MIcrobiota Health Regulates Il-10 and Resistance to LPS in the Gut~!

Comment: This supports the idea it is probably not a good thing to mess up the gut in wildlife in addition to people!

"these results demonstrate that the activity of LM to produce pro-inflammatory cytokines is negatively regulated through commensal microbiota-dependent IL-10 production in the large intestine."

CiteULike: Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10.:

I NEED This: UV LIght Improve Vacuum Effectiveness~!

"New research suggests that the addition of ultraviolet light to the brushing and suction of a vacuum cleaner can almost double the removal of potentially infectious microorganisms from a carpet's surface when compared to vacuuming alone."

UV Light Nearly Doubles Vacuum's Effectiveness In Reducing Carpet Microbes:

Making A Case for Tregs and LPS in Multiple Chemical Sensitivity~!

If there is injury and disruption of activities of olfactory neurons that has a connection to memory- can alteration of these proteins be a factor in MCS because of alteration of signals that exist between them?

Different studies have shown some interesting things about the sense of olfaction. It would be interesting to understand better how long-term toxic exposures alter the general patterns of operation of receptors in neurons and what circumstances make one more vulnerable. Zhang expressed that gap junctons modulate activity and sensitivity of olfactory neurons that have been shown to have receptors for one odorant whereas, cortical neurons get imputs from a number of different ones. (Buck) Kay writes that when the nose is first exposed to odor the molecules are absorbed into the olfactory receptor cells that line the mucous membranes at the back of the nostrils.  There are some 350 varieties of these receptor cells, each specialized to detect certain odor molecules which convert this information into nerve impulses and then transmit them to the brain’s two olfactory bulbs (one for each nostril), which sit just behind the nose. The olfactory bulbs then translates the impulses into information the brain can understand and are sent on to the olfactory cortex where the "odor information" is processed.

Several recent studies show disruptions in the sense of smell are indicative of the early signs of diseases including Alzheimer's disease, autism, Parkinson's disease and schizophrenia. Dr. Wilson, an expert in the neurobiology of olfaction explains that olfaction is a unique "sense" because it has direct links to the amygdala that is important for regulating emotion and physiology and to the prefrontal cortex that is involved with cognition and planning.  He also points out that this connection is also the short path that links olfaction with memory. (Kay) As noted, olfactory disfunction is a "early-warning" sign of schizophrenia and Turetsky's data indicates structural and functional abnormalities run from the cortex to the olfactory system. "These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression." This is also in line with some of the most current hypotheses of neuroinflammation and epigenetic influences in autism.

  "gap junctional communication in the olfactory epithelium modulates olfactory activity at the peripheral level and alters glomerular activation patterns (odor maps) in the olfactory bulb. Topological changes in odor maps due to gap junctional modulation could affect perception of odor quality or quantity." (Zhang)

To what extent do disruptions of Tregs contribute to disease development?

Many patients that have chemical sensitivity describe that the worst of the symptoms began occurring after a bout of infection. Multiple chemical sensitivity is a condition where symptoms such as nausea, respiratory problems, mood changes, cognitive problems and numerous other repored symptoms occur at a very low exposure of an "odor" stimulus. In the past, we have suggestedTreg impairment may be important for the development of many responses in MCS which may be long lasting or transient depending on factors including other secondary exposures that influence or prevent their activity. In addition, Treg disfunction has been implicated in a number of co-morbid health conditions such as inflammatory bowel disease and the sensitivities in autism. Interestingly, many common current treatments for MCS were used for treatments for autism before they were used for MCS.  Recent reports have also suggested that suppression of regulatory T cells from air pollution may be an important factor in the development and augmentation of respiratory disease like asthma. (Berkley) Air pollutants and particulate matter contain a variety of contaminants including LPS endotoxin from bacteria, hydrocarbons and metals. A recent study demonstrates that LPS a common contaminant of most environments can alter the expression of Cx43 and caveolin-3. The former Cx43 is a connexin protein that has been found to be important for the integrity of gap junctions shown to dictate olfactory sensitivity. Interestingly, regulatory T cells also play a role in the communication activities of gap junctions. Taking these recent studies into consideration the newest research on regulatory T cells in promotion of the adaptive response and maintaining tolerance support, one could propose that altered communication may play a role in chemical sensitivity and odor and olfactory function and prvode parallel support to the recent research of how Tregs disfunction may influence respiratory problems from air pollution. In addition, because their is a relationship gap functions to activity of NO/cGMP and its downstream targets and related biological roles in relation to memory -- this could explain some of the cognitive problems associated with MCS. Generally, suppression of Tregs and their role in gap function has implications for both animals and humans. In animals impairment of the olfactory system may negatively influence instinctual patterns of navigation and other behaviors.



Related: Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

****Read more research blogs: Kimberly Kramer
















Kay, Sharon. Memory and the Senses. New York University Physician. Spring 2010. Retrieved on October 1, 2010. webdoc.nyumc.org/nyumc/files/.../u3/NYUPhysSpring2010.pdf
The Logic of Smell. MedGadget, Internet Journal of Emerging Medical Technologies. Retrieved on October 14, 2010. http://medgadget.com/archives/2005/05/
BMC Neuroscience, Vol. 11, No. 1. (2010), 108. http://www.citeulike.org/user/HEIRS/article/7724812?show_msg=already_posted
Yang, Sarah. Air pollution alters immune function, worsens asthma symptoms. UCBerkelyNews.com. Retrieved on 10/13/2010.  http://www.berkeley.edu/news/media/releases/2010/10/05_asthma.shtml
Ring, S., Karakhanova, S., Johnson, T., Enk, A. H., and Mahnke, K. (2010). Gap junctions between regulatory t cells and dendritic cells prevent sensitization of cd8(+) t cells. The Journal of allergy and clinical immunology, 125(1). http://www.citeulike.org/user/HEIRS/article/8006437
Bopp, T., Radsak, M., Schmitt, E., and Schild, H. (2010). New strategies for the manipulation of adaptive immune responses. Cancer Immunology, Immunotherapy, 59(9):1443-1448. http://www.citeulike.org/user/HEIRS/article/6973883
Yao, J., Hiramatsu, N., Zhu, Y., Morioka, T., Takeda, M., Oite, T., and Kitamura, M. (2005). Nitric oxide-mediated regulation of connexin43 expression and gap junctional intercellular communication in mesangial cells. Journal of the American Society of Nephrology : JASN, 16(1):58-67. http://www.citeulike.org/user/HEIRS/article/8006401
González-Flores, O., Beyer, C., Lima-Hernández, F. J. J., Gómora-Arrati, P., Gómez-Camarillo, M. A., Hoffman, K., and Etgen, A. M. (2007). Facilitation of estrous behavior by vaginal cervical stimulation in female rats involves alpha1-adrenergic receptor activation of the nitric oxide pathway. Behavioural brain research, 176(2):237-243. http://www.citeulike.org/user/HEIRS/article/8006383
Lowe, G., Buerk, D. G., Ma, J., and Gelperin, A. (2008). Tonic and stimulus-evoked nitric oxide production in the mouse olfactory bulb. Neuroscience, 153(3):842-850. http://www.citeulike.org/user/HEIRS/article/8006357
Liao, C.-K. K., Wang, S.-M. M., Chen, Y.-L. L., Wang, H.-S. S., and Wu, J.-C. C. (2010). Lipopolysaccharide-induced inhibition of connexin43 gap junction communication in astrocytes is mediated by downregulation of caveolin-3. The international journal of biochemistry & cell biology, 42(5):762-770. http://www.citeulike.org/user/HEIRS/article/6580463
Kawasaki, A., Hayashi, T., Nakachi, K., Trosko, J. E., Sugihara, K., Kotake, Y., and Ohta, S. (2009). Modulation of connexin 43 in rotenone-induced model of parkinson's disease. Neuroscience, 160(1):61-68. http://www.citeulike.org/user/HEIRS/article/7971659
Zhang, C. (2010). Gap junctions in olfactory neurons modulate olfactory sensitivity. BMC neuroscience, 11(1):108+. http://www.citeulike.org/user/HEIRS/article/7724812

Li, D.-q., Li, X.-j., Duan, J.-f., and Cai, W. (2010). Wuling capsule promotes hippocampal neurogenesis by improving expression of connexin 43 in rats exposed to chronic unpredictable mild stress. Journal of Chinese Integrative Medicine, 8(7). http://www.citeulike.org/user/HEIRS/article/7971605

LPS stimulates nitric oxide synthase-2 expression in murine skeletal muscle and C(2)C(12) myoblasts via Toll-like receptor-4 and c-Jun NH(2)-terminal kinase pathways.

"Frost, R. A., Nystrom, G. J., and Lang, C. H. (2004). Lipopolysaccharide stimulates nitric oxide synthase-2 expression in murine skeletal muscle and c(2)c(12) myoblasts via toll-like receptor-4 and c-jun nh(2)-terminal kinase pathways. American journal of physiology. Cell physiology, 287(6)."

CiteULike: Lipopolysaccharide stimulates nitric oxide synthase-2 expression in murine skeletal muscle and C(2)C(12) myoblasts via Toll-like receptor-4 and c-Jun NH(2)-terminal kinase pathways.:

Nrf2 Involved in Fatty Acid Suppression of LPS Inflammation

"our study clearly shows for the first time that, DHA/EPA would induce Nrf2 signaling pathway and that Nrf2 plays a role in DHA/EPA suppression of LPS-induced inflammation."

Read asrac: CiteULike: Role of Nrf2 in Suppressing LPS-induced Inflammation in Mouse Peritoneal Macrophages by Polyunsaturated Fatty Acids Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA).:

Inhibition of ornithine decarboxylase potentiates nitric oxide production in LPS-activated J774 cells.

These results show that DFMO potentiates LPS-induced nitrite production in the murine macrophage cell line J774. Since the only known mechanism of action of DFMO is inhibition of ODC, and thus polyamine biosynthesis, we conclude that expression of iNOS can be critically regulated by endogenous polyamines.

CiteULike: Inhibition of ornithine decarboxylase potentiates nitric oxide production in LPS-activated J774 cells.: "Baydoun, A. R. and Morgan, D. M. (1998). Inhibition of ornithine decarboxylase potentiates nitric oxide production in lps-activated j774 cells. British journal of pharmacology, 125(7):1511-1516."

Contaminants in Air Pollution Including Endotoxin and Dioxin May Increase Insulin Resistance~!

Complications associated with insulin resistance may play a significant role in environmental diseases including obesity, sleep apneas and potentially Gulf War Syndrome and chemical sensitivity just for examples. Other studies show that sustained endotoxin, a potential consideration in CFS and other environmental illnesses, is a common component of particulate matter and environmental pollutants may alter insuling signalling in muscle especially under sustained stress such as malnutrition. These conditions may potentiate one another if they occur at the same time.....


"TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance."

Read more: CiteULike: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.:


For further understanding: IRS-1

McCowen, K. C., Ling, P. R., Ciccarone, A., Mao, Y., Chow, J. C., Bistrian, B. R., and Smith, R. J. (2001). Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade. Critical care medicine, 29(4):839-846. http://www.citeulike.org/user/HEIRS/article/7782376

PFOS Significantly Elevates Inflammatory Cytokines From LPS Stimulation.

CiteULike: Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male C57BL/6 mice.: "Dong, G.-H. H., Zhang, Y.-H. H., Zheng, L., Liang, Z.-F. F., Jin, Y.-H. H., and He, Q.-C. C. (2010). Subchronic effects of perfluorooctanesulfonate exposure on inflammation in adult male c57bl/6 mice. Environmental toxicology."

PPAR-gamma Protects Against Pathogenic Strains of Influenza~!

Considering the evidence from this study and others, chemical pollutants, drugs and environmental conditions that positively or negative regulate PPAR-gamma should be an important consideration when evaluating an individual for different environmental illnesses and alterations in cellular homeostasis. In addition, the recent studies that PPAR-gamma is regulated by Nrf2 also puts more emphasis as an important target for environmentally-induced disease.

 

"preliminary evidence that two classes of drugs, peroxisome proliferator-activated receptor-gamma agonists and AMP-activated protein kinase agonists, provide protection in mice infected with highly pathogenic and pandemic strains of influenza virus."

Read more: CiteULike: Moseley, C. E., Webster, R. G., and Aldridge, J. R. (2010). Peroxisome proliferator-activated receptor and amp-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza and other respiratory viruses, 4(5):307-311. http://www.citeulike.org/user/HEIRS/article/7679239


For Further Reading: Nrf2, PPAR-gamma
 
 
 

Antioxidant System Deficiency Increases Allergic Immune Response~!

Background: Nrf2 expression can be influenced by a number of factors including diet and age and may influence or be influenced by the expression of other proteins.

Rangasamy demonstrates that immune reactions from ragweed are more severe in Nrf2-deficiency. The author's findings suggest that "defect in Nrf2 mediated signaling mechanisms alters the response of DC to a common environmental allergen, which may contribute to the susceptibility to allergic diseases." Importantly, one must also note that other studies have suggest endotoxin reduces the threshold for allergic reactions and EGCG, the compound found in green tea, has a suppressive influence on histamine producing cells. More and more studies are providing evidence that EGCG acts through the Nrf2 antioxidant system and therefore should warrant further study as therapeutic for allergic-type reactions.


Rangasamy, T., Williams, M. A., Bauer, S., Trush, M. A., Emo, J., Georas, S. N., and Biswal, S. (2009). Nrf2 inhibits the maturation of murine dendritic cells by ragweed extract. American Journal of Respiratory Cell and Molecular Biology.
http://www.citeulike.org/user/HEIRS/article/7652681
Melgarejo, E., Medina, M. A. A., Sánchez-Jiménez, F., and Urdiales, J. L. L. (2010). Targeting of histamine producing cells by egcg: a green dart against inflammation? Journal of physiology and biochemistry, 66(3):265-270.
http://www.citeulike.org/user/HEIRS/article/7652686

Endotoxin and Loss of Tolerance via Reduced HO-1: Potential Mechanism in CFS and MCS?

It has been suggested that chemical sensitivity and possibly other environmental illness conditions can be the result of a "loss of tolerance".  Notably, this "loss of tolerance" may be the result of altered signaling of the immune response and contrbuting factors may include the presence of endotoxin which can 1) activate inflammatory responses, 2) reduce the threshold of reactions to allergens and 3) alter gene expression from ROS and alterations in methylation. In addition, endotoxin through activtion of GSK3b provides a mechanism to "deactivate" the antioxidant system, Nrf2. High fat diets and hyperglycemia may also promote the translocation of bacteria in the respiratory and intestinal tract. This may further increase inflammation and promote neuroinflammation in the brain as a consequence of cytokine activity in the intestinal tract and liver. At some point, the break down of the blood brain barrier may increase the likelihood of brain inflammation and changes in behavior and neurotransmission.

A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification.  Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome.  There is debate on the benefits and potential harmful effects of  exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.


Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057.  http://www.citeulike.org/user/HEIRS/article/7586285

Estrogen's Influence on Neuroinflammation May Explain Sex Differences in Environmental Illness.

Previously we noted that the estrogen signalling may influence expression of Nrf2 enzymes. A new study provides support that estrogen may provide some protection against LPS exposure effects. It has been noted by a number of researchers the sexual dimorphism that occurs with environmental conditions including CFS, FM and MCS and this relationship could provide a mechanism for the significantly higher prevalence of some EI conditions in women especially as they get older.

"these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ERalpha- and ERbeta-mediated ligand-dependent and ligand-independent mechanisms"

Read more: CiteULike: Production of Proinflammatory Cytokines and Chemokines During Neuroinflammation: Novel Roles for Estrogen Receptors alpha and beta:

Supplemental Resource: Yao, Y., Brodie, A. M., Davidson, N. E., Kensler, T. W., and Zhou, Q. (2010). Inhibition of estrogen signaling activates the nrf2 pathway in breast cancer. Breast cancer research and treatment. http://www.citeulike.org/user/HEIRS/article/7493023?show_msg=already_posted

Endotoxin-induced Enzyme Causes Depressive Symtoms Before Cytokine/NO Production~!

"IDO by direct application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 protein and activation of iNOS while IFNgamma expression was undetectable."

CiteULike: Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

TLRs Regulates Reactions to Particulate Matter and Other Contaminant Considerations~!

In this article, the author explains "it is plausible that PM2.5 contains bacterial or mycoplasma lipoproteins, which are known activators of TLR2 . Because PM2.5 contain high concentrations of a large number of metals. One or more of these metals could be involved in increased TLR2- mediated cytokine production triggered by microbial lipoprotein constituents of the PM2.5. In this regard, it is interesting that TLR2 has been implicated in proinflammatory cytokine expression by airway epithelial cells stimulated with air PM containing high amounts of metals. Another possibility is that PM2.5 cytokine-inducing effects are mediated by an indirect mechanism, via the generation of endogenous “danger” host molecules activating macrophages via TLR2."

Note: Recent findings by Notch show a potentiation effect between cyanobacteria and heavy metals and thus support an important mechanism although the mechanism remains to be elicited. In addition, one must always consider alterations in methylation which can be caused by endotoxin and heavy metals. Walsh and Usman demonstrated that in autism there is alterations in the functioning of metallotheinin protein which modulates and detoxifies metals. (Treat Autism and AD/HD, Wright) In other blogs, we have explained that metallotheinin inhibits GSK-3b (Wang)which can turn off the Nrf2 antioxidant system. This could explain why there are reports that the antioxidant system is negatively effected by metals (and by endotoxin)and thus, one must also consider that in mixed environmental pollutants, there is a reduction of function of this system. In addition, there is also potential that the AhR and metals interact to influence antioxidant and detoxification. These interactions of metals and the AhR are currently being investigated through a number of projects. (Korashy) Further study may shed more light on the interactions of the Nrf2 and AhR gene batteries and how they are effected by metals from environmental exposures.

Shoenfelt, J., Mitkus, R. J., Zeisler, R., Spatz, R. O., Powell, J., Fenton, M. J., Squibb, K. A., and Medvedev, A. E. (2009). Involvement of tlr2 and tlr4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. Journal of Leukocyte Biology, 86. http://www.citeulike.org/user/HEIRS/article/7367529

Vita. Hesham Korashy, PhD. Retrieved on June 29, 2010.
http://faculty.ksu.edu.sa/hkorashy/Pages/index.aspx

Notch, E. G., Miniutti, D. M., Berry, J. P., and Mayer, G. D. (2010). Cyanobacterial lps potentiates cadmium toxicity in zebrafish (danio rerio) embryos. Environmental toxicology.
http://www.citeulike.org/user/HEIRS/article/7367622

Heavy Metals. Treat Autism and ADHD. Retrieved on June 30, 2010. http://www.treatautism.ca/?page_id=126

Wang et al. Inactivation of GSK-3 by Metallothionein PreventsDiabetes-Related Changes in Cardiac EnergyMetabolism, Inflammation, Nitrosative Damage, and Remodeling. Diabetes. June 2009. Pgs. 1391-1402.

Wright, R. O. and Baccarelli, A. (2007). Metals and neurotoxicology. The Journal of Nutrition.
http://www.citeulike.org/user/HEIRS/article/7367642

GSK-3 Knock-down Allows for Endotoxin Tolerance in Astrocytes~!

"GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance"

Link: CiteULike: Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes.:

SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.

"critical role for SphK1 in endotoxin signaling and sepsis-induced inflammatory responses and suggest that inhibition of SphK1 is a potential therapy for septic shock."

CiteULike: SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.:

Intestinal bacteria drive obesity and metabolic disease in immune-altered mice

"Mice lacking a gene called TLR5 have an altered ability to recognize and control bacteria in their intestines, leading them to develop obesity and insulin resistance, which is often referred to as "pre-diabetes." The bacteria appear to influence appetite and metabolism rather than how well calories are absorbed. Obesity and insulin resistance can be transferred from TLR5-deficient mice via intestinal bacteria."
Intestinal bacteria drive obesity and metabolic disease in immune-altered mice

Notes:

• GSK-3b regulates TLR production including TLR5. Studies have demonstrated that TLR signaling increases IL-10 which has an anti-inflammatory effect and inhibition of GSK-3b may be protective against endotoxic shock.
• Changes in inflammatory cytokines may influence TLR functioning in mesenchymal stromal cells.

Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/260512
Abreu, M. T. (2010). Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Reviews Immunology, 10(2):131-144. http://www.citeulike.org/user/HEIRS/article/6589668
Palmer, Eric. Innate immune defense against intestinal bacteria. Videocast. National Institutes of Health. Retrieved on Monday March 1, 2010. http://videocast.nih.gov/ram/iig102109.ram

Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats

"In conclusion, LPS impairs hepatic ammonia detoxification by both downregulation of GS and its inactivation because of tyrosine nitration. The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis."

Görg, B., Wettstein, M., Metzger, S., Schliess, F., and Häussinger, D. (2005). Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat. Hepatology (Baltimore, Md.), 41(5):1065-1073.

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:

• 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)

For Further Reading:

• 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

Original article and citations located here.

Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness

Background: I happened on an article this morning that no doubt has important health implications, at least for I and others with impairments of detoxification are concerned. I doubt it evoked much interest by the "Powers That Be" that study this stuff everyday but none-the-less, it seems important for me, not to dismiss it so readily. What I write here are my own thoughts and I by no means am or claim to be, an expert on autism and autistic behavior.

As you may recall, we recently discussed the similiarities of autism and other environmental illnesses including ADHD and multiple chemical sensitivity. Previous studies have shown that certain exposures may inhibit metabolic pathways such the one for production of methionine synthase important for DNA synthesis and repair and may increase concentrations of homocysteine, a potentially toxic byproduct of methionine metabolism. To demonstrate, the inhibition of this pathway by nitrous oxide causes lasting impairment in spatial working memory in aged rats via mitochondrial swelling and subsequent neuronal death.(Culley) In line with this thinking,severa; studies provide evidence that inhibiting or the presense of impairments in pathways such as the one for methionine synthase or others may contribute to a number of mental and physical health conditions including environmental illnesses such as mood disorders, Alzheimer's, autism and MCS.

In the past, I have noted several "remedies" including B12, Q10 and tetrahydrobiopterin recommended for chemical sensitivity which are also commonly used therapies for autism. Curiously, methylhydrofolate is a precursor of BH4 and often prescribed to reduce ammonia levels produced as a side-effect from different supplement treatments and also ammonia produced from gut-derived exogenous bacteria. In addition to hyperammonemia, excess ammonia may lead to elevations in production of nitric oxide synthase and enhanced nitric oxide, free radicals and oxidative stress.

Jalan and Bernuau propose that endotoxin may increase the severity of complications associated with hyperammonemia which of course may have important safety implications for a number of occupational and residential settings including farms and agricultural areas. In this article the authors explain, the "ammonia is detoxified by astrocyctes in the brain". Notably, the deficiency of protective pathways which protect astocytes such as Nrf2 should be an important concern. Jalan further explains that "during hyperammonemia, astrocytes swell from the effect of glutamine. In addition, recent studies show these cells are more swollen in animals exposed to endotoxin and interestingly, the swelling of the atrocytes occur in an environment of an intact blood brain barrier which indicates a functional abnormality. It is assumed that astrocytes are critical managers of blood flow and it may be that during hyperammonemia the astrocytes are sensitized to a "second hit" by LPS endotoxin. The author also proposes other mechanims may be involved in the astrocyte swelling in addition to the ammonia-glutamine hypothesis and one may suggest it includes the activation of P53 and its suppressive effects on Nrf2. (Panickar, Faraonion) The author also mentions pharmacological pre-treatment doses of amiloride, a diuretic used to treat congestive heart failure and hypertension, were required that were 200 fold higher in animals with hyperammonemia in association with exposure to endotoxin." This should demonstrate to anyone whether toxicologically inclined or not, that "something just ain't right",,,,!

He goes on to say, "several substances have been shown to cross the BBB under hepatoxic conditions such as acute liver failure. Incidently, he points out ammonia induces the expression of GLUT1, a transporter across the BBB and this report suggests a non-specific increase in permeability of the BBB and proposes hyperammonia could "unlock" the BBB." It has been shown that ammonia can "alter endothelial cell gene expression and transporter function." (Belanger Of course, this is an important issue to consider whenever a condition of hyperammonemiua occurs. It very well could contribute to the neuroinflammatory consequences in pathological conditions such as autism and conditions that where elevated homocysteine levels impair renal function and as this article suggests, exposures to endotoxin exacerbate related metabolic consequences.

Jalan, R. and Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2):168-171. http://www.citeulike.org/user/HEIRS/article/6556614
Essa, M. M. and Subramanian, P. (2006). Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. eCAM. http://www.citeulike.org/user/HEIRS/article/6556740
Panickar, K. S., Jayakumar, A. R., Rao, K. V. R., and Norenberg, M. D. (2009). Ammonia-induced activation of p53 in cultured astrocytes: Role in cell swelling and glutamate uptake. Neurochemistry International, 55(1-3):98-105. http://www.citeulike.org/user/HEIRS/article/4523207
Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G. G., Napolitano, M., Russo, T., and Cimino, F. (2006). p53 suppresses the nrf2-dependent transcription of antioxidant response genes. The Journal of biological chemistry, 281(52):39776-39784. http://www.citeulike.org/user/HEIRS/article/4364516?show_msg=already_posted
Culley, D. J., Raghavan, S. V., Waly, M., Baxter, M. G., Yukhananov, R., Deth, R. C., and Crosby, G. (2007). Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg, 105(1):83-88. http://www.citeulike.org/user/HEIRS/article/6557028
Bélanger, M., Asashima, T., Ohtsuki, S., Yamaguchi, H., Ito, S., and Terasaki, T. (2007). Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochemistry international, 50(1):95-101.
http://www.citeulike.org/group/7833/article/6557716