BDNF, LRRK and Pink and Environment Play Role in Parkinson's Disease~!

"PD risk is modulated by both genetic factors including BDNF, PINK, and LRRK and environmental exposures."

Read more: CiteULike: Lrrk2 S1647T and BDNF V66M interact with environmental factors to increase risk of Parkinson's disease.:

Combining NO release W/ anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a MPTP model of Parkinson's disease

Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse

"These findings suggest that the EAAC1−/− mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD. ANN NEUROL 2010"


Read more: CiteULike: N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse:

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

"diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure."

Read more:Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet:

Metals, oxidative stress and neurodegenerative disorders.

"Jomova, K., Vondrakova, D., Lawson, M., and Valko, M. (2010). Metals, oxidative stress and neurodegenerative disorders. Molecular and cellular biochemistry."

Abstract link: CiteULike: Metals, oxidative stress and neurodegenerative disorders.:

Different Susceptibility to Parkinson's in Mice Lacking Nrf2 vs. HO-1~!

"HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols"

Read abstract: Different Susceptibility to the Parkinson's Toxin ... [PLoS One. 2010] - PubMed result:

Astroglial Amino Acid Shuttle Involved in Nociceptive Pain Sensitization!

"This study has demonstrated that the central sensitization induced in functionally identified nociceptive neurons in trigeminal subnucleus caudalis (the medullary dorsal horn) by application of an inflammatory irritant to the rat's tooth pulp can be significantly attenuated by continuous intrathecal superfusion of methionine sulfoximine, an inhibitor of the astroglial enzyme glutamine synthetase that is involved in the glutamate–glutamine shuttle......Further, the lack of any observed significant effects of MSO alone, in contrast to our findings that it significantly attenuates MO-induced central sensitization, suggests that its action on astroglial GS is not evident in basal conditions but is apparent in hyperexcitable states, consistent with findings by ourselves and others that glia may not affect basal nociceptive processing but rather participate in exaggerated pain states. It is also noteworthy that an excess of glutamine in the CNS is involved in ammonia neurotoxicity possibly through its detrimental effects on mitochondrial function."

CiteULike: Astroglial Glutamate Glutamine Shuttle Is Involved in Central Sensitization of Nociceptive Neurons in Rat Medullary Dorsal Horn: "Chiang, C.-Y., Wang, J., Xie, Y.-F., Zhang, S., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. (2007). Astroglial glutamate glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J. Neurosci., 27(34):9068-9076."


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Mhalla, A., de Andrade, D. C. C., Baudic, S., Perrot, S., and Bouhassira, D. (2010). Alteration of cortical excitability in patients with fibromyalgia. Pain, 149(3):495-500.
http://www.citeulike.org/user/HEIRS/article/6962057
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Chen, P.-C., Vargas, M. R., Pani, A. K., Smeyne, R. J., Johnson, D. A., Kan, Y. W., and Johnson, J. A. (2009). Nrf2-mediated neuroprotection in the mptp mouse model of parkinson's disease: Critical role for the astrocyte. Proceedings of the National Academy of Sciences, 106(8):2933-2938. http://www.citeulike.org/user/HEIRS/article/6551224?show_msg=already_posted

Pathway Impairment that Regulates Stress Response Could Lead to A Variety of Environmental Diseases

A recent study determined that caffeine can be a preventative against some of the health effects in Parkinson's disease caused by pesticides. The following pathway is a good representation of the NO/cGMP pathway that is more than likely effected by caffeine in these conditions and can account for some of the locomoter problems in PD. As one can see, expression of other proteins including BDNF rely on its activity. In other blogs, we have noted that BDNF is altered in environmental illnesses including CFS and may account for mood changes that occur with the condition. Proper signaling of the NO/cGMP pathway is important for a number of health conditions because the pathways are consistently activated by a number of different xenobiotics and environmental cues.

Alterations in the functioning of Nrf2 and other conditions like excretory defects that increase ammonia levels with negatively impact this system. While NO is an important component of this pathway - the actual dysfunction is not related to peroxynitrite, although oxidative stress to some may increase dysfunction though loss of NO signalling. Madhusoodanan explains that in this case, "nitric oxide is a short lived free radical species synthesized by NOS. The physiological role of NO depends on its local concentration as wells as the availability of downstream targets. At low levels, activation of guanalyl cyclase is the major event by NO. The resulting elevation of cGMP serves as an regulator of many events." I suggest that many environmental diseases including CFS and MCS are probably due more to the impairments of NO/cGMP which is also negatively effected by endogenous gases including ammonia and the impairment of the system results in astrocyte damage. Because Nrf2 is also neuroprotective --- alterations in Nrf2 will contribute to neural injury. Also, cGMP inhibits the protein GSK-3b which is an off/on switch for Nrf2. Studies have demonstrated that Nrf2 regulates the antioxidant complexes of HO-1/CO which modulates CRF (which can be activated by odors) and CO activates cGMP. These pathways seem to strongly suggest that Nrf2 ultimately may influence the regulation of the stress response from environmental cues. In any case, HO-1/CO does modulate the CRF system which can be activated by response cytokines such as Il-1.

Recent studies show that increasing Nrf2 may be beneficial in limiting neural injury and in this case, I would say it probably would too. The article discusses hormetic responses that we have also discussed at length and as Mattson describes "recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors." This of course may act on activities involved in methylation.



Notes:

• Diabetes exacerbates functional deficiency of NO/cGMP in ED

Madhusoodanan, K. and Murad, F. (2007). No-cgmp signaling and regenerative medicine involving stem cells. Neurochemical Research, 32(4):681-694.
http://www.citeulike.org/user/HEIRS/article/1245237
Chan, M.-H., Chien, T.-H., Lee, P.-Y., and Chen, H.-H. (2004). Involvement of no/cgmp pathway in toluene-induced locomotor hyperactivity in female rats. Psychopharmacology, 176(3):435-439.
http://www.citeulike.org/user/HEIRS/article/7170771
van Staveren, W. (2001). The effects of phosphodiesterase inhibition on cyclic gmp and cyclic amp accumulation in the hippocampus of the rat. Brain Research, 888(2):275-286.
http://www.citeulike.org/user/HEIRS/article/7170748
Kachroo, A., Irizarry, M. C., and Schwarzschild, M. A. (2010). Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration. Experimental neurology, 223(2):657-661.
http://www.citeulike.org/user/HEIRS/article/6835294
Mattson, M. P., Son, T. G., and Camandola, S. (2007). Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose-response : a publication of International Hormesis Society, 5(3):174-186.
http://www.citeulike.org/user/HEIRS/article/3812627
Angulo, J., González-Corrochano, R., Cuevas, P., Fernández, A., Fuente, J. L. M., Rolo, F., Allona, A., and Sáenz de Tejada, I. (2009). Diabetes exacerbates the functional deficiency of no/cgmp pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. The journal of sexual medicine. http://www.citeulike.org/user/HEIRS/article/7170872

Yang, R., Wang, J., Chen, Y., Sun, Z., Wang, R., and Dai, Y. (2008). Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. J Androl, 29(5):586-591. http://www.citeulike.org/user/HEIRS/article/7170883
Nisoli, E. and Carruba, M. O. (2006). Nitric oxide and mitochondrial biogenesis. J Cell Sci, 119(14):2855-2862.http://www.citeulike.org/user/HEIRS/article/7170901

Keap1-Nrf2 activation in the presence and absence of DJ-1

Keap1-Nrf2 activation in the presence and absence of DJ-1. Li Gan. 2010; European Journal of Neuroscience - Wiley InterScience: "In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2–ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson's disease."

Parkinson's and Link To Muscle Protein and Cell Signaling Pathway?

I recently noted that transcription factors such as MEF2, NRF1, NRF2 are co-activated by PGC-1a (important for mitochondrial biogenesis) results in kind of a loop to increase the expression of PGC-1a. PGC-1a regulates a number of transporters that regulate chemicals across membranes and alterations in these proteins may increase or lead to tissue dysfunction.

Recent evidence indicates that chaperone-mediated autophagy plays a role in direct degradation of neuronal transcription factor MEF2D, a protein known to promote neuronal survival. Disruption of this regulatory pathway by α-synuclein leads to neuronal stress, which may underlie neuronal loss in Parkinson’s disease.

For further reading:

• Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 -- Piantadosi et al. 103 (11): 1232 Figure IG7 -- Circulation Research
• Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

Yang, Q. and Mao, Z. (2010). Dysregulation of autophagy and parkinson's disease: the mef2d link. Apoptosis. http://www.citeulike.org/user/HEIRS/article/6715832
Wright, D. C., Han, D.-H. H., Garcia-Roves, P. M., Geiger, P. C., Jones, T. E., and Holloszy, J. O. (2007). Exercise-induced mitochondrial biogenesis begins before the increase in muscle pgc-1alpha expression. The Journal of biological chemistry, 282(1):194-199. http://www.citeulike.org/user/HEIRS/article/6580001
Brockmann, K., Wang, D., Korenke, C. G., Von Moers, A., Ho, Y.-Y., Pascual, J. M., Kuang, K., Yang, H., Ma, L., Kranz-Eble, P., Fischbarg, J., Hanefeld, F., and De Vivo, D. C. (2001). Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Annals of Neurology, 50(4):476-485. http://www.citeulike.org/user/HEIRS/article/6715941
Hernandez, M. J., Roberts, T. M., and Hardin, C. D. (2007). Caveolin-1 and the organization of glycolysis in astrocytes: Modulation by ammonia. The FASEB Journal, 21. http://www.citeulike.org/user/HEIRS/article/6715979
Klinge, C. M. (2008). Estrogenic control of mitochondrial function and biogenesis. Journal of Cellular Biochemistry, 105(6):1342-1351. http://www.citeulike.org/user/HEIRS/article/3879108

Parkinsons Model Identifies Protein & Mitochondria Metabolic Dysruptions

In Parkinson's disease model, while oxygen consumption is similar to control lines, PD lines demonstrate reduced SIRT1 phosphorylation, lower PGC-1a levels and increased NF-kabbaB activation. Results suggest altered aerobic metabolism and mitochondrial respiration.

Mitochondrial Respiration and Respiration Associated Proteins in Cell Lines Created through Parkinson's Subject Mitochondrial Transfer.: "Raquel Esteves, A., Lu, J., Rodova, M., Onyango, I., Lezi, E., Dubinsky, R., Lyons, K. E., Pahwa, R., Burns, J. M., Cardoso, S. M., and Swerdlow, R. H. (2010). Mitochondrial respiration and respiration associated proteins in cell lines created through parkinson's subject mitochondrial transfer. Journal of neurochemistry."

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:

• 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 Ünexplained 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

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

More Evidence of Metals Contributing Parkinson's Disease and Other Adverse Effects

CiteULike: A system-based comparison of gene expression reveals alterations in oxidative stress, disruption of ubiquitin-proteasome system and altered cell cycle regulation after exposure to cadmium and methylmercury in Mouse Embryonic Fibroblast (MEF): "Yu, X., Robinson, J. F., Sidhu, J. S., Hong, S., and Faustman, E. M. (2010). A system-based comparison of gene expression reveals alterations in oxidative stress, disruption of ubiquitin-proteasome system and altered cell cycle regulation after exposure to cadmium and methylmercury in mouse embryonic fibroblast (mef). Toxicol. Sci., pages kfq003+."

T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.

One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.

Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.

Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)

It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.

Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.




For original document and citations.


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Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease.

Background: Nrf2 is a regulator of the antioxidant system including the production of HO-1 that provides protection against a number of toxic insults and GSK-3b acts as an on/off switch of that system. In addition, it has been shown that GSk-3b regulates the inflammatory response of LPS endotoxin through modulation of toll receptors. TLR4 has been shown to be instrumental in initializing and maintaining neuropathic pain.

Infante, J., García-Gorostiaga, I., Sánchez-Juan, P., Sierra, M., Martín-Gurpegui, J. L., Terrazas, J., Mateo, I., Rodríguez-Rodríguez, E., Berciano, J., and Combarros, O. (2009). Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease. European Journal of Neurology, 9999(9999). http://www.citeulike.org/user/HEIRS/article/6426071


HEIRS Library Tags: GSK-3b, HO-1

Supplemental citation: Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/2605
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., and Watkins, L. R. (2008). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (tlr4). The European journal of neuroscience, 28(1):20-29. http://www.citeulike.org/user/HEIRS/article/2997140

Cybrid models of parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships

Keeney, P. M., Dunham, L. D., Quigley, C. K., Morton, S. L., Bergquist, K. E., and Bennett, J. P. (2009). Cybrid models of parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships. Experimental neurology, 220(2):374-382. http://www.citeulike.org/user/HEIRS/article/5913095

Hope For New Parkinson's Disease Treatment Through RXR Activation

Hope For New Parkinson's Disease Treatment Through RXR Activation: "URL: Hope For New Parkinson's Disease Treatment Through RXR Activation

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Expression of TLR4 and CD14 in the Central Nervous System (CNS) in a MPTP Mouse Model of Parkinson's-Like Disease

Title: Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease.

Summary: Results demonstrated an augmented expression of both CD14 and TLR4 in the substantia nigra of mice treated with MPTP in comparison to untreated animals, suggesting that the endotoxin receptors are over expressed in different manner in specific areas of the CNS during Parkinson's-like disease.

Panaro‌, M. A., Lofrumento, D. D., Saponaro‌, C., De Nuccio, F., Cianciulli, A., Mitolo, V., and Nicolardi‌, G. (2008). Expression of tlr4 and cd14 in the central nervous system (cns) in a mptp mouse model of parkinson's-like disease. Immunopharmacology and Immunotoxicology, 30(4):729-740. http://www.citeulike.org/user/HEIRS/article/6334780

Glutathione depletion in nigrostriatal slice cultures: Gaba loss, dopamine resistance and protection by the tetrahydrobiopterin precursor sepiapterin

Gramsbergen, J. B. B., Sandberg, M., Møller Dall, A., Kornblit, B., and Zimmer, J. (2002). Glutathione depletion in nigrostriatal slice cultures: Gaba loss, dopamine resistance and protection by the tetrahydrobiopterin precursor sepiapterin. Brain research, 935(1-2):47-58. http://www.citeulike.org/user/HEIRS/article/6307660