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.:

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

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

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

HO-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.

CiteULike: Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.: "cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response."

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.:

Glutamine Synthetase, PFOS and Neurotransmission

PFC are chemicals that are ubiquitous in the environmental and can or could be found in products including building materials, fabrics, packaging, clothing, protective gear etc. Recent studies show that these chemicals have the capacity to regulate or impair gene expression including those that regulate the excretion of toxic waste products that may result in alterations of neurotransmission and contribute to their toxicity. In addition, genetic problems may aggravate this inhibition and augment the physical consequences of exposure. Glutamine synthetase is one enzyme that is important for regulation of toxins such as ammonia in the brain as well as production of glutathione. In addition, certain conditions, such as in endotoxemia and implicated as a causal factor is CFS, the activity of this enzyme is further reduced. Nrf2 is protective against PFOS through the generation of HO-1 and reductions in its production may augment oxidative stress damage from PFOS.


Yang, X., Wang, L., Sun, W., and Xue, Z. (2009). [effects of perfluorooctane sulfonate on amino acid neurotransmitters and glutamine synthetase in rats]. Wei sheng yan jiu = Journal of hygiene research, 38(1):19-21. http://www.citeulike.org/user/HEIRS/article/6999108
Häussinger, D. and Schliess, F. (2007). Glutamine metabolism and signaling in the liver. Frontiers in Bioscience, 12:371-391.
http://www.citeulike.org/user/HEIRS/article/7208003
Shi, X. and Zhou, B. (2010). The role of nrf2 and mapk pathways in pfos-induced oxidative stress in zebrafish embryos. Toxicol. Sci., 115(2):391-400.
http://www.citeulike.org/user/HEIRS/article/6761678

Impaired Liver Glucose Production in a Murine Model of Steatosis and Endotoxemia: Protection by Inducible Nitric Oxide Synthase

Comparison between wild-type and iNOS-knockout mice under these conditions demonstrated a protective role of iNOS against fatal hypoglycemia. Nitric oxide (NO) signaling effects were confirmed by treatment of hepatocytes in culture with an NO donor, which resulted in increased expression of PGC-1α and gluconeogenic genes.

CiteULike: Impaired Liver Glucose Production in a Murine Model of Steatosis and Endotoxemia: Protection by Inducible Nitric Oxide Synthase: "Tirosh, O., Artan, A., Aharoni-Simon, M., Ramadori, G., and Madar, Z. (2010). Impaired liver glucose production in a murine model of steatosis and endotoxemia: Protection by inducible nitric oxide synthase. Antioxidants and Redox Signaling."

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

Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?

A number of researchers now believe endotoxin from bacterial contaminants may be a pathway that leads to the development of chronic fatigue syndrome. In addition it has been determined that high-fat diets exacerbate inflammatory conditions by altering the TLR signaling pathway which contributes to the loss of suppression of inflammatory responses by regulatory T cells (tregs) after endotoxin injury. Many experts believe this loss of tolerance may play an important role in MCS which is a condition that exhibits symptoms that often appear autoimmune in nature. In the lungs, TLR signaling and other proteins induced by endotoxin lead to the increased expression of inflammatory mediators including IL-6 which suppress Treg expression resulting in loss of tolerance in the airway and increase inflammation. Incidentally, a very small amount of endotoxin can lower the threshold of immune reactions in some people and since humans do not live in sterile environments, we are consistantly exposed to endogenous and exogenous bacteria (and endotoxin) in the air we breath, the food we eat, the things we touch, etc.

EGCG, the compound in green tea, has been shown to provide relief in animal models of chronic fatigue syndrome and several studies show it may have several modes of action. Currently Tufts University is performing an in-depth analysis of EGCG and the preliminary results show EGCG has the capacity to regulate different subsets of T cells including those responsible for playing a role in the development of autoimmune-type disease such as tregs. In support of these preliminary findings, a few years ago, Yoneyama demonstrated EGCG can regulate IL-10 and does have substantial immunosuppressive properties.

Over the past few months I have written how humans and animals demonstrate sickness behavior and the related behavioral changes are consistent with many of the symptoms in CFS and may include fatigue, malaise, mood changes, decreased appetite, etc. Also, the severity of sickness syndrome is dependant on the production or absence of Il-10 which is necessary for Treg production. One inflammatory cytokine produced by endotoxin is Il-6 which has the ability to suppress Treg expression and is most often responsible for sickness syndrome behavior and the polyphenols in green tea inhibit the expression of it. Considering all of this, it makes sense the loss of Treg through abherrant signaling is a causal factor in the loss of tolerance and MCS, sickness syndrome and chronic fatigue syndrome. Lastly, Nrf2 along may influence and regulate Treg expression through HO-1 and Il-10.

CiteULike: A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.: "Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529." http://www.citeulike.org/user/HEIRS/article/6496762
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. J Immunol, 181(12):8650-8659.
http://www.citeulike.org/user/HEIRS/article/3752381?show_msg=already_posted
Wu, D. Green tea egcg and t cell function in autoimmune inflammation.
http://www.citeulike.org/user/HEIRS/article/6496862
Yoneyama, S., Kawai, K., Tsuno, N., Okaji, Y., Asakage, M., Tsuchiya, T., Yamada, J., Sunami, E., Osada, T., and Kitayama, J. (2008). Epigallocatechin gallate affects human dendritic cell differentiation and maturation. Journal of Allergy and Clinical Immunology, 121(1):209-214. http://www.citeulike.org/user/HEIRS/article/6496680
Singal, A., Tirkey, N., Pilkhwal, S., and Chopra, K. (2006). Green tea (camellia sinensis) extract ameliorates endotoxin induced sickness behavior and liver damage in rats. Phytotherapy Research, 20(2):125-129.
http://www.citeulike.org/user/HEIRS/article/6496875

Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway.

Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway.: "URL: Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway.

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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)

Click to view original document and citations.

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Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

CiteULike: Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior.: "Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930."

Runaway vigilance hormone linked to panic attacks. National Institute of Mental Health. http://www.citeulike.org/user/HEIRS/article/6463151