochondrial constituents were increased beforeelevations in protein levels. Other studies have demostrated that P38 activation is linked to an adaptive increase in mitochondrial biogenesis. Wright agrees and believes that generally PGC-1a production occurs in this order 1) exercise activates P38 which in turn activates PGC-1a 2) PGC-1a activates transciption factors and nuclear receptors that regulate mitochondrial expression which is part of the first phase of an adaptive response, 3) activation of the PGC-1a by the promoter and transcription factors coactivated by PGC-1a results in an increase in PGC-1a expression and 4) this mediates the second phase of an adaptive response and includes sustaining and enhancing mitochondrial biogenesis by PGC-1a. With all this in mind, one must consider that mitochondrial biogenesis and homostastic metabolism is dependant at least in part on participation of Nrf2 antioxidant system because it also regulates NRF1 and therefore, impairments of this system may contribute to conditions in metabolism where PGC-1a plays a central role.
Notes:
Original document and citations.
In a recent blog, I wrote about my interest in nutrition as well as, a variety of other topics I have studied that impact health and wellness. In that blog, I discussed how a number of dietary excesses or deficiencies may influence environmental disease. Specifically dietary deficiencies include vitamin D, vitamin B and folate and also may include methionine(either too little or too much). I added changes in human dietary patterns and lifestyles over the last several decades or more may have contributed to this. There is debate on whether we get too much or too little methionine from our diet. The most recent articles provide evidence that methionine actually increases mitochondrial stress and lack of DNA repair even though others recommend supplementation of methionine. Generally, our bodies use methionine to make something called s-adenosyl methionine (SAM) which is used for biosynthesis of hormones like dopamine and serotonin. (Deth, Cully) It breaks down into homocysteine which can be toxic at excess amounts but with the help of B6, B12 and folate it recycles back into methionine or glutathione. (This means we have to have substantial amounts of these nutrients too!) Methionine can also be used to make cysteine, cartinine, taurine and lecithin. Excess levels of homocysteine (homocysteinemia) has been demonstrated to have negative effects on the cardiovascular system, impair the urea cycle and may produce problematic cognitive effects. It has recently been demonstrated that PGC-1a effects homocysteine metabolism and overexpression of the antioxidant may elevate levels of homocysteine and lower PGC-1a expression is associated with lower plasma homocysteine levels. Low levels of homocysteine can alter the normal metabolism of glutathione, taurine and sulfate and therefore can be a health concern. Because homocysteine is the intermediate in the production of methionine to cysteine, it may make one more susceptible to oxidative stress and certain toxic exposures. In these cases, NAC, methionine and taurine are often recommended.
Now that we have reviewed how PGC-1a interacts with the methionine synthase pathway, let us now discuss more about this protein and its importance for maintaining overall cellular metabolism and homestasis. Homeostasis inside cells can be severely impaired without proper expression of PGC-1a because its expression influences the regulation of a number of other proteins including the PPARS, estrogen, thyroid hormone, glucocorticoids and the pregnane X receptor, just to name a few. (Finck) To demonstrate this take for example how the pregnane X receptor interacts with PGC-1a in the synthesis of CYPA26 and CYPA34. These are two enzymes necessary for the metabolism and/or detoxification of certain anesthetics, antidepressants, nicotine and other contaminants like certain molds. Additional key targets for PGC-1a include NRF1 and NRF2 which regulate mitochondrial function. The former, NRF1, is regulated by Nrf2 and taken together, Nrf2 and PGC-1a are responsible for most of the activities that promote oxidative stress resistance and cellular survival in toxic environments. PGC-1a also interacts with vitamin D and "because the expression of PGC-1α is regulated by environmental stimuli, such as diet and lower temperatures, it follows that the function of VDR could be influenced in response to these external stimuli in the tissues that exhibit an overlap in the expression of PGC-1α." (Savkur)
The PGC-1a gene responds to a number of different environmental cues including diet like fasting, caffeine, exercise and cold exposure and is preferentially expressed in tissues with high oxidative capacity. (Finck) On the other hand, it is inhibited by obesity, lack of exercise and the exposure to endotoxin. These factors lead one to consider important policy and regulatory concerns for the elderly and vulnerable populations, those with access issues to proper nutrition or individuals living with unhospitable conditions like contaminated water supplies. In general, the inhibition of PGC-1a expression has a variety of physiological effects including lower cardiac function, lower mitochondrial function, endothelial and epithelial dysfunction, poor thermoregulation, lower protection against environmental toxins, reduced energy metabolism, alterations of muscle fiber type and numerous others. One will note, all of these contribute to a variety of complications indentified in patients with environmental illnesses. As Patti describes, one complication from reduced PGC-1a expression leading to oxidative stress and altered cellular metabolism is insulin resistance and diabetes. As we noted earlier, PGC-1a interacts with NRF-1 a nuclear respiratory factor. This author demonstrates that although NRF-1 is reduced in diabetics, a number of other proteins that interact with and including PGC-1a such as PGC-1b, PPAR-gamma and NRF1 are also reduced in members of their families. From this it is assumed that decreased expression of PGC-1a is responsible for a decrease in NRF genes and the associated disturbances of insulin resistance and diabetes.
At this point, it would be worth suggesting here that metabolic disturbances may not only be the result of a reduction in expression in PGC-1a but may also be due to a reduction in the expression or regulation of NRF1 by Nrf2 at least in some cell types. One protein that has been implicated in a number of mental and physical health disorders, GSK-3b, is like an off and on switch for the Nrf2 antioxidant system that allows for cellular stress resistance. Also, other proteins may participate and PGC-1a inhibition. Tnf-a from cigarette smoke inhibites PGC-1a and may be a "key step" to vascular and myocyte dysfunction. (Tang) Both NRF1 and NRF2 are involved in the generation of the respiratory chain and it seems NRF1's role includes inducing gene expression and maintaining cytochrome C levels. An interesting article explains that several pathways exist that inhibit PGC-1a which may be different in different tissues. In addition to possible inhibition of PGC-1a in hepatocytes by Akt/PKB, there is evidence expression of PGC-1a can be dependant on reduction of a ligase called Cdc4 or through the activation of GSK-3b which also contributes to neuroinflammation. GSK-3b increases in response to oxidative stress and can regulate the TH1/Th2 balance (Ohtani) and its inhibition according to one author may lead to "stabilization of PGC-1a". Cdc4 is elevated in Parkinson's disease and as one author mentions, "it will be interesting to see if Cdc4 is responsible for the reduction of PGC-1a in the brains of PD patients." (Olson) For GSK-3b, metallothionein which can be upregulated by Nrf2 is an effective inhibitor of GSK-3b and prevents a number of diabetic-induced changes in inflammation, nitrosative stress and energy metabolism. (Wang) In cardiac cells the presense of metallothionein "abrogates mitochondrial damage, loss of mitochondrial DNA and downregulation of PGC-1a and its downstream targets. In this article the author proposes eNOS uncoupling induces the down-regulation of PGC-1a, NRF1, NRF2 and other proteins which contributes to the loss of mitochondrial biogenesis while saying further the precise mechanism for loss of mitochondrial biogenesis under eNOS uncoupling is not known. It might be important to stress here that it is now understood that Nrf2 is an important protective component against eNOS uncoupling. (Heiss) Recent evidence provides evidence of an alternative mechanism involving elevations in CO and H2O2 activates mitochondrial biogenesis through PGC-1a independantly of eNOS. In any event, PGC-1a expression is vital for normal heart function, because reductions in expression of PGC-1a results in compromised function. Other important inducers of PGC-1a include cAMP, CAMKII, AMPK and NO.
Numerous studies demonstrate and as we mentioned earlier, exercise elevates both PGC-1a gene and protein expression. As Wright explains, "with this discovery it was initially believed that exercise-induced biogenesis was mediated by increases in PGC-1a but suggests that activation of PGC-1a mediates mitochondrial biogenesis rather than the increases in protein expression." His study provides support for this because a) PGC-1a regulates binding of NRF1 and NRF2 and he demonstrates that their binding increased after exercise but before there was an increase in PGC-1a protein expression and b) a number of mitochondrial constituents were increased beforeelevations in protein levels. Other studies have demostrated that P38 activation is linked to an adaptive increase in mitochondrial biogenesis. Wright agrees and believes that generally PGC-1a production occurs in this order 1) exercise activates P38 which in turn activates PGC-1a 2) PGC-1a activates transciption factors and nuclear receptors that regulate mitochondrial expression which is part of the first phase of an adaptive response, 3) activation of the PGC-1a by the promoter and transcription factors coactivated by PGC-1a results in an increase in PGC-1a expression and 4) this mediates the second phase of an adaptive response and includes sustaining and enhancing mitochondrial biogenesis by PGC-1a. With all this in mind, one must consider that mitochondrial biogenesis and homostastic metabolism is dependant at least in part on participation of Nrf2 antioxidant system because it also regulates NRF1 and therefore, impairments of this system may contribute to conditions in metabolism where PGC-1a plays a central role.
Notes:
- Lipoic acid increases mitochondrial biogenesis and improves muscular energy through a AMPK-PGC-1a pathway which increases GLUT4 expression in aged mice. (Wang)
Original document and citations.
Thursday, January 21, 2010
Methylation-Dependent Gene Silencing Induced by Interleukin 1beta via Nitric Oxide Production
CiteULike: Methylation-Dependent Gene Silencing Induced by Interleukin 1beta via Nitric Oxide Production: "Hmadcha, A., Bedoya, F. J., Sobrino, F., and Pintado, E. (1999). Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production. J. Exp. Med., 190(11):1595-1604."
Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.
In a preceding blog, we discussed how FOXP3 in important for autoimmune suppressing T cells. We also described how a recent study suggests that the loss of Tregs may be a contributing factor in chemical sensitivity and environmental illnesses from exposures to air contaminants. Here we see that NO is a factor in the altered expression in FOX3P Tregs.
CiteULike: Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.: "Brahmachari, S. and Pahan, K. (2010). Myelin basic protein priming reduces the expression of foxp3 in t cells via nitric oxide. Journal of immunology (Baltimore, Md. : 1950)."
CiteULike: Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.: "Brahmachari, S. and Pahan, K. (2010). Myelin basic protein priming reduces the expression of foxp3 in t cells via nitric oxide. Journal of immunology (Baltimore, Md. : 1950)."
Stain repellent chemical linked to thyroid disease in adults
Stain repellent chemical linked to thyroid disease in adults
ScienceDaily (2010-01-21) -- For the first time, a study links thyroid disease with human exposure to perfluorooctanoic acid (PFOA) -- a persistent organic chemical used in industrial and consumer goods including nonstick cookware and stain- and water-resistant coatings for carpets and fabrics. ... > read full article
Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling
Background: GSk-3b has been shown to be an "on-off" switch for the Nrf2 antioxidant system. The following article discusses how metallothionein ( MT)prevent changes in heart function from diabetes by inactivation of this protein. MT which can be regulated by Nrf2 also have also been demonstrated to abrogate other changes in the mitochondria from O2 production and the downregulation of PGC-1a and its downstream targets.
CiteULike: Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling: "Wang, Y., Feng, W., Xue, W., Tan, Y., Hein, D. W., Li, X.-K., and Cai, L. (2009). Inactivation of gsk-3β by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes, 58(6):1391-1402."
CiteULike: Inactivation of GSK-3β by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling: "Wang, Y., Feng, W., Xue, W., Tan, Y., Hein, D. W., Li, X.-K., and Cai, L. (2009). Inactivation of gsk-3β by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes, 58(6):1391-1402."
Discovery Of Compounds That Help Protect Nerve Cells
Last week we wrote about heat shock proteins could elevate Tregs - a class of T cells that help suppress autoimmune-like responses. We also discussed how these proteins may play a protective role against PD. Here is more on new discoveries on heat shock factor which induces the proteins.
Discovery Of Compounds That Help Protect Nerve Cells
Discovery Of Compounds That Help Protect Nerve Cells
Wednesday, January 20, 2010
FOXP3 Promoter Demethylation Reveals the Committed Treg Population in Humans
Background: A report last year suggests that loss of regulatory T cells may contribute to chemical sensitivity from environmental exposures. As this author describes, "the transcription factor FOXP3 is crucial for the suppressive activity of Tregs and is considered the most specific marker for this population.....The results of his most recent findings show that "only complete demethylation of the conserved FOXP3 promoter region support stable long term FOXP3 expression and a committed Treg phenotype in humans."
CiteULike: FOXP3 Promoter Demethylation Reveals the Committed Treg Population in Humans: "Janson, P. C. J., Winerdal, M. E., Marits, P., Thörn, M., Ohlsson, R., and Winqvist, O. (2008). Foxp3 promoter demethylation reveals the committed treg population in humans. PLoS ONE, 3(2):e1612+."
Mićović, V., Vojniković, B., Bulog, A., Coklo, M., Malatestinić, D., and Mrakovcić-Sutić, I. (2009). Regulatory t cells (tregs) monitoring in environmental diseases. Collegium antropologicum, 33(3):743-746.http://www.citeulike.org/group/6057/article/6090770
CiteULike: FOXP3 Promoter Demethylation Reveals the Committed Treg Population in Humans: "Janson, P. C. J., Winerdal, M. E., Marits, P., Thörn, M., Ohlsson, R., and Winqvist, O. (2008). Foxp3 promoter demethylation reveals the committed treg population in humans. PLoS ONE, 3(2):e1612+."
Mićović, V., Vojniković, B., Bulog, A., Coklo, M., Malatestinić, D., and Mrakovcić-Sutić, I. (2009). Regulatory t cells (tregs) monitoring in environmental diseases. Collegium antropologicum, 33(3):743-746.http://www.citeulike.org/group/6057/article/6090770
Effects of ammonia and allopurinol on rat hippocampal NMDA receptors.
CiteULike: Effects of ammonia and allopurinol on rat hippocampal NMDA receptors.: "Yonden, Z., Aydin, M., Kilbas, A., Demirin, H., Sutcu, R., and Delibas, N. (2010). Effects of ammonia and allopurinol on rat hippocampal nmda receptors. Cell biochemistry and function."
Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density.
CiteULike: Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density.: "Barrès, R., Osler, M. E., Yan, J., Rune, A., Fritz, T., Caidahl, K., Krook, A., and Zierath, J. R. (2009). Non-cpg methylation of the pgc-1alpha promoter through dnmt3b controls mitochondrial density. Cell metabolism, 10(3):189-198."
Tuesday, January 19, 2010
Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents.
CiteULike: Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents.: "Gu, X., Ke, S., Liu, D., Sheng, T., Thomas, P. E., Rabson, A. B., Gallo, M. A., Xie, W., and Tian, Y. (2006). Role of nf-kappab in regulation of pxr-mediated gene expression: a mechanism for the suppression of cytochrome p-450 3a4 by proinflammatory agents. The Journal of biological chemistry, 281(26):17882-17889"
Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression.
CiteULike: Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression.: "Shah, Y. M., Ma, X., Morimura, K., Kim, I., and Gonzalez, F. J. (2007). Pregnane x receptor activation ameliorates dss-induced inflammatory bowel disease via inhibition of nf-kappab target gene expression. American journal of physiology. Gastrointestinal and liver physiology, 292(4)."
PXR and LXR in Hepatic Steatosis: A New Dog and an Old Dog with New Tricks
CiteULike: PXR and LXR in Hepatic Steatosis: A New Dog and an Old Dog with New Tricks: "Lee, J. H., Zhou, J., and Xie, W. (2008). Pxr and lxr in hepatic steatosis: A new dog and an old dog with new tricks. Molecular Pharmaceutics, 5(1):60-66."
Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha.
CiteULike: Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha.: "Itoh, M., Nakajima, M., Higashi, E., Yoshida, R., Nagata, K., Yamazoe, Y., and Yokoi, T. (2006). Induction of human cyp2a6 is mediated by the pregnane x receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha. The Journal of pharmacology and experimental therapeutics, 319(2):693-702."
Prevention of Nitric Oxide-Mediated 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinson's Disease in Mice by Tea Phenolic EGCG
CiteULike: Prevention of Nitric Oxide-Mediated 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinson's Disease in Mice by Tea Phenolic Epigallocatechin 3-Gallate: "Choi, J. (2002). Prevention of nitric oxide-mediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinson's disease in mice by tea phenolic epigallocatechin 3-gallate. NeuroToxicology, 23(3):367-374."
Nitrous Oxide Inactivates Methionine Synthetase in Human Liver
CiteULike: Nitrous Oxide Inactivates Methionine Synthetase in Human Liver: "Koblin, D. D., Waskell, L., Watson, J. E., Stokstad, E. L. R., and Eger, E. I. (1982). Nitrous oxide inactivates methionine synthetase in human liver. Anesth Analg, 61(2):75-78."
Extremely Low Activity of Methionine Synthase in Vitamin B-12-Deficient Rats May Be Related to Effects on Coenzyme Stabilization Rather than to Changes in Coenzyme Induction
CiteULike: Extremely Low Activity of Methionine Synthase in Vitamin B-12-Deficient Rats May Be Related to Effects on Coenzyme Stabilization Rather than to Changes in Coenzyme Induction: "Yamada, K., Kawata, T., Wada, M., Isshiki, T., Onoda, J., Kawanishi, T., Kunou, A., Tadokoro, T., Tobimatsu, T., Maekawa, A., and Toraya, T. (2000). Extremely low activity of methionine synthase in vitamin b-12-deficient rats may be related to effects on coenzyme stabilization rather than to changes in coenzyme induction. J. Nutr., 130(8):1894-1900."
Monday, January 18, 2010
Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia.
CiteULike: Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia.: "Schlachetzki, J. C. C., Fiebich, B. L., Haake, E., de Oliveira, A. C. C., Candelario-Jali, E., Heneka, M. T., and Hull, M. (2010). Norepinephrine enhances the lps-induced expression of cox-2 and secretion of pge2 in primary rat microglia. Journal of neuroinflammation, 7(1):2+."
Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness
Background: I happened on an article this morning that no doubt has important health implications, at least for I and others with impairments of detoxification are concerned. I doubt it evoked much interest by the "Powers That Be" that study this stuff everyday but none-the-less, it seems important for me, not to dismiss it so readily. What I write here are my own thoughts and I by no means am or claim to be, an expert on autism and autistic behavior.
As you may recall, we recently discussed the similiarities of autism and other environmental illnesses including ADHD and multiple chemical sensitivity. Previous studies have shown that certain exposures may inhibit metabolic pathways such the one for production of methionine synthase important for DNA synthesis and repair and may increase concentrations of homocysteine, a potentially toxic byproduct of methionine metabolism. To demonstrate, the inhibition of this pathway by nitrous oxide causes lasting impairment in spatial working memory in aged rats via mitochondrial swelling and subsequent neuronal death.(Culley) In line with this thinking,severa; studies provide evidence that inhibiting or the presense of impairments in pathways such as the one for methionine synthase or others may contribute to a number of mental and physical health conditions including environmental illnesses such as mood disorders, Alzheimer's, autism and MCS.
In the past, I have noted several "remedies" including B12, Q10 and tetrahydrobiopterin recommended for chemical sensitivity which are also commonly used therapies for autism. Curiously, methylhydrofolate is a precursor of BH4 and often prescribed to reduce ammonia levels produced as a side-effect from different supplement treatments and also ammonia produced from gut-derived exogenous bacteria. In addition to hyperammonemia, excess ammonia may lead to elevations in production of nitric oxide synthase and enhanced nitric oxide, free radicals and oxidative stress.
Jalan and Bernuau propose that endotoxin may increase the severity of complications associated with hyperammonemia which of course may have important safety implications for a number of occupational and residential settings including farms and agricultural areas. In this article the authors explain, the "ammonia is detoxified by astrocyctes in the brain". Notably, the deficiency of protective pathways which protect astocytes such as Nrf2 should be an important concern. Jalan further explains that "during hyperammonemia, astrocytes swell from the effect of glutamine. In addition, recent studies show these cells are more swollen in animals exposed to endotoxin and interestingly, the swelling of the atrocytes occur in an environment of an intact blood brain barrier which indicates a functional abnormality. It is assumed that astrocytes are critical managers of blood flow and it may be that during hyperammonemia the astrocytes are sensitized to a "second hit" by LPS endotoxin. The author also proposes other mechanims may be involved in the astrocyte swelling in addition to the ammonia-glutamine hypothesis and one may suggest it includes the activation of P53 and its suppressive effects on Nrf2. (Panickar, Faraonion) The author also mentions pharmacological pre-treatment doses of amiloride, a diuretic used to treat congestive heart failure and hypertension, were required that were 200 fold higher in animals with hyperammonemia in association with exposure to endotoxin." This should demonstrate to anyone whether toxicologically inclined or not, that "something just ain't right",,,,!
He goes on to say, "several substances have been shown to cross the BBB under hepatoxic conditions such as acute liver failure. Incidently, he points out ammonia induces the expression of GLUT1, a transporter across the BBB and this report suggests a non-specific increase in permeability of the BBB and proposes hyperammonia could "unlock" the BBB." It has been shown that ammonia can "alter endothelial cell gene expression and transporter function." (Belanger Of course, this is an important issue to consider whenever a condition of hyperammonemiua occurs. It very well could contribute to the neuroinflammatory consequences in pathological conditions such as autism and conditions that where elevated homocysteine levels impair renal function and as this article suggests, exposures to endotoxin exacerbate related metabolic consequences.
Jalan, R. and Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2):168-171. http://www.citeulike.org/user/HEIRS/article/6556614
Essa, M. M. and Subramanian, P. (2006). Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. eCAM. http://www.citeulike.org/user/HEIRS/article/6556740
Panickar, K. S., Jayakumar, A. R., Rao, K. V. R., and Norenberg, M. D. (2009). Ammonia-induced activation of p53 in cultured astrocytes: Role in cell swelling and glutamate uptake. Neurochemistry International, 55(1-3):98-105. http://www.citeulike.org/user/HEIRS/article/4523207
Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G. G., Napolitano, M., Russo, T., and Cimino, F. (2006). p53 suppresses the nrf2-dependent transcription of antioxidant response genes. The Journal of biological chemistry, 281(52):39776-39784. http://www.citeulike.org/user/HEIRS/article/4364516?show_msg=already_posted
Culley, D. J., Raghavan, S. V., Waly, M., Baxter, M. G., Yukhananov, R., Deth, R. C., and Crosby, G. (2007). Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg, 105(1):83-88. http://www.citeulike.org/user/HEIRS/article/6557028
Bélanger, M., Asashima, T., Ohtsuki, S., Yamaguchi, H., Ito, S., and Terasaki, T. (2007). Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochemistry international, 50(1):95-101.
http://www.citeulike.org/group/7833/article/6557716
As you may recall, we recently discussed the similiarities of autism and other environmental illnesses including ADHD and multiple chemical sensitivity. Previous studies have shown that certain exposures may inhibit metabolic pathways such the one for production of methionine synthase important for DNA synthesis and repair and may increase concentrations of homocysteine, a potentially toxic byproduct of methionine metabolism. To demonstrate, the inhibition of this pathway by nitrous oxide causes lasting impairment in spatial working memory in aged rats via mitochondrial swelling and subsequent neuronal death.(Culley) In line with this thinking,severa; studies provide evidence that inhibiting or the presense of impairments in pathways such as the one for methionine synthase or others may contribute to a number of mental and physical health conditions including environmental illnesses such as mood disorders, Alzheimer's, autism and MCS.
In the past, I have noted several "remedies" including B12, Q10 and tetrahydrobiopterin recommended for chemical sensitivity which are also commonly used therapies for autism. Curiously, methylhydrofolate is a precursor of BH4 and often prescribed to reduce ammonia levels produced as a side-effect from different supplement treatments and also ammonia produced from gut-derived exogenous bacteria. In addition to hyperammonemia, excess ammonia may lead to elevations in production of nitric oxide synthase and enhanced nitric oxide, free radicals and oxidative stress.
Jalan and Bernuau propose that endotoxin may increase the severity of complications associated with hyperammonemia which of course may have important safety implications for a number of occupational and residential settings including farms and agricultural areas. In this article the authors explain, the "ammonia is detoxified by astrocyctes in the brain". Notably, the deficiency of protective pathways which protect astocytes such as Nrf2 should be an important concern. Jalan further explains that "during hyperammonemia, astrocytes swell from the effect of glutamine. In addition, recent studies show these cells are more swollen in animals exposed to endotoxin and interestingly, the swelling of the atrocytes occur in an environment of an intact blood brain barrier which indicates a functional abnormality. It is assumed that astrocytes are critical managers of blood flow and it may be that during hyperammonemia the astrocytes are sensitized to a "second hit" by LPS endotoxin. The author also proposes other mechanims may be involved in the astrocyte swelling in addition to the ammonia-glutamine hypothesis and one may suggest it includes the activation of P53 and its suppressive effects on Nrf2. (Panickar, Faraonion) The author also mentions pharmacological pre-treatment doses of amiloride, a diuretic used to treat congestive heart failure and hypertension, were required that were 200 fold higher in animals with hyperammonemia in association with exposure to endotoxin." This should demonstrate to anyone whether toxicologically inclined or not, that "something just ain't right",,,,!
He goes on to say, "several substances have been shown to cross the BBB under hepatoxic conditions such as acute liver failure. Incidently, he points out ammonia induces the expression of GLUT1, a transporter across the BBB and this report suggests a non-specific increase in permeability of the BBB and proposes hyperammonia could "unlock" the BBB." It has been shown that ammonia can "alter endothelial cell gene expression and transporter function." (Belanger Of course, this is an important issue to consider whenever a condition of hyperammonemiua occurs. It very well could contribute to the neuroinflammatory consequences in pathological conditions such as autism and conditions that where elevated homocysteine levels impair renal function and as this article suggests, exposures to endotoxin exacerbate related metabolic consequences.
Jalan, R. and Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2):168-171. http://www.citeulike.org/user/HEIRS/article/6556614
Essa, M. M. and Subramanian, P. (2006). Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. eCAM. http://www.citeulike.org/user/HEIRS/article/6556740
Panickar, K. S., Jayakumar, A. R., Rao, K. V. R., and Norenberg, M. D. (2009). Ammonia-induced activation of p53 in cultured astrocytes: Role in cell swelling and glutamate uptake. Neurochemistry International, 55(1-3):98-105. http://www.citeulike.org/user/HEIRS/article/4523207
Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G. G., Napolitano, M., Russo, T., and Cimino, F. (2006). p53 suppresses the nrf2-dependent transcription of antioxidant response genes. The Journal of biological chemistry, 281(52):39776-39784. http://www.citeulike.org/user/HEIRS/article/4364516?show_msg=already_posted
Culley, D. J., Raghavan, S. V., Waly, M., Baxter, M. G., Yukhananov, R., Deth, R. C., and Crosby, G. (2007). Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg, 105(1):83-88. http://www.citeulike.org/user/HEIRS/article/6557028
Bélanger, M., Asashima, T., Ohtsuki, S., Yamaguchi, H., Ito, S., and Terasaki, T. (2007). Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochemistry international, 50(1):95-101.
http://www.citeulike.org/group/7833/article/6557716
Sunday, January 17, 2010
Elevating Tregs and Heat Shock Proteins in EI - The Role of Food and Exercise
Background: In a recent blog, we expressed an interest in a recent study that showed alterations in the distributions of suppressive T cells called Tregs which may influence environmental illness.(Micovic) According to the author, these cells are normally upregulated upon chronic inhalation of pollutants but in this case, the researcher noted a decrease in these suppressive cells. In other studies, a decrease in Foxp3 Tregs are often associated with autoimmune-like conditions. In addition, we also discussed a study the showed that particulate matter may alter "immunological footprints" and may lead to a autoimmune-like presentation. Also, regulatory Treg suppression plays a role in protection of striatal neurons and reductions of microglial neuroinflammation and alpha-synuclein and therefore, Tregs may play an important protective role in Parkinson's disease. It also suggests an explanation of how environmental exposures may contribute to PD and other neurodegenerative diseases. Catecholamines have been shown to downregulate the expression of Tregs and this is dependant on the expression of the dopamine D1-like receptors.
Other studies have revealed some insights into the relationship of Tregs and other proteing called heat shock proteins. Heat shock proteins are normally considered protective and often chaperone proteins during specific metabolic processes. De Zoeten recently showed that Tregs with HSP70 had more suppressive effects than those without. It was concluded that at least for this study of colitis, there was an important interaction with HSP70 and FoxP3+. Interestingly, a recent CFS study which is often co-morbid with colitis, demonstrated altered profiles of a number of heat shock proteins including HSP70 (Jammes) and suggested these proteins may be used as a biomarker for CFS. Wieten describes heat shock proteins as proteins that are normally upregulated in response to stress, including thermal and oxidative stress and inflammation and help prevent cellular damage by increasing the expression of anti-inflammatory T cells.
Weiten explains that by elevating the levels of heat shock proteins, an individual may be able to restore or increase their resistance to cellular stress. Weiten provides evidence that dietary phytonutrients can elevate levels of heat shock proteins. In his study, he found that several compounds found in food elevated HSP70 that elevated the expression of T cells. One such compound called carvacol is found in thyme and oregano. In other blogs, we have noted that the latter is associated with expression of PPAR-gamma which has anti-inflammatory properties. Hontecillas demonstrates in his research that PPAR-gamma can influence the activity of Tregs against inflammation. This seems to entail down-regulation of certain other T cells (Konturek) and as we have noted numerous times before, PPAR-gamma expression can be influenced by the expression of Nrf2.
Different studies have shown positive and negative consequences of exercise on environmental illnesses and this may be dependant on the levels of expression of a number of different proteins. In any case, it has been demonstrated that exercise positively influences the expression of HSP70.(Milne)Researchers from University of Alabama at Birmingham recently demonstrated that Treg cells in exercised mice increased cells with FoxP3+ and were better able to fascilitate suppression of inflammatory cytokines in an experimental model of murine asthama. In contrast, increasing age may negatively influence the expression of both Tregs and HSP70. Also, exposure to paraquat decreases expression of both HO-1 and HSP70 and increases oxidation of proteins. (Nakanishi) Muscle atrophy is often associated with aging and serious illness; the prevention of which can be influenced by the expression of HSP70. (Senf) Other studies show HSP are regulated through exercise-induced SIRT1 but interactions with HSP regulation is not the only way SIRT1 is involved in immune regulation. Reports now show that the dysregulation of SIRT1 leads to abnormal T cells responses and loss of tolerance and the development of autoimmunity. Zhang explains that while SIRT1 regulation is required for normal T cell activity, this responsibility does not involve maintaining Treg function or Th17 but does involve control of autoreactive T cells. In contrast, van Loosdregt mentions that use of HDAC inhibitors may be an alternative method for modulating FoxP3+ in Tregs. So it seems, the level of involvement of SIRT1 of Treg function is not at all clear and needs further study. In any case, the findings of the studies above, definitively demonstrate the importance of both Nrf2 and SIRT1 in regulation/dysregulation of immune function in a number of environmental illnesses.
Mićović, V., Vojniković, B., Bulog, A., Coklo, M., Malatestinić, D., and Mrakovcić-Sutić, I. (2009). Regulatory t cells (tregs) monitoring in environmental diseases. Collegium antropologicum, 33(3):743-746. http://www.citeulike.org/user/HEIRS/article/6090770
De Zoeten, E. F., Wang, L., Sai, H., Dillmann, W. H., and Hancock, W. W. (2009). Expression of hdac9 by t regulatory cells prevents colitis in mice. Gastroenterology. http://www.citeulike.org/user/HEIRS/article/6553713
Wieten, L., van der Zee, R., Goedemans, R., Sijtsma, J., Serafini, M., Lubsen, N. H., van Eden, W., and Broere, F. (2010). Hsp70 expression and induction as a readout for detection of immune modulatory components in food. Cell stress & chaperones, 15(1):25-37.
http://www.citeulike.org/user/HEIRS/article/4675555
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1).
http://www.citeulike.org/user/HEIRS/article/6553728
Nakanishi, Y. and Yasumoto, K. (1997). Induction after administering paraquat of heme oxygenase-1 and heat shock protein 70 in the liver of senescence-accelerated mice. Bioscience, biotechnology, and biochemistry, 61(8):1302-1306.
http://www.citeulike.org/group/7833/article/6553731
Konturek, P. C., Dembinski, A., Warzecha, Z., Burnat, G., Ceranowicz, P., Hahn, E. G., Dembinski, M., Tomaszewska, R., and Konturek, S. J. (2005). Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World journal of gastroenterology : WJG, 11(40):6322-6329.
http://www.citeulike.org/user/HEIRS/article/6553866
Hontecillas, R. and Bassaganya-Riera, J. (2007). Peroxisome proliferator-activated receptor gamma is required for regulatory cd4+ t cell-mediated protection against colitis. Journal of immunology (Baltimore, Md. : 1950), 178(5):2940-2949.
Milne, K. J. and Noble, E. G. (2002). Exercise-induced elevation of hsp70 is intensity dependent. Journal of applied physiology (Bethesda, Md. : 1985), 93(2):561-568.
http://www.citeulike.org/user/HEIRS/article/6553732
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1). http://www.citeulike.org/user/HEIRS/article/6553728
Lowder, T., Dugger, K., Deshane, J., Estell, K., and Schwiebert, L. M. (2010). Repeated bouts of aerobic exercise enhance regulatory t cell responses in a murine asthma model. Brain, behavior, and immunity, 24(1):153-159. http://www.citeulike.org/user/HEIRS/article/5842541
Reynolds, A. D., Banerjee, R., Liu, J., Gendelman, H. E., and Mosley, R. L. (2007). Neuroprotective activities of cd4+cd25+ regulatory t cells in an animal model of parkinson's disease. Journal of leukocyte biology, 82(5):1083-1094. http://www.citeulike.org/user/HEIRS/article/6554146
Cosentino, M., Fietta, A. M., Ferrari, M., Rasini, E., Bombelli, R., Carcano, E., Saporiti, F., Meloni, F., Marino, F., and Lecchini, S. (2007). Human cd4+cd25+ regulatory t cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood, 109(2):632-642. http://www.citeulike.org/user/HEIRS/article/6554165
Iwata, S., Shimizu, T., Nomoto, M., and Fukuda, T. (1996). Characteristic upregulation of dopamine d1-receptor in rat striatum after 6-hydroxydopamine treatment. Japanese journal of pharmacology, 71(3):255-258.
http://www.citeulike.org/user/HEIRS/article/6554215
It is Hot in Here, or is it Just SIRT1. SIRT1 Activate Heat Shock Transcription. Retrieved on January 16, 2010.
Zhang, J., Lee, S.-M. M., Shannon, S., Gao, B., Chen, W., Chen, A., Divekar, R., McBurney, M. W., Braley-Mullen, H., Zaghouani, H., and Fang, D. (2009). The type iii histone deacetylase sirt1 is essential for maintenance of t cell tolerance in mice. The Journal of clinical investigation, 119(10):3048-3058.
http://www.citeulike.org/user/HEIRS/article/6554270
Jammes, Y., Steinberg, J. G., Delliaux, S., and Brégeon, F. (2009). Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and hsp responses. Journal of internal medicine, 266(2):196-206. http://www.citeulike.org/user/HEIRS/article/4695048
Other studies have revealed some insights into the relationship of Tregs and other proteing called heat shock proteins. Heat shock proteins are normally considered protective and often chaperone proteins during specific metabolic processes. De Zoeten recently showed that Tregs with HSP70 had more suppressive effects than those without. It was concluded that at least for this study of colitis, there was an important interaction with HSP70 and FoxP3+. Interestingly, a recent CFS study which is often co-morbid with colitis, demonstrated altered profiles of a number of heat shock proteins including HSP70 (Jammes) and suggested these proteins may be used as a biomarker for CFS. Wieten describes heat shock proteins as proteins that are normally upregulated in response to stress, including thermal and oxidative stress and inflammation and help prevent cellular damage by increasing the expression of anti-inflammatory T cells.
Weiten explains that by elevating the levels of heat shock proteins, an individual may be able to restore or increase their resistance to cellular stress. Weiten provides evidence that dietary phytonutrients can elevate levels of heat shock proteins. In his study, he found that several compounds found in food elevated HSP70 that elevated the expression of T cells. One such compound called carvacol is found in thyme and oregano. In other blogs, we have noted that the latter is associated with expression of PPAR-gamma which has anti-inflammatory properties. Hontecillas demonstrates in his research that PPAR-gamma can influence the activity of Tregs against inflammation. This seems to entail down-regulation of certain other T cells (Konturek) and as we have noted numerous times before, PPAR-gamma expression can be influenced by the expression of Nrf2.
Different studies have shown positive and negative consequences of exercise on environmental illnesses and this may be dependant on the levels of expression of a number of different proteins. In any case, it has been demonstrated that exercise positively influences the expression of HSP70.(Milne)Researchers from University of Alabama at Birmingham recently demonstrated that Treg cells in exercised mice increased cells with FoxP3+ and were better able to fascilitate suppression of inflammatory cytokines in an experimental model of murine asthama. In contrast, increasing age may negatively influence the expression of both Tregs and HSP70. Also, exposure to paraquat decreases expression of both HO-1 and HSP70 and increases oxidation of proteins. (Nakanishi) Muscle atrophy is often associated with aging and serious illness; the prevention of which can be influenced by the expression of HSP70. (Senf) Other studies show HSP are regulated through exercise-induced SIRT1 but interactions with HSP regulation is not the only way SIRT1 is involved in immune regulation. Reports now show that the dysregulation of SIRT1 leads to abnormal T cells responses and loss of tolerance and the development of autoimmunity. Zhang explains that while SIRT1 regulation is required for normal T cell activity, this responsibility does not involve maintaining Treg function or Th17 but does involve control of autoreactive T cells. In contrast, van Loosdregt mentions that use of HDAC inhibitors may be an alternative method for modulating FoxP3+ in Tregs. So it seems, the level of involvement of SIRT1 of Treg function is not at all clear and needs further study. In any case, the findings of the studies above, definitively demonstrate the importance of both Nrf2 and SIRT1 in regulation/dysregulation of immune function in a number of environmental illnesses.
Mićović, V., Vojniković, B., Bulog, A., Coklo, M., Malatestinić, D., and Mrakovcić-Sutić, I. (2009). Regulatory t cells (tregs) monitoring in environmental diseases. Collegium antropologicum, 33(3):743-746. http://www.citeulike.org/user/HEIRS/article/6090770
De Zoeten, E. F., Wang, L., Sai, H., Dillmann, W. H., and Hancock, W. W. (2009). Expression of hdac9 by t regulatory cells prevents colitis in mice. Gastroenterology. http://www.citeulike.org/user/HEIRS/article/6553713
Wieten, L., van der Zee, R., Goedemans, R., Sijtsma, J., Serafini, M., Lubsen, N. H., van Eden, W., and Broere, F. (2010). Hsp70 expression and induction as a readout for detection of immune modulatory components in food. Cell stress & chaperones, 15(1):25-37.
http://www.citeulike.org/user/HEIRS/article/4675555
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1).
http://www.citeulike.org/user/HEIRS/article/6553728
Nakanishi, Y. and Yasumoto, K. (1997). Induction after administering paraquat of heme oxygenase-1 and heat shock protein 70 in the liver of senescence-accelerated mice. Bioscience, biotechnology, and biochemistry, 61(8):1302-1306.
http://www.citeulike.org/group/7833/article/6553731
Konturek, P. C., Dembinski, A., Warzecha, Z., Burnat, G., Ceranowicz, P., Hahn, E. G., Dembinski, M., Tomaszewska, R., and Konturek, S. J. (2005). Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World journal of gastroenterology : WJG, 11(40):6322-6329.
http://www.citeulike.org/user/HEIRS/article/6553866
Hontecillas, R. and Bassaganya-Riera, J. (2007). Peroxisome proliferator-activated receptor gamma is required for regulatory cd4+ t cell-mediated protection against colitis. Journal of immunology (Baltimore, Md. : 1950), 178(5):2940-2949.
Milne, K. J. and Noble, E. G. (2002). Exercise-induced elevation of hsp70 is intensity dependent. Journal of applied physiology (Bethesda, Md. : 1985), 93(2):561-568.
http://www.citeulike.org/user/HEIRS/article/6553732
Senf, S. M., Dodd, S. L., and Judge, A. R. (2010). Foxo signaling is required for disuse muscle atrophy and is directly regulated by hsp70. American journal of physiology. Cell physiology, 298(1). http://www.citeulike.org/user/HEIRS/article/6553728
Lowder, T., Dugger, K., Deshane, J., Estell, K., and Schwiebert, L. M. (2010). Repeated bouts of aerobic exercise enhance regulatory t cell responses in a murine asthma model. Brain, behavior, and immunity, 24(1):153-159. http://www.citeulike.org/user/HEIRS/article/5842541
Reynolds, A. D., Banerjee, R., Liu, J., Gendelman, H. E., and Mosley, R. L. (2007). Neuroprotective activities of cd4+cd25+ regulatory t cells in an animal model of parkinson's disease. Journal of leukocyte biology, 82(5):1083-1094. http://www.citeulike.org/user/HEIRS/article/6554146
Cosentino, M., Fietta, A. M., Ferrari, M., Rasini, E., Bombelli, R., Carcano, E., Saporiti, F., Meloni, F., Marino, F., and Lecchini, S. (2007). Human cd4+cd25+ regulatory t cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood, 109(2):632-642. http://www.citeulike.org/user/HEIRS/article/6554165
Iwata, S., Shimizu, T., Nomoto, M., and Fukuda, T. (1996). Characteristic upregulation of dopamine d1-receptor in rat striatum after 6-hydroxydopamine treatment. Japanese journal of pharmacology, 71(3):255-258.
http://www.citeulike.org/user/HEIRS/article/6554215
It is Hot in Here, or is it Just SIRT1. SIRT1 Activate Heat Shock Transcription. Retrieved on January 16, 2010.
Zhang, J., Lee, S.-M. M., Shannon, S., Gao, B., Chen, W., Chen, A., Divekar, R., McBurney, M. W., Braley-Mullen, H., Zaghouani, H., and Fang, D. (2009). The type iii histone deacetylase sirt1 is essential for maintenance of t cell tolerance in mice. The Journal of clinical investigation, 119(10):3048-3058.
http://www.citeulike.org/user/HEIRS/article/6554270
Jammes, Y., Steinberg, J. G., Delliaux, S., and Brégeon, F. (2009). Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and hsp responses. Journal of internal medicine, 266(2):196-206. http://www.citeulike.org/user/HEIRS/article/4695048
Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia.
CiteULike: Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia.: "Grima, G., Benz, B., Parpura, V., Cuénod, M., and Do, K. Q. (2003). Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. Schizophrenia research, 62(3):213-224."
Exercise-induced histone modifications in human skeletal muscle.
CiteULike: Exercise-induced histone modifications in human skeletal muscle.: "McGee, S. L., Fairlie, E., Garnham, A. P., and Hargreaves, M. (2009). Exercise-induced histone modifications in human skeletal muscle. The Journal of physiology, 587(Pt 24):5951-5958."
Friday, January 15, 2010
The Chemical Defensive System in the Pathobiology ... [Curr Drug Metab. 2010] - PubMed result
The Chemical Defensive System in the Pathobiology ... [Curr Drug Metab. 2010] - PubMed result: "The Chemical Defensive System in the Pathobiology of Idiopathic Environment-Associated Diseases."
Exercise Stimulates Transcription Factors (Nrf2 & NFkB), Increases Antioxidant Defenses, Decreases Oxidative Stress, and Restores Renal Dopamine D1 Receptor Function in Aging
CiteULike: Exercise Stimulates Transcription Factors (Nrf2 & NFkB), Increases Antioxidant Defenses, Decreases Oxidative Stress, and Restores Renal Dopamine D1 Receptor Function in Aging: "George, L., Asghar, M., and Lokhandwala, M. F. (2008). Exercise stimulates transcription factors (nrf2 & nfkb), increases antioxidant defenses, decreases oxidative stress, and restores renal dopamine d1 receptor function in aging. The Faseb Journal."
Chronic Stress and Elevated Norepinephrine - Effects on the Heart
Summary: "enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in increased reactive oxygen species generation which can lead to cardiac dysfunction from chronic stress."
Increased Norepinephrine Breakdown Adverse for Heart. Mpdern Medicine. Retrieved January 14, 2009.
Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002). Identification of nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res, 62(18):5196-5203.
http://www.citeulike.org/user/HEIRS/article/3728059
Increased Norepinephrine Breakdown Adverse for Heart. Mpdern Medicine. Retrieved January 14, 2009.
Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002). Identification of nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res, 62(18):5196-5203.
http://www.citeulike.org/user/HEIRS/article/3728059
Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin
CiteULike: Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin: "Gonçalves, J., Baptista, S., Martins, T., Milhazes, N., Borges, F., Ribeiro, C. F., Malva, J. O., and Silva, A. P. (2010). Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. European Journal of Neuroscience, 9999(9999)."
Contaminated House Dust Linked to Parking Lots with Coal Tar Sealant
Contaminated House Dust Linked to Parking Lots with Coal Tar Sealant
ScienceDaily (2010-01-15) -- Coal-tar-based sealcoat -- the black, shiny substance sprayed or painted on many parking lots, driveways, and playgrounds -- has been linked to elevated concentrations of the contaminants polycyclic aromatic hydrocarbons (PAHs) in house dust. Apartments with adjacent parking lots treated with the coal-tar based sealcoat contained house dust with much higher concentrations of PAHs than apartments next to other types of parking lots according to new research. ... > read full article
CiteULike: Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin
CiteULike: Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin: "Gonçalves, J., Baptista, S., Martins, T., Milhazes, N., Borges, F., Ribeiro, C. F., Malva, J. O., and Silva, A. P. (2010). Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. European Journal of Neuroscience, 9999(9999)."
Friedrich's Ataxia Patients Show Increased DNA Damage
Comment: It is often useful to study diseases that are similar to gain further insight into each of them. As we have noted, dysfunctions in the Nrf2 system can exacerbate symptoms and influence the development of environmental disease and other health problems from Nrf2 deficiency have been associated with alterations in iron transport. 1 in 50,000 patients are effected by Friedrich's ataxia which is an inherited disorder that causes substantial neurological damage over a lifetime leading to early disability.
Background: Friedrich's ataxia (FA) is a condition that is the result of loss of mitochondrial frataxin leading to damage in a certain neurons. Recent studies show some of this is due to impairment in the Nrf2 signaling system. In Friedrich's ataxia, iron overload leads to damaged nerves and muscle cells.
A new study demonstrates one of the characteristics in FA is an increase in DNA damage. According to the head researcher, in FA "gene activity patterns that are associated with responses to DNA damage, and our comparisons and follow-up tests showed us that FRDA patients have far more damage than seen in healthy people." A better understanding of this disease should lead to better treatments.
Source: Excess DNA damage found in cells of patients with Friedreich's ataxia.
Pietsch, E. C., Chan, J. Y., Torti, F. M., and Torti, S. V. (2003). Nrf2 mediates the induction of ferritin h in response to xenobiotics and cancer chemopreventive dithiolethiones. Journal of Biological Chemistry, 278(4):2361-2369. http://www.citeulike.org/user/HEIRS/article/6543977
Background: Friedrich's ataxia (FA) is a condition that is the result of loss of mitochondrial frataxin leading to damage in a certain neurons. Recent studies show some of this is due to impairment in the Nrf2 signaling system. In Friedrich's ataxia, iron overload leads to damaged nerves and muscle cells.
A new study demonstrates one of the characteristics in FA is an increase in DNA damage. According to the head researcher, in FA "gene activity patterns that are associated with responses to DNA damage, and our comparisons and follow-up tests showed us that FRDA patients have far more damage than seen in healthy people." A better understanding of this disease should lead to better treatments.
Source: Excess DNA damage found in cells of patients with Friedreich's ataxia.
Pietsch, E. C., Chan, J. Y., Torti, F. M., and Torti, S. V. (2003). Nrf2 mediates the induction of ferritin h in response to xenobiotics and cancer chemopreventive dithiolethiones. Journal of Biological Chemistry, 278(4):2361-2369. http://www.citeulike.org/user/HEIRS/article/6543977
Thursday, January 14, 2010
The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium.
CiteULike: The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium.: "Arisawa, T., Tahara, T., Shibata, T., Nagasaka, M., Nakamura, M., Kamiya, Y., Fujita, H., Yoshioka, D., Arima, Y., Okubo, M., Hirata, I., and Nakano, H. (2008). The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant dna methylation in gastric epithelium. Oncology reports, 19(1):211-216."
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.
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