Showing posts with label dopamine. Show all posts
Showing posts with label dopamine. Show all posts
Friday, October 1, 2010
Friday, July 30, 2010
Insulin Resistance Drug Protects Neurons from NO Damage: Potential CFS Implications~!
Backgrond: A recent study has shown improvements in CFS mouse model after the use of pioglitazone and caffeic acid. Other studies suggest pathogenic influences on CFS including exposure to gram (-) bacteria. Rosiglitazone, another PPAR-gamma agonist, has shown positive effects as an anti-inflammatory in conditions that lead to neurodegenerative disease like Parkinson's. Schintu demontrates that Rosiglitazone inhibits microglia reactivity.
Read more:CiteULike: Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt.:
For further Reading: HEIRS Research Blog July 24, 2010
***Inflammation, Insulin Resistance and Decreased PPARs-- A Pathway to CFS?
Additional Resource:
*Schintu, N., Frau, L., Ibba, M., Caboni, P., Garau, A., Carboni, E., and Carta, A. R. (2009). Ppar-gamma-mediated neuroprotection in a chronic mouse model of parkinson's disease. The European journal of neuroscience, 29(5):954-963.
http://www.citeulike.org/user/HEIRS/article/4136907?show_msg=already_posted
"pioglitazone protects dopaminergic neurons against LPS insult at least via inhibiting iNOS expression and NO generation, which is potentially mediated via inhibition of p38 MAPK activity. In addition, the PI3K pathway actively participates in the negative regulation of LPS-induced NO production"
Read more:CiteULike: Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt.:
For further Reading: HEIRS Research Blog July 24, 2010
***Inflammation, Insulin Resistance and Decreased PPARs-- A Pathway to CFS?
Additional Resource:
*Schintu, N., Frau, L., Ibba, M., Caboni, P., Garau, A., Carboni, E., and Carta, A. R. (2009). Ppar-gamma-mediated neuroprotection in a chronic mouse model of parkinson's disease. The European journal of neuroscience, 29(5):954-963.
http://www.citeulike.org/user/HEIRS/article/4136907?show_msg=already_posted
Monday, July 26, 2010
NO/cGMP signaling pathway limits inflammatory degeneration of dopaminergic neurons: via regulation of HO-1
"NO-cyclic GMP signaling pathway promotes the induction of HO-1 specifically in dopaminergic neurons, which acts as an endogenous protective system to limit inflammatory degeneration of this cell population."
CiteULike: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression.:
CiteULike: Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression.:
Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.
"These results suggest that, by recruiting cyclic GMP and PKG, nNOS-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons."
Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.:
Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.:
Tuesday, July 20, 2010
Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity.
"Fibroblast growth factor upregulates gamma-GCS and HO-1 expression to protect cortical and dopaminergic neurons from MPP(+)-induced oxidative insult."
CiteULike: Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity.:
Friday, April 23, 2010
Sunday, April 11, 2010
Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?
One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez) Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.
In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)
Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.
Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.
HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine
HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,
HEIRS H & H
**** Follow me on Twitter: HEIRS_Health
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Original Article and Citations:
In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)
Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.
Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.
HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine
HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,
HEIRS H & H
**** Follow me on Twitter: HEIRS_Health
**** Read My Bio: HEIRS_Health
Original Article and Citations:
Sunday, March 7, 2010
BDNF Regulates Hedonic Feeding by Acting on the Dopamine System
"amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core."
Brain-Derived Neurotrophic Factor Regulates Hedonic Feeding by Acting on the Mesolimbic Dopamine System -- Cordeira et al. 30 (7): 2533 -- Journal of Neuroscience:
Brain-Derived Neurotrophic Factor Regulates Hedonic Feeding by Acting on the Mesolimbic Dopamine System -- Cordeira et al. 30 (7): 2533 -- Journal of Neuroscience:
Wednesday, January 27, 2010
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
Tuesday, January 26, 2010
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"
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
Wednesday, January 13, 2010
ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!
ImmunoGenetics in Autism, MCS and Cancer --
What Has Food Got To Do With It
Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.
B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.
Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.
To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)
The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!
Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.
An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.
Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.
Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.
New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).
In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.
It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.
Original document and citations
What Has Food Got To Do With It
Research scientists are gaining more understanding why certain physical changes occur and are passed on to successive generations without changes to DNA. The field of research that studies involving these kinds of changes is called epigenetics and ultimately examines how behaviors and their influence on biological systems, whether beneficial or detrimental, can be passed on to their descendants. This process is called methylation and simply put, is a where a methyl group attaches to an amino acid which permanently or temporarily silences gene expression. Interestingly, as understanding of methylation advances, its role as a cause of environmental illnesses becomes more and more ignored, at least in the media. Why this is true I can tell you but need to stress here that methylation may be the one or one of the most important factors that contributes to environmental illness including chemical sensitivity, autism, cancer and as you will read probably more....Methylation and its impact on genetic expression provides a mechanism that explains why environmental illnesses run in families and why environmental illnesses and exposures effect children, the elderly and males and females differently. It also provides an explanation for the wide range of reactions and "immunological footprints" present in EI patients.
B12 is considered an important part of most therapy protocals for chemical sensitivity. In addition, it has also been shown that it is beneficial as a cancer treatment because of its ability to cycle homocysteine to methionine which provides a "methyl" group for methylation. Research shows that a B12 deficiency can lead to hypomethylation of DNA which increases the risk for cancer. On the other hand, methylation is important for any number of processes in metabolism that occur billions of times in the body each second and therefore, it is an indespensable process for life. One physician, Dr. Schneider explains that silencing viral genes, methylating the dopamine receptor, changing brainwaves and increasing attention and focus are just a few biological processes that utilize methylation. In addition, she describes that "low methylators" will suffer from a variety of health conditions including eczema, asthma, arthritis, colitis and a host of other illnesses because methylation is necessary to make glutathione; the primary antioxidant used in the body to battle inflammation. S-adenosylmethionine (SAMe) is a "product of methionine metabolism" which modulates Il-10 and Il-6. Both Il-6 and Il-10 are involved in pathogies of environmental diseases including sickness syndrome, PTSD and inflammatory and autoimmune diseases. Il-10 provides a number of effects including protection against cytokine-induced insulin resistance, Il-6, fatigue and motor deficits after pathogenic exposure. It also plays a role in adaptive immunity and differentiation of T cells.
Chronic inflammation can lead to autoimmune diseases. Alterations in Nrf2 function are also implicated in driving TH2 that may present very much like autoimmune disease. If one looks a little closer at autism, one may see some similarities to symptoms common in multiple chemical sensitivity. Autistic children also suffer from a variety of maladies including chemical sensitivity. All in all, it leads one to suspect they may have common "roots" so to speak and the "root" of malfunction lies in the methylation pathway. Remember, autism spectrum disorders include by its definition a spectrum of disorders. It is noteworthy to mention several "methy donors" mentioned for treatments of autism and are also considered to be effective for the treatment of MCS. These include methylcobalamin which is a form of B12, the active form of folate which is a precursor to tetrahydrobiopterin (BH4) and Q10 which improves mitochondrial function.
To further understand the relationships between MCS, autism and other environmental illnesses, we propose and Dr. Scheider, MD suggests, it might be useful to look at several autism pathways which include catecholamine-o-methyltransferase (COMT), methionine synthase, crystathione beta synthase (CBS) and PON1. (Care) These are also pathways suggested in MCS, CFS and other environmentally-induced conditions. Just today, it was announced mutations in PON1 and the exposure to pesticides make one more susceptible to at least one type of Parkinson's disease. (Manthripragada) Methionine is protective against dopamine induced oxidative stress but may induce cellular damage of its own. A cellular enzyme called methionine sulfoxide reductase protects against methionine oxidation; a deficiency in Msra may increase DNA damage. Thus, Msra dysfunction must be considered as a factor in environmental illness. Several studies show that Nrf2 is protective against liver injury which is of course, what one has to consider after chronic or acute toxic injury and Nrf2 deficiency has been associated with autoimmune-type disease. (Li) Homocysteine has also been shown to contribute to liver disease and whether caused by genetic or diet, elevated homocysteine levels "alter the abundance of liver enzymes in methionine metabolism, the urea cycle and antioxidant defense. Homocysteine may impair the urea cycle.Normally this cycle is responsible for converting ammonia into urea for subsequent excretion by the kidneys. As we noted above, pesticides and other crop treatments may influence the development of environmental diseases including Parkinson's disease, autism and MCS. Studies have determined hydrazine, a chemical in fertilizer, causes a reduction in methionine reductase with no involvement from NO or NOS or reversal by arginine, increases homocysteine and impairs the sulphur amino acid pathway. In addition, several gene variants including cysteine b synthase, the less active MTHFR allele and weaker forms of nitric oxide synthase can predispose an individual to high ammonia levels that may also be produced by gut bacteria. Methytetrahydrofolate is often prescribed for high ammonia levels and its mode of action raises tetrahydrobiopterin (BH4). BH4 is an important component of the NO/ONOO cycle mechanism for causing environmental illness including multiple chemical sensitivity developed by Dr. Martin Pall, PhD. As he states, when "BH4 is limited, nitric oxide synthase produces superoxide instead of NO". To support Nrf2's role in chemical sensitivy, it is now understood that Nrf2 sustains the balance between eNOS and the production of NO. Also, gut dysbiota has been suggested as a factor in a number of environmental illnesses including chemical sensitivity, fibromyalgia and especially autism. (Care)
The methionine synthase pathway is dependant on B12 and as Deth explains this pathway is a link between folate and methionine. Recent discoveries have revealed methionine synthase is required for the normal metabolism of dopamine such as its neurotransmission and cognitive functioning of attention and focus and can be inhibited both by thimerasol and heavy metals. At the same time, dopamine activates Nrf2 to minimize the effects of the oxidative stress it produces. Some scientists believe abnormal levels of B12-dependant methionine synthase may contribute to ADHD which occurs much more often in boys and may be, as some experts believe, a mild form of autism. Other studies suggest the difference in prevalence of ADHD in boy and girls is less significant and more likely a consequence of failure to diagnose it accurately in girls. (Consentino) In any case and in keeping with this train of thought, caffeine, a methyl donor, is given to remedy some of the symptoms of ADHD but is more addictive to boys than girls. (MedPage Today) From this, one must ask is there a metabolic difference in the methylation cycle and dopamine cycling or another gene such as COMT that effects males and females differently which increases a male's risk for ADHD? Or could there be a sexual dimorphism in Nrf2 expression that can account for this difference. There is no reason why this could not be true, considering caffeine mediates some of its effects through the Nrf2 antioxidant system? (Cavin) Health studies of Nrf2's role in autoimmune disease shows sexual dimorphism with an increased risk for females. It may be the methionine synthase pathway and Nrf2 together account for the sexual dimorphism of ADHD, in caffeine addiction and possibly overall fitness. It could be these two systems have different influences both positive and negative in both boys and girls.(One study demonstrates methionine deficiency complicates Nrf2 deficiency and Nrf2 regulates the MAO system which can control the expression of neurotransmitters and as a result, influence behavior.) Also, why are male flies more resistant to Paraquat and live longer than females flies that are heterozygous for Keap1. (Keap 1 is an an important regulating protein of Nrf2 and sensor for oxidative stress environments.) These are interesting questions and future research may provide answers to these and other questions such as why do more females suffer from environmental diseases like CFS and fibromyalgia but males suffer more from ADHD! (Sykiotis) An Adaptive Biologist and Medical Anthropologist might suggest these dimorphisms exist as trade-offs in behavior control and provide a protective and limiting mechanism for fertility and child-bearing in females but increase lifespan and elevate the drive for sexual foraging in males. At this point, I do not think anyone really knows!
Deficiencies in Nrf2 null animals of methionine and choline, both methyl donors, make them more susceptible to inflammation and fatty liver. This demonstrates Nrf2 deficiency adds to medical pathologies of "poor methylation". In addition, reduced expression of other proteins that coordinate activities with Nrf2 such as the AhR may also influence susceptibility to symptoms of environmental disease including autism and chemical sensitivity. For instance, both the AhR and Nrf2 are required for the induction of UGT transferases which aid in the excretion of toxic compounds such as drugs, bilirubin, hormones and steroids. In the literature, the alteration of UGT function has been implicated in multiple chemical sensitivity and different cancers. Also, the increase of IGF and dopamine increases methionine synthase activity which also requires an increase in B12 and other biological resources. Studies have shown that blocking the methionine synthase pathways inhibits nerve growth factor's (NGF) induction of differentiation and another researcher reports elevation in NGF in B12 deficiency increases neurogenic inflammation resulting in chronic cough and chronic airway discomfort which are symptoms attributed to MCS. (Battaglia-Hsu) The result of B12 deficiency includes "a peripheral sensory neuropathy, causing symptoms such as numbness, tingling, burning, and complete lack of sensation". (Jockers) These are also commonly reported symptoms in MCS. Mercury and lead have been demonstrated to block this pathway, in addition to, an agent called wortmannin which blocks the pathway PI3K. PI3K inhibitors are used experimentally against inflammation and eventually may be used in cancer therapy. (Crane, Science) In a type of liver cancer, the loss of methyltransferases results in uncontrolled epigenetic methylation of DNA. By looking at some of these other pathways that influence methionine metabolism, one must consider a relationship to MCS and autism spectrum disorders.
An important study was released last year by a Canadian research team that demonstrated inflammation in peripheral organs may cause neuroinflammation in the brain. Specifically, the study explains that diseases such as inflammatory bowel disease, hepatitis, and others can lead to inflammatory processes in the brain that can change neurotransmission, alter gene regulation, etc. One of these cytokines is Tnf-a which activates MCP-1. Currently, neuroimmune inflammation is considered one of "the best" hypotheses of what causes autism spectrum disorders and as Dr. Bratt explains, autism is a complex medical condition involving dysfunction in the brain and nervous system, as well as gastrointestinal, immune, emdocrine and detoxification systems." Specifically, "dysregulated immune responses either directly or indirectly adversely affect the course of neurodevelopment in the brain, leading to the development of autism. Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6), proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1). (Enstrom)In addition to the inflammatory mediators above, altered levels of Il23 are found in patients with autism.
Interestingly, these inflammatory processes have been implicated in most environmental illnesses including MCS. IL-23 is a cytokine that initiates T cells to differentiate into IL17 cells which are different from Th1 or Th2. The difference, is a very recent distinction which adds to confusion in the literature of whether inflammatory and autoimmune diseases such as rheumatoid athritis, lupus and MS are Th2 or Il17. Nonetheless, IL17 can stimulate the battery of inflammatory cytokines mentioned above which is capable of neuroimmune dysregulation in the brain and body systems. Last week, we suggested that the absence of Tregs may influence a Nrf2 positive or negative phenotype into an autoimmune-type disorder and demonstrated how environmental pollutants can change the "immune footprint" depending on the type of pollutant and accordingly drive a Th2 driven phenotype characteristic of environmental illnesses such as MCS because they have inflammatory and autoimmune-like presentations. In addition, a study set of CFS patients have been identified with a lower freguency of a protective variant against an anti-inflammatory phenotype of Il-17 giving credibility to the idea that IL-17 may also play an important role in CFS. This also gives support to the idea that CFS and other environmental illnesses including autism are closely linked to one another, are autoimmune and inflammation driven and Nrf2 and cytokine profiles may significantly influence disease presentation and inflammation severity. In addition, individual genetics can influence the exact nature of disease development and the level of methylation may be key to more differences in genetic expression.
Nutrition is an important mechanism for controlling environmental illnesses. Recent nutritional studies show Western Diets promote inflammation. One reason for this, is because saturated fat alters TLR signals that can lead to potentially harmful "immunological footprints". Personally, in addition to the impact of the influences of environment and genetics on environmental illness, another research focus I have is animal health and human nutrition and how different aspects of both can be effect environmental illness. Domesticated pets suffer from many of the same diseases people do and many experts believe these disease may be attributed to imbalances from eating extruded kibble. Poor diet adaptation is common in both animals and humans. Numerous studies have shown that as humans culturally adapt to a more modern diet the prevalence of several diseases increases. As we have demonstrated a number of dietary factors influence environmental illnesses such as autism, CFS and MCS and the modern diet may not only be lacking in B12, vitamin D and fatty acids (ie omega 3) but may lack other macro and micronutrients. Specifically for the diseases I mention here, including autism and chemical sensitivity one must consider methionine (too much or too little) and the pathway that regulates it as a contributing factor.
New studies suggest that dietary restriction and subsequent restrictions of methionine reduces the amount of oxidative stress on mitochondrial DNA and there are studies have shown that patients with environmental illness have higher levels of oxidative stress. (Caro) From these results, the subject of limiting dietary sources of methionine and supplementation of methionine could be an important conversation to have with a physician. Anthropolically, it is true different people can tolerate different foods and the nutritional resources they provide better than others and this is all due to genetics. It becomes a problem when an individual's genetics do not "mesh" well - so to speak or as I have often said "do not get along" or specific influences (like a lack of biological resources, ie. B12) are altering genetic expression at "that point in time". This, unfortunately, adds to the complexity for diagnosis and treatment of environmental diseases and may contribute to the "fluctuating presentation" of these conditions. Interestingly, elk and fish contain higher levels of methionine and are eaten more by indigenous people. Compare that to a higher consumption of beef (also high in fat) which is part of a more "Western and Modern Diet" and contains less methionine. (eHow) Unfortunately, the prevalence of environmental diseases like cardiovascular disease and diabetes in indigenous people is increasing at an astounding rate and experts believe that eating more foods from "modern" diets in contrast to foods from a traditional diet may be partly to blame. Ethnically-derived genetic mutations in Nrf2 may increase liver injury (and increase environmental disease) exaggerating the effects of inhibiting factors on the methionine synthase pathway. Conditions like these may increase the prevalence of autoimmune and inflammatory disease in some more than others (like indigenous people and their descendants).
In other blogs we discuss how other dietary factors influence environmental illness. Several studies show polyphenols can effect methylation. As we noted above, DNA methylation has been associated with the silencing of genes and the most current research shows there is a relationship of methylation to different kinds of cancer such as bladder and prostate cancer. Fang points out both hypermethylation and hypomethylation are associated with carcinogenesis. Currently, prostate cancer is the second leading cause of cancer in men and a common cause is the silencing of GSTP1. This is a process that occurs through the methylation of "CG islands" by DNA methyltransferase (DMNT) early on in the cancer process. Polyphenols inhibit DMNT and in theory, can reverse hypermethylation of suppressed genes. (Fang) Other studies show abherrant methylation and suppression of Nrf2 expression in prostate tumorigenesis and as Arisawa demonstrates the polymorphisms in Nrf2 greatly effect abherrant methylation and for cancer, Nrf2 becomes a "very" significant factor. Over the years, studies with sulphoraphane (a chemical in broccoli) have shown health benefits at slowing prostate cancer growth and inhibiting colon cancer. Another study demonstrates isothiocyanate prevents glutathione depletion in Parkinson's disease. Also, EGCG, a compound in green tea, has demonstrated promising therapeutic benefits for prostate, breast, pancreatic cancer and most recently, lung cancer. Both sulphoraphane and EGCG activate the Nrf2 antioxidant system, in addition to other mode of therapeutic modes of action.
It has been reported that autism now effects 1 out of 150 children. Although some believe this figure is closer to 1 in 100. Yet there are no "specifics" on the major cause of the spectrum of these disorders. In 2006, over 11 million cases of cancer were reported and the combined cases of prostate, skin, breast and colon cancer cases made up almost 50% of them. While the study of epigenetics is in its infancy, there is substantial support, as we have discussed here, that methylation influences can and do lead to the development of environmental illness. In addition, new research seems to support that all of these conditions are very similar to one another but present with different "genetic footprints" and Nrf2 expression only adds to their complexity. Because of the complexity of environmental illnesses, the severity of their consequences including high morbidity and mortality and the tremendous toll they take on public health resources, there is a critical need for an increase in credible and verifiable environmental illness research which will undoubtedly reveal more about how to diagnose, treat and cure them. In addition, it is important for medical practioners to be trained in both allopathic and complementary and holistic care that emphasizes understanding the genetic, cultural and environmental influences that impact wellness and disease. Lastly, more informed communications should be disseminated to the media and the public at large about new insights and discoveries in environmental medicine and new, innovative and alternative therapies used to treat these diseases that work and to objectively clarify why there are some therapies out there that do not work.
Original document and citations
Saturday, January 9, 2010
Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.
Summary: We have noted that MsrA can be regulated by perioredoxin through Nrf2. "It is suggested that caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse."
CiteULike: Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.: "Oien, D. B., Osterhaus, G. L., Lundquist, B. L., Fowler, S. C., and Moskovitz, J. (2010). Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase a knockout mouse. Neuroscience letters, 468(1):38-41."
CiteULike: Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.: "Oien, D. B., Osterhaus, G. L., Lundquist, B. L., Fowler, S. C., and Moskovitz, J. (2010). Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase a knockout mouse. Neuroscience letters, 468(1):38-41."
Friday, January 1, 2010
Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of Oxidative Stress.
Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of Oxidative Stress.: "URL: Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of Oxidative Stress.
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How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.
Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.
We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.
Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)
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We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.
Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)
Click to view original document and citations.
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Tuesday, December 29, 2009
GSK-3b is required for hyperdopamine and d2 receptor-mediated inhibition of synaptic nmda receptor function in the rat prefrontal cortex.
Summary: This study suggests that GSK-3beta is required for the hyperdopamine/D(2) receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D(2) receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.Li, Y.-C. C., Xi, D., Roman, J., Huang, Y.-Q. Q., and Gao, W.-J. J. (2009). Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and d2 receptor-mediated inhibition of synaptic nmda receptor function in the rat prefrontal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(49):15551-15563. http://www.citeulike.org/user/HEIRS/article/6347607#
Saturday, December 26, 2009
Ghrelin: A Stomach Hormone Impacts Mood, Behavior, Sickness and Parkinson's Disease.
Background: In our last blog, we discussed the relationship of environmental toxicants on TLR receptor activation and reviewed how LPS endotoxin is a ligand for the TLR4 receptor. In addition, we mentioned how endotoxin and TLR plays a role in immune related disorders including RA and neurodegenerative disease and that it is also implicated as a causal factor in a number of environmental diseases including chronic fatigue syndrome. Generally, TLR signaling may contribute to a number of conditions considered environmental diseases through the interaction and modulation of inflammatory cytokines. Lastly, in the past we noted that oxidation of phospholipids occurs at the site of inflammation and provides a small level of protection against TLR signaling but not against against Il-1 and Tnf-a. The level of TLR protection is dependant on the balance between the types of involved phospholipids. Smoking and ozone increase one type, PGCP that prevents the protection by Nrf2 against this type of stress.
A recent study has provided evidence that a stomach hormone called ghrelin may prevent or slow the onset of Parkinson's disease. As we noted above, TLR signaling has been implicated in the development of the condition and this study helps to provide insight in to a possible as to why. As Wipedia explains, ghrelin is a hormone that is produced in the stomach and the pancreas to produce the feeling of hunger. It also is produced in the part of the brain called the hypothalamus and stimulates secretion of growth hormone in the pituitary gland. Importantly, it is a hormone needed for learning and cognitive functioning necessary for adaptive behaviors and stimulates the endothelial form of nitric oxide. Ghrelin levels fluctuate during a 24-hour period and consequently this hormone has important implications in alterations of sleep duration, stress-induced depression, obesity and anorexia nervosa. Researchers are also focusing their attention on how alterations of ghrelin production may influence the development of addictive behaviors.
In 2006, Wang demonstrated that LPS endotoxin can inhibit the production of ghrelin and that exogenous application of ghrelin may normalize endotoxic-induced digestive dysfunction. There are findings of different studies that show that LPS endotoxin can raise or lower this hormones secretion and it is highly likely, other immune interactions, individual circumstances and genetics may impact this. In any event, the increase or decrease of ghrelin levels has important health consequences. Wang's findings have important applications for environmental illness practioners considering that intestinal disease are often co-morbid with environmentally-induced conditions. Parkinson's disease is considered an environmental illness because it is exacerbated or believe to be caused by environmental factors. No doubt genetic factors play a part but there is mounting evidence that environmental toxicants may influence genetic disposition for the development of the disease. Understanding the relationship of ghrelin to Parkinson's disease (PD) is dependant on understanding that lower actions of ghrelin in the brain are associated with an increase in the loss of dopamine and lower dopamine levels in the brain are consistent with the etiology of PD. The author of this recent study remarks that further study will be needed to determine whether ghrelin can be used as a biomarker for PD or at least help to identify an increase in vulnerability. In any case, considering that LPS endotoxin may inhibit the production of ghrelin, normalizing ghrelin levels systemically may have the potential to have a positive impact on diseases where low/altered dopamine levels play a role such as PD and ADHD.
Dr. Lutter of UT Southwestern points out that "regulated" control of the production of this hormone is important for regulating behavior and mood and therefore, alterations in ghrelin may influence that condition of sickness syndrome. Lutter's findings show that ghrelin regulates mood, stress and energy levels and while blocking ghrelin production may provide a mechanism for weight control it can also increase feelings of depression and anxiety. In his experiments he found that ghrelin increases during stress and elevations can last for weeks after the stress event ends and animals which did not respond normally to ghrelin exhibited more depressive or anxious behaviors. The above findings may help to identify at least some of the causes of behavioral changes in this PD and other environmentally-induced illnesses. Another experiment demonstrated that endotoxemia in dogs resulted in an increase in leptin and ghrelin which correlated to an increase in NO, inflammatory mediators, cortisol and injury markers. Interestingly, ghrelin increases occurred in cachetic mice with cancer with symptoms of changes of metabolism so the increase or decrease in ghrelin production may be dependant on production of cytokines such as TNF-a. Other studies show it attenuates other cytokine-induced anorexia and therefore, chnages in ghrelin production/secretion should be considered a factor in behavioral appetite changes associated with sickness and wasting syndrome (Hataya). Evidence shows that exogenous ghrelin inhibits Il-1 and TNF-a while augmenting the synthesis of Il-10 in endotoxin-stimulated immune cells. Waseem explains this modulatory action of ghrelin warrants further investigation. As we have explained in other blogs, Il-10 modulates sickness syndrome through HO-1 and therefore ghrelin has potential to indirectly modulate antioxidant mechanisms.
Because ghrelin has important roles in a number of animal behaviors, future research findings may provide important insight and provide natural and pharmacological treatments for a number of diseases where ghrelin production is a factor.
The Balance Within: The Science Connecting Health and Emotions
The Psychoneuroimmunology of Chronic Disease: Exploring the Links Between Inflammation, Stress, and Illness
View original document and citations.
A recent study has provided evidence that a stomach hormone called ghrelin may prevent or slow the onset of Parkinson's disease. As we noted above, TLR signaling has been implicated in the development of the condition and this study helps to provide insight in to a possible as to why. As Wipedia explains, ghrelin is a hormone that is produced in the stomach and the pancreas to produce the feeling of hunger. It also is produced in the part of the brain called the hypothalamus and stimulates secretion of growth hormone in the pituitary gland. Importantly, it is a hormone needed for learning and cognitive functioning necessary for adaptive behaviors and stimulates the endothelial form of nitric oxide. Ghrelin levels fluctuate during a 24-hour period and consequently this hormone has important implications in alterations of sleep duration, stress-induced depression, obesity and anorexia nervosa. Researchers are also focusing their attention on how alterations of ghrelin production may influence the development of addictive behaviors.
In 2006, Wang demonstrated that LPS endotoxin can inhibit the production of ghrelin and that exogenous application of ghrelin may normalize endotoxic-induced digestive dysfunction. There are findings of different studies that show that LPS endotoxin can raise or lower this hormones secretion and it is highly likely, other immune interactions, individual circumstances and genetics may impact this. In any event, the increase or decrease of ghrelin levels has important health consequences. Wang's findings have important applications for environmental illness practioners considering that intestinal disease are often co-morbid with environmentally-induced conditions. Parkinson's disease is considered an environmental illness because it is exacerbated or believe to be caused by environmental factors. No doubt genetic factors play a part but there is mounting evidence that environmental toxicants may influence genetic disposition for the development of the disease. Understanding the relationship of ghrelin to Parkinson's disease (PD) is dependant on understanding that lower actions of ghrelin in the brain are associated with an increase in the loss of dopamine and lower dopamine levels in the brain are consistent with the etiology of PD. The author of this recent study remarks that further study will be needed to determine whether ghrelin can be used as a biomarker for PD or at least help to identify an increase in vulnerability. In any case, considering that LPS endotoxin may inhibit the production of ghrelin, normalizing ghrelin levels systemically may have the potential to have a positive impact on diseases where low/altered dopamine levels play a role such as PD and ADHD.
Dr. Lutter of UT Southwestern points out that "regulated" control of the production of this hormone is important for regulating behavior and mood and therefore, alterations in ghrelin may influence that condition of sickness syndrome. Lutter's findings show that ghrelin regulates mood, stress and energy levels and while blocking ghrelin production may provide a mechanism for weight control it can also increase feelings of depression and anxiety. In his experiments he found that ghrelin increases during stress and elevations can last for weeks after the stress event ends and animals which did not respond normally to ghrelin exhibited more depressive or anxious behaviors. The above findings may help to identify at least some of the causes of behavioral changes in this PD and other environmentally-induced illnesses. Another experiment demonstrated that endotoxemia in dogs resulted in an increase in leptin and ghrelin which correlated to an increase in NO, inflammatory mediators, cortisol and injury markers. Interestingly, ghrelin increases occurred in cachetic mice with cancer with symptoms of changes of metabolism so the increase or decrease in ghrelin production may be dependant on production of cytokines such as TNF-a. Other studies show it attenuates other cytokine-induced anorexia and therefore, chnages in ghrelin production/secretion should be considered a factor in behavioral appetite changes associated with sickness and wasting syndrome (Hataya). Evidence shows that exogenous ghrelin inhibits Il-1 and TNF-a while augmenting the synthesis of Il-10 in endotoxin-stimulated immune cells. Waseem explains this modulatory action of ghrelin warrants further investigation. As we have explained in other blogs, Il-10 modulates sickness syndrome through HO-1 and therefore ghrelin has potential to indirectly modulate antioxidant mechanisms.
Because ghrelin has important roles in a number of animal behaviors, future research findings may provide important insight and provide natural and pharmacological treatments for a number of diseases where ghrelin production is a factor.
The Balance Within: The Science Connecting Health and Emotions
The Psychoneuroimmunology of Chronic Disease: Exploring the Links Between Inflammation, Stress, and Illness
View original document and citations.
Wednesday, December 23, 2009
Recent Links Added to the HEIRS Library!
1. The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1. http://www.citeulike.org/user/HEIRS/article/6430465#
2.Weight loss, body fat mass, and leptin in Parkinson's disease. http://www.citeulike.org/user/HEIRS/article/6429319
3. High-fat diet induces apoptosis of hypothalamic neurons. http://www.citeulike.org/user/HEIRS/article/4292700
4. Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. http://www.citeulike.org/user/HEIRS/article/6429237
5. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). http://www.citeulike.org/user/HEIRS/article/2997140
6. Sympathetic premotor neurons mediating thermoregulatory functions http://www.citeulike.org/user/HEIRS/article/6429118
7. Up-regulation in expression of vesicular glutamate transporter 3 in substantia nigra but not in striatum of 6-hydroxydopamine-lesioned rats http://www.citeulike.org/user/HEIRS/article/6428977
8. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors http://www.citeulike.org/user/HEIRS/article/6428976
9. Acute and subacute chemical pneumonitis http://www.citeulike.org/user/HEIRS/article/6428868
10. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner http://www.citeulike.org/user/HEIRS/article/6428693
11. Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson's disease http://www.citeulike.org/user/HEIRS/article/6426071
12. Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo http://www.citeulike.org/user/HEIRS/article/6425259
13. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells http://www.citeulike.org/user/HEIRS/article/1496816
14. Cigarette Smoking Blocks the Protective Expression of Nrf2/ARE Pathway in Peripheral Mononuclear Cells of Young Heavy Smokers Favouring Inflammation http://www.citeulike.org/user/HEIRS/article/6425199
15. Coenzyme Q10 deficiency in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardi. http://www.citeulike.org/user/HEIRS/article/6414392
16. TLR4 is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness After Ozone Inhalation http://www.citeulike.org/user/HEIRS/article/6424875
Nrf2 as a Therapeutic Target for Stroke and Neurodegeneration
2.Weight loss, body fat mass, and leptin in Parkinson's disease. http://www.citeulike.org/user/HEIRS/article/6429319
3. High-fat diet induces apoptosis of hypothalamic neurons. http://www.citeulike.org/user/HEIRS/article/4292700
4. Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. http://www.citeulike.org/user/HEIRS/article/6429237
5. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). http://www.citeulike.org/user/HEIRS/article/2997140
6. Sympathetic premotor neurons mediating thermoregulatory functions http://www.citeulike.org/user/HEIRS/article/6429118
7. Up-regulation in expression of vesicular glutamate transporter 3 in substantia nigra but not in striatum of 6-hydroxydopamine-lesioned rats http://www.citeulike.org/user/HEIRS/article/6428977
8. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors http://www.citeulike.org/user/HEIRS/article/6428976
9. Acute and subacute chemical pneumonitis http://www.citeulike.org/user/HEIRS/article/6428868
10. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner http://www.citeulike.org/user/HEIRS/article/6428693
11. Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson's disease http://www.citeulike.org/user/HEIRS/article/6426071
12. Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo http://www.citeulike.org/user/HEIRS/article/6425259
13. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells http://www.citeulike.org/user/HEIRS/article/1496816
14. Cigarette Smoking Blocks the Protective Expression of Nrf2/ARE Pathway in Peripheral Mononuclear Cells of Young Heavy Smokers Favouring Inflammation http://www.citeulike.org/user/HEIRS/article/6425199
15. Coenzyme Q10 deficiency in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardi. http://www.citeulike.org/user/HEIRS/article/6414392
16. TLR4 is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness After Ozone Inhalation http://www.citeulike.org/user/HEIRS/article/6424875
Nrf2 as a Therapeutic Target for Stroke and Neurodegeneration
Thursday, December 17, 2009
MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.
MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.: "URL: MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.
"
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Read and find out more...
HEIRS Health & Home
http://www.heirs-online.com/
heirshealth@gmail.com
Check out some of our cool, more eco-friendly, non-toxic or got-to-have items in the HEIRS Web Store at Amazon or specialty items on our store portal.
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