Nrf2 activation and tetraflouroethylcysteine toxicity

Nrf2 activation involves an oxidative-stress indep... [Toxicol Sci. 2005] - PubMed result: "Nrf2 activation involves an oxidative-stress independent pathway in tetrafluoroethylcysteine-induced cytotoxi"

Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.

Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.

Scientists observe protein folding in living cells for the first time

Observations: Scientists observe protein folding in living cells for the first time: "Scientists observe protein folding in living cells for the first time"

SIRT1 Suppresses Activator Protein-1 Transcriptional Activity and Cyclooxygenase-2 Expression in Macrophages — JBC

SIRT1 Suppresses Activator Protein-1 Transcriptional Activity and Cyclooxygenase-2 Expression in Macrophages — JBC: "SIRT1 Suppresses Activator Protein-1 Transcriptional Activity and Cyclooxygenase-2 Expression in Macrophages"

Hydrogen Sulfide Attenuates Hyperhomocysteinemia-Induced Cardiomyocytic Endoplasmic Reticulum Stress in Rats

Hydrogen Sulfide Attenuates Hyperhomocysteinemia-Induced Cardiomyocytic Endoplasmic Reticulum Stress in Rats

Stress Raises The Risk Of Memory Loss And Cognitive Decline Among Older People With Diabetes, Research Suggests

Stress Raises The Risk Of Memory Loss And Cognitive Decline Among Older People With Diabetes, Research Suggests

p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting -- McClung et al. 298 (3): C542 -- AJP - Cell Physiology

p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting -- McClung et al. 298 (3): C542 -- AJP - Cell Physiology: "p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting"

Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure

Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure

Lindane Induces Toxic Reproductive Effects -Curcumin Helps Attenuate It!

CiteULike: Protective Role of Curcumin on Lindane Induced Reproductive Toxicity in Male Wistar Rats.: "Sharma, P. and Singh, R. (2010). Protective role of curcumin on lindane induced reproductive toxicity in male wistar rats. Bulletin of environmental contamination and toxicology."

Reduced Adult Neurogenesis and Altered Emotional Behaviors in Autoimmune-Prone B-Cell Activating Factor Transgenic Mice

Reduced Adult Neurogenesis and Altered Emotional Behaviors in Autoimmune-Prone B-Cell Activating Factor Transgenic Mice

Mary Ann Liebert, Inc. - Antioxidants & Redox Signaling - 0(0):

Mary Ann Liebert, Inc. - Antioxidants & Redox Signaling - 0(0):: "Cigarette Smoke–induced Oxidative/Nitrosative Stress Impairs VEGF- and Fluid Shear Stress–Mediated Signaling in Endothelial Cells"

A Calcium/Calmodulin-regulated Member of the Receptor-like Kinase Family Confers Cold Tolerance in Plants [Signal Transduction]

A Calcium/Calmodulin-regulated Member of the Receptor-like Kinase Family Confers Cold Tolerance in Plants [Signal Transduction]

Encephalomyeloradiculoneuropathy following exposur... [Clin Neurol Neurosurg. 1999] - PubMed result

Encephalomyeloradiculoneuropathy following exposur... [Clin Neurol Neurosurg. 1999] - PubMed result: "Encephalomyeloradiculoneuropathy following exposure to an industrial solve"

Catalytic combustion of methane over commercial ca... [Chemosphere. 2004] - PubMed result

Catalytic combustion of methane over commercial ca... [Chemosphere. 2004] - PubMed result: "Catalytic combustion of methane over commercial catalysts in presence of ammonia and hydrogen sulphide."

Depletion Of Oxidative And Endoplasmic Reticulum Stress Regulators In Pick's Disease.

Depletion Of Oxidative And Endoplasmic Reticulum Stress Regulators In Pick's Disease.

Biotin Deficiency and Restless Legs Syndrome in Dialysis

Biotin Deficiency and Restless Legs Syndrome in Dialysis

IFN-{gamma} is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes

IFN-{gamma} is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes

Proline reduces the binding of transcriptional reg... [Appl Microbiol Biotechnol. 2010] - PubMed result

Proline reduces the binding of transcriptional reg... [Appl Microbiol Biotechnol. 2010] - PubMed result: "Proline reduces the binding of transcriptional regulator ArgR to upstream of argB in Corynebacterium glutamicum."

Molecular modeling of Helicobacter pylori arginase... [J Mol Graph Model. 2010] - PubMed result

Molecular modeling of Helicobacter pylori arginase... [J Mol Graph Model. 2010] - PubMed result: "Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions."

Lower B12 Transport Mechanim from Infection Identified-- Does it Parallel MCS?

Background: Inflammatory activities in the gut may influence neuroinflammatory cytokines in the brain to influence behaviors. In the brain and other organ systems including the intestines, efflux pumps help to minimize the damage done to tissue from xenobiotics and other molecules by transporting across biological barriers to reduce the "waiting" time for cytochrome enzymes to break them down to make them more excretable . ABC transporters are an example of these pumps and their presence or absence can alter the excretion rate of harmful drugs and other toxins as well as, potentially determine the level of tissue damage from environmental toxins.

A new study provides evidence that the MRP1/ABCC1 transporters are important for proper metabolic balance of B12 in addition to other conjugates including sulfates and glutathione. We have previously noted how certain metabolic pathways are dependant on the availability of B12 and in B12-deficiency, impairments in the renal excretion of ammonia and elevations in homocysteine may occur to cause tissue damage. In general, the availability of B12 is invaluable because low levels may cause health effects in the blood and neurological problems. Studies on MRP1 knock-out mice, "confirm the ability of MRP1 to mediate ATP-dependent Cbl transport and the physiologic role of MRP1 in mammalian Cbl homeostasis is indicated with disruption of MRP1. These animals have a reduced concentration of Cbl in plasma and in the storage organs liver and kidney." On the other hand, the class of efflux transporters are important for proper detoxification of 50% or more of the prescription drugs on the market. Certain bacterial infections can upregulate the expression of these transporters and therefore they may play a role in functional diseases of the intestines, unexpected results of medical therapies and contribute to drug interactions and potentiate effects of shutting off the antioxidant system from altered GSK-3b signals.  MRP transporters are critical components in olfaction and their disfunction may lead to tissue damage and aberrant neural signaling of the olfactory secondary pathway may alter neurotransmission, therefore, it is not beyond the bounds of reason to assume MRP signaling may influence MCS through regulation of evolutionary olfactory pathways of IGF-1, BDNF, etc.


Berggren, S., Gall, C., Wollnitz, N., Ekelund, M., Karlbom, U., Hoogstraate, J., Schrenk, D., and Lennernäs, H. (2007). Gene and protein expression of p-glycoprotein, mrp1, mrp2, and cyp3a4 in the small and large human intestine. Molecular Pharmaceutics, 4(2):252-257. http://www.citeulike.org/user/HEIRS/article/6740818
Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., and Keppler, D. (1996). Transport of glutathione, glucuronate, and sulfate conjugates by the mrp gene-encoded conjugate export pump. Cancer Res, 56(5):988-994. http://www.citeulike.org/user/HEIRS/article/6740844
Beedholm-Ebsen, R., van de Wetering, K., Hardlei, T., Nexo, E., Borst, P., and Moestrup, S. K. (2010). Identification of multidrug resistance protein 1 (mrp1/abcc1) as a molecular gate for cellular export of cobalamin. Blood, 115(8):1632-1639. http://www.citeulike.org/user/HEIRS/article/6740799
Kudo, H., Doi, Y., and Fujimoto, S. (2010). Expressions of the multidrug resistance-related proteins in the rat olfactory epithelium: a possible role in the phase iii xenobiotic metabolizing function. Neuroscience letters, 468(2):98-101. http://www.citeulike.org/user/HEIRS/article/6740891
Silverstein, P. S., Audus, K. L., Qureshi, N., and Kumar, A. (2009). Lipopolysaccharide increases the expression of multidrug resistance-associated protein 1 (mrp1) in raw 264.7 macrophages. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. http://www.citeulike.org/user/HEIRS/article/6083484

Germs In Tobacco Are Potential Source Of Respiratory Infections Blamed On Smoking - Science News

Germs In Tobacco Are Potential Source Of Respiratory Infections Blamed On Smoking - Science News: "Germs in tobacco are potential source of respiratory infections blamed on smoking"

Increasing neurogenesis might prevent drug addiction and relapse

Increasing neurogenesis might prevent drug addiction and relapse

Dietary medium-chain triglycerides prevent chemica... [Transl Res. 2010] - PubMed result

Dietary medium-chain triglycerides prevent chemica... [Transl Res. 2010] - PubMed result: "Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats."

Early lactate clearance is associated with biomark... [J Inflamm (Lond). 2010] - PubMed result

Early lactate clearance is associated with biomark... [J Inflamm (Lond). 2010] - PubMed result: "Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock."

Anti-inflammatory effect by lentiviral-mediated ov... [Gene Ther. 2010] - PubMed result

Anti-inflammatory effect by lentiviral-mediated ov... [Gene Ther. 2010] - PubMed result: "Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages."

Antibodies Linked To Cardiovascular Disease Increase In Patients With Active Lupus

Antibodies Linked To Cardiovascular Disease Increase In Patients With Active Lupus: "Antibodies Linked To Cardiovascular Disease Increase In Patients With Active Lupus"

Paper medical lab the size of a fingerprint

Paper medical lab the size of a fingerprint (w/ Video)

(PhysOrg.com) -- A Harvard University chemistry professor is aiming to produce a blood analyzer for the developing world that will be the size of a human fingerprint, and will cost around a penny.

Hormone Study Gives Scientists a Sense of How Animals Bond - insciences

Hormone Study Gives Scientists a Sense of How Animals Bond - insciences: "Hormone Study Gives Scientists a Sense of How Animals Bond"

Link Found Between Liver Disease And Falls In Old Age

Link Found Between Liver Disease And Falls In Old Age

Sepsis Treatments Save Lives

Sepsis Treatments Save Lives | Ivanhoe's Medical Breakthroughs: "About 750,000 people in the United States are affected by sepsis each year, but now, new information can help improve treatment for the potentially deadly condition."

Brain Map Reveals Secret of Intelligence | Ivanhoe's Medical Breakthroughs

Brain Map Reveals Secret of Intelligence | Ivanhoe's Medical Breakthroughs: "Brain Map Reveals Secret of Intelligence"

New Building at University of Michigan Health System Expands Eye Care, Unites Diabetes Researchers

New Building at University of Michigan Health System Expands Eye Care, Unites Diabetes Researchers

Reduced Adult Neurogenesis and Altered Emotional Behaviors in Autoimmune-Prone B-Cell Activating Factor Transgenic Mice

Reduced Adult Neurogenesis and Altered Emotional Behaviors in Autoimmune-Prone B-Cell Activating Factor Transgenic Mice

Antibodies Linked To Cardiovascular Disease Increase In Patients With Active Lupus

Antibodies Linked To Cardiovascular Disease Increase In Patients With Active Lupus

Vitamin D Deficiency Likely Among Some Kidney Disease Patients Starting Dialysis

Vitamin D Deficiency Likely Among Some Kidney Disease Patients Starting Dialysis

Minocycline protects dopaminergic neurons against long-term rotenone toxicity.

Minocycline protects dopaminergic neurons against long-term rotenone toxicity.

Minocycline protects dopaminergic neurons against long-term rotenone toxicity.

Minocycline protects dopaminergic neurons against long-term rotenone toxicity.

Knocking-down Cav1 Calcium Channels Implicated in Th2-cell Activation Prevents Experimental Asthma.

Knocking-down Cav1 Calcium Channels Implicated in Th2-cell Activation Prevents Experimental Asthma.

Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype [Signal Transduction]

Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype [Signal Transduction]

Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle.

Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle.

Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice.

Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice.

Omega-3, vitamins, minerals may reduce aggressive behaviour

Omega-3, vitamins, minerals may reduce aggressive behaviour

Chronic Methanol/Formaldehyde Poisoning From Aspartame

"Chronic Methanol/Formaldehyde Poisoning From Aspartame"

Histamine and Orexin in the Control of Arousal, Locomotion, and Motivation

Histamine and Orexin in the Control of Arousal, Locomotion, and Motivation

Ornithine decarboxylase prevents tumor necrosis factor alpha-induced apoptosis by decreasing intracellular reactive oxygen species.

Ornithine decarboxylase prevents tumor necrosis factor alpha-induced apoptosis by decreasing intracellular reactive oxygen species.

2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor {alpha} in adipocytes

2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor {alpha} in adipocytes

Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury

CiteULike: Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury: "Tolins, J. P., Hostetter, M. K., and Hostetter, T. H. (1987). Hypokalemic nephropathy in the rat. role of ammonia in chronic tubular injury. Journal of Clinical Investigation, 79(5)."

"Mouse model reveals a cause of ADHD

The Rockefeller University » Newswire: "Mouse model reveals a cause of ADHD"

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

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

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

For further reading:

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

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

Reactive Sulfur Species Act as Prooxidants in Liposomal and Skeletal Muscle Model Systems - Journal of Agricultural and Food Chemistry (ACS Publications)

Reactive Sulfur Species Act as Prooxidants in Liposomal and Skeletal Muscle Model Systems - Journal of Agricultural and Food Chemistry (ACS Publications): "Reactive Sulfur Species Act as Prooxidants in Liposomal and Skeletal Muscle Model Systems"

AMPK{alpha}2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo. Role of 26S Proteasomes.

AMPK{alpha}2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo. Role of 26S Proteasomes.

Researchers Find Gut Protein that Protects Against Infection

A signaling protein that is key in orchestrating the body’s overall immune response has an important localized role in fighting bacterial infection and inflammation in the intestinal tract, according to a study by UC San Diego School of Medicine investigators, published in the journal Cell Host and Microbe. Further the author says, "diminished levels may be potentially an underlying factor in the severe illness caused by pathogens such as E. coli, and inflammation of the intestine by diseases such as Crohn’s disease

Researchers Find Protein that Protects Gut from Infection: "Researchers Find Protein that Protects Gut from Infection"

Human genetic vulnerabilities may underlie infectious diseases, scientist argues

Human genetic vulnerabilities may underlie infectious diseases, scientist argues

ScienceDaily (2010-02-21) -- Infectious diseases in the general population depend to a large extent on underlying genetic vulnerabilities, an expert in innate immunity says. While microbes are required for infection, he says, one's genetic background could make the difference between fighting an infection and succumbing to it. ... > read full article

Effects of Interleukin-6 on Depression Risk in Dialysis Patients.

Effects of Interleukin-6 on Depression Risk in Dialysis Patients.

Iron Leads to Memory Impairment that is Associated... [Curr Neurovasc Res. 2010] - PubMed result

Iron Leads to Memory Impairment that is Associated... [Curr Neurovasc Res. 2010] - PubMed result: "on Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways."

Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.

Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.

Inter-connection between mitochondria and HIFs.

Inter-connection between mitochondria and HIFs.

Primary biliary cirrhosis is associated with falls and significant fall related injury

Primary biliary cirrhosis is associated with falls and significant fall related injury

Age-dependent differences of interleukin-6 activity in cardiac function after burn complicated by sepsis

Age-dependent differences of interleukin-6 activity in cardiac function after burn complicated by sepsis

Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

Autism, Ammonia, Irritable Bowel Syndrome, Inflammatory Bowel Disease and Environmental Odorants

It is often asked whether or not intestinal problems such as irritable bowel syndrome and inflammatory bowel disease are associated with environmental illnesses such as chemical sensitivity. As a researcher, I would say undoubtedly so and to explain some of the reasons for this and present some interesting hypotheses and studies as well. First, it is true there is still no general consensus on what causes irritable bowel syndrome. However, in the last few years inroads have been made on settling the debate. In a preliminary report out of Heidelberg, the author states they have found mutations possibly associated with IBS, that "appear to cause changes in the composition or number of receptors on the cell surface. "The signal transduction in the digestive tract may be disturbed and this may lead to over stimulation of the intestine. Resulting disturbances in fluid balance could explain the occurrence of diarrhea," says Johannes Kapeller, a PhD student in the team.  Other studies and researchers have found similar findings and other possible causative agents for the development of both conditions.

I recently discussed at length the potential relationship of high ammonia levels in autism, in addition to the fact it may be implicated as a causal factor in a number of environmental illnesses including multiple chemical sensitivity and irritable bowel syndrome. Chemical sensitivity in autism has been noted for many years and I find it curious that a writer from 2003 notes several things about autism including autism therapies (Deth, Cully) that are similar to therapies for treatment of MCS in Pall's book "Unexplained Illness" and the NO/ONOO cycle. While the true cause of autism is still unknown, for the last several years, a number of health experts have proposed that symptoms of autism may be associated with small bacterial overgrowth (SIBO) and excess ammonia in the intestinal tract. Recent reports also suggest a role of bacteria and high ammonia in the inflammatory and pain and anxiety conditions, inflammatory bowel disease and irritable bowel syndrome, respectively. Enterochromaffin cells are secretory cells in the digestive tract and regulates intestinal responses depending on the immunological profile of the inflammatory response (TH1/Th2). In post-infectious IBS (PI-IBS) the enterocromaffin cells which are associated with serotonin secretion are implicated in some of the "mood" issues including anxiety and depression as well as, responding to the chemical composition of gut contents and pathophysiological contractions. (Nozawa) Of MCS significance, Tack has recently identified that "odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells" that may influence gut motility, nausea, vomiting and IBS. (Braun) Also, TRPV1 nociception which has been implicated in MCS also may alter motility through EC cells. (Nozawa, Pall)  Kim explains that the normal mucosal layers of the intestinal tract may play a role in the chronic inflammatory process in inflammatory bowel disease. Further he says,  "the enteric microbiota may drive the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD although the precise etiology is still unknown. However, the interactions with microbiota with T cells, intestinal epithelial cells, dendritic cells have all been implicated as contributors to the condition. (Kim) It might be wise to consider that environmental triggers might influence the constituents of the microbiota to act differently that lead to more pathogenic behavior. In colitis, a recent report suggests that a higher level of serotonin is the result of an increase in enterochromaffin cells (EC), and/or more serotonin in them and a decrease in the serotonin exporter RNA. (Bertrand)  Other reports show the involvement of GSK-3b protein which interacts with something called the Wnt/Catenin pathway and may increase ammonia levels as well as, shut of the astrocyte protective and antioxidant system Nrf2 which increases the likelihood of tissue injury and potential nerve damage from intestinal inflammation. Inhibitors of GSK-3b have been protective of endotoxic shock and also show significant benefits in treating mood disorders, prevent weight loss and activations of the inflammatory cascade by a protein called NF-kappaB. (Whittle) These mechanisms also support a recent discovery of a significant communication pathway of regulation between the gut and the brain, and even more strongly supports why inflammation in the gut may lead to changes in neurotransmission and upregulate or downregulate a number different genes and therefore, play a part in sickness syndrome.

Two decades ago, a study determined that H pylori, a bacteria in the gut, causes elevations of gastric juice ammonia (which can also bind transition metals) and subsequent findings include alterations in other gastric juices and enterochromaffin cells, changes in stomach mucosa and general injury and inflammation. (Lichtenberger) As far as the role of bacterial overgrowth goes as an important factor in IBS, this is still somewhat controversial, however, the idea is gaining in popularity. Spiller explains that recovery from post infectious-IBS can take 5 years or more and that time-table does not include potential for reinfection. The most recent studies on some strains of probiotics show promise for treatment and these findings are interesting because they support ammonia involvement in intestinal issues. Hyperammonemia is a common complication of acute and chronic liver disease and therapy may consist of antibiotics and lactulose that slows down the production and absorption of ammonia. In treating, hepatic encephalopathy lactulose works by reducing absorption from the gut to prevent the toxin from getting to the brain. Under pathological conditions, ammonia can pass through the blood brain barrier and may impair brain function, cause confusion and in the most severe cases, coma. (NetDoctor) Elevated levels can be consistent with chronic conditions and as we noted before, have been implicated in causing symptomatic issues in autism. Nicaise et al demonstrates that in his study probiotics decrease blood and fecal levels of ammonia and were better at it than lactulose. He found the study probiotics strains were able to convert ammonia to alanine to reduce ammonia levels. Astrocyte swelling is reduced with probiotic use and expression of Nrf2 has been shown to protect astrocytes from damage in hyperammonemia. Also, the probiotics decreased hyperammonemia by acting on the ammonia transporter and genetically-altered-probiotic-consuming NH3 strains reduced ammonia levels even farther. Recently, other studies show probiotics may be used effectively in IBS, colitis and Crohns and are able to modulate IL-10 an anti-inflammatory cytokine. This same cytokine is implicated in modulating sickness syndrome and is regulated by HO-1 which is modulated by Nrf2.

Alterations in cortico-releasing factors (CRF), a key regulator of cortisol in the brain have been associated with IBS, depression and anxiety. I recently wrote how hyperammonemia is associated with negative effects of cortico-releasing hormone(CRF) on mood and how high ammonia levels cause a number physiological effects in trout that are comparable to symptoms in sickness syndrome. These changes may include changes in dopamine and serotonin and the latter, may influence ammonia-mediated appetite suppression. While I hesitate to compare health conditions in humans to those in animals such as fish, these finding are interesting never-the-less. (Ortega) In mice, CRF effects similar behaviors including feeding, anxiety and activation of the sympathetic nervous system. Hyperammonemia alters the circadian rhythym of corticosteroids and motor activity in rats while not producing anxiety (Ahabrach) while flavanoids such as quercetin, can reduce CRF's activation of the HPA axis. (Kawabata)

Therer are any number of genes and polymorphisms that can effect metabolism that may lead to diseases of the intestinal tract or any organ for that matter and ammonia is just one of many. At present, scientists have only just begun to discover with the use of genetic studies to discover how these polymorphisms may differently effect the health of individuals and populations. There are many yet to be discovered. Genetic counselors can be a tremendous help in this respect, sometimes just by noting and being familiar with "patterns".  Dr. Yasko supplies a pretty good break-down of genetic conditions that may alter and contribute to high ammonia levels in one posted article but it is not all inclusive.  A genetic counselor I am not going to discuss each of the genes SNPs because the article is long and detailed but quite informative. She does note that ammonia regimines need to be monitored and sometimes changed and therefore, any therapeutic program that addresses genetic influences needs to be done in consultation with a physician. I have explained how different genetic conditions can impair proper ammonia excretion and much of that is explained in this paper. I am not a doctor and therefore will not comment on her treatments but have read about her practice in the literature. She points out a few things I found interesting including hazards associated with some "alternative" therapeutics including epsom salts, MSM and the consequence they can be metabolically be converted to ammonia and may effect the function of another enzyme. I have researched this enzyme and indeed, there may be some concerns with this enzyme in some people with environmental illnesses. This article in this respect and as a whole provides an interesting read and more importantly possibly warrants a discussion with your doctor. (Yasko) Because ammonia levels may influence autism and other conditions as mentioned above, I believe this discussion may be an important priority.

It is difficult to predict how endogenous and exogenous chemicals are going to react to produce health effects including increasing the tendency for chronic conditions like IBS and autoimmune-type inflammatory disease. A recent study demonstrated different mouse strains have different before and after levels of antioxidant genes including glutathione, Nrf2 and HO-1 and also have higher levels of oxidative stress upon exposure to cigarette smoke. It also demonstrates variations exist between individual organisms (mice) which may be comparable to differences in the immune response that might occur in individuals in different populations. From a population health standpoint, different populations may be more or less susceptible to exposures and consequently certain diseases. This potentially becomes more of a concern when there is a poor quality of health care system and disparities already exist in those populations. To support this idea, a study was released in 2007 that identified population differences exist in the Nrf2 gene and concluded they may make them more or less resistent to oxidative stress and lead to an increased prevalence of disease and lower quality of life. (Marzec) Conditions of mixed and chronic environmental stress where there is a reduction in the ability to activate and control the adaptive response has important and broad implications for the health status and adaptive ability of a population as a whole. Several years ago, one researcher found hydrazine, an agricultural product, had a negative effect on the B12-dependant methionine synthase pathway and as a consequence from homocysteine elevations impaired the urea cycle and sulphur amino acid detoxification. (Kenyon) Exposure to nitrous oxide (laughing gas) can deactivate B12 and potentiate impairments in the cyles that eliminate ammonia and in recent weeks, it was reported that exposure to the greenhouse gas nitrous oxide from home maintainance of lawns can be as significant as the amount produced by agriculture and therefore ubiquitous in the environment. With this in mind and in a mixed environment, the study on cigarette smoke mentioned earlier becomes more significant because in the past cigarettes have added ammonia to make themmaking them more addictive. In addition to the hundreds of contaminants in cigarette smoke, it also contains bacteria that may have the potential to cause infectious disease and contains endotoxin that elicits inflammatory responses. Interestingly, the absence of GSK-3b, the on and off switch for Nrf2, eliminates Tnf-a and NF-kappaB signaling from both endotoxin and cigarette smoke. (Takada) This suggests ammonia in cigarette smoke has the potential to down-regulate the Nrf2 system and may help explain the variety of health effects from these exposures and increased sensitivity to them in some individuals. In support the research by Hubner reported that Nrf2 plays "important roles in cellular defenses against smoking in the epithelium and there is variability within populations of oxidant burden. (Hubner) All of this, can lead one to assume that variants in the exposures to agricultural products, alterations in nutritional status and genetic variants may increase the likelihood of any number of diseases including irritable bowel syndrome and inflammatory bowel disease.

Finally, it is important to review some important general health consequences of high ammonia levels. As we have noted, hyperammonemia can be caused by enzyme deficiencies or liver disease and because liver damage and impairment of antioxidant systems are concerns upon exposures, high ammonia levels should be considered as a factor in patients with environmental illnesses. "Hyperammonemia does cause astrocyte swelling (acute hyperammonemia) to astrocytosis (chronic hyperammonemia) and when the urea cycle is impaired, changes to allow for the excretion of ammonia occur in the brain. Some of these changes include changes in glutamate regulation and drug receptors (benzodiazipine) in the mitochondria. Acute changes include activation of NMDA receptors (although some may argue this) and chronic hyperammonemia may cause increases in tryptophan metabolites including serotonin. As one author stresses, current therapies for hyperammonemia are mediated through reduction of ammonia levels through the gastrointestinal tract and increased ammomia in the muscle." (Butterworth) Further studies show that IDO, an enzyme involved in the catabolism of tryptophan, has protective qualities against certain immune reactions and this is achieved through T cell suppression. These findings may lead to more supportive evidence of a loss of T cell suppression and an increase in autoimmune responses in MCS reactions. Other studies show oxidative stress plays a role in the neuropathology of ammonia toxicity and cause derangements in the cerebellum and cerebral cortex that lead to both increasing or decreasing antioxidant levels in both of these areas in acute and chronic ammonia toxicity.(Singh)

For further emphasis:

• Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.

For Clinical Professionals:

Citations located here.

Hesperidin Upregulates Heme Oxygenase-1 To Attenuate Hydrogen Peroxide-Induced Cell Damage in Hepatic L02 Cells

Hesperidin Upregulates Heme Oxygenase-1 To Attenuate Hydrogen Peroxide-Induced Cell Damage in Hepatic L02 Cells

Individual Responses to Volatile Contaminants Are Influenced By Genetic Makeup

Definition:
Aerosol:suspension of fine solid particles or liquid droplets in a gas. Examples are smoke, oceanic haze, air pollution, smog and CS gas. The word aerosol derives from the fact that matter "floating" in air is a suspension. (Wipedia)
Particulate Matter: are tiny subdivisions of solid or liquid matter suspended in a gas or liquid.
Redox potential (reduction potential): a tendency of a chemical species to acquire electrons and thereby be reduced.
Electrophile: electron lover- a substance that accepts an electron pair. Carbonyls and acids are examples.
quinone: a class of organic compounds that are formally derived from aromatic compounds.


Background: In other blogs, we have explained how particulate matter is a health hazard and the smaller or more fine the particulate the more likely it is to cause a heightened inflammatory response. There are several reasons for this but two important ones are because they have a larger surface area to bind with other contaminants and they are small enough to reach the deeper part of the lungs (if inhaled) or digestive tissue (if ingested) and infiltrate lower levels of tissue where they increase inflammation. Recently, a study of mice demonstrated how different strains have different basal levels of antioxidant genes that could potentially cause a increased or decreased risk for health consequences. In this case, it was a model for COPD which is an inflammatory respiratory disease and cigarette smoke. One can conclude from the results of this study and if the same is true for humans as it is for mice, different ethnic groups, lineages, etc. may be more susceptible than others to environmental contaminants. Interestingly, different mouse strains exhibit differences in basal levels of proinflammatory cytokines, oxidative stress and also expression of antioxidant genes Nrf2, HO-1, glutathione and others including IL-6. (Vecchio) These results augment controversial findings that suggest infections are less environmental than they are genetic and a person's susceptibility and ability to recover has to do less with environmental factors than it does genetics. (EurekAlert)

A few new studies shed a little bit more light on the chemical properties of PM and provides support for the idea that "semi-volatile and volatile contaminants have been implicated in causing adverse health effects. From this study, the author examined hazard levels in regards to the particle or vapor in an aerosol. He explains that redox-active components are particle-phase and vapors are more electrophilic and noted that latter contaminants were capable of inducing HO-1, a strong antioxidant and stress response protein. From this he concluded that volatile properties should be considered when determining the hazardous nature of a contaminant." While this may seem like greek to some, a general conclusion one can make from this is volatile properties of contaminants have adverse health effects. In addition, an investigator must be cognizant and consider genetic expression may influence a person's immune response to environmental contaminants including those that are volatile vapors.

Comment: The findings of these studies should have important influence on treatments descisions for MCS patients.


Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology. http://www.citeulike.org/user/HEIRS/article/6675046?show_msg=already_posted
Eiguren-Fernandez, A., Shinyashiki, M., Schmitz, D. A., Distefano, E., Hinds, W., Kumagai, Y., Cho, A. K., and Froines, J. R. (2010). Redox and electrophilic properties of vapor- and particle-phase components of ambient aerosols. Environmental research. http://www.citeulike.org/group/7769/article/6704033
(2010). Rockefeller scientist to speak at aaas on infections as genetic disorders.
http://www.citeulike.org/user/HEIRS/article/6704247
Shinyashiki, M., Eiguren-Fernandez, A., Schmitz, D. A., Di Stefano, E., Li, N., Linak, W. P., Cho, S.-H. H., Froines, J. R., and Cho, A. K. (2009). Electrophilic and redox properties of diesel exhaust particles. Environmental research, 109(3):239-244. http://www.citeulike.org/group/7833/article/6705178

Study Reveals How Genes Interact With Environment To Cause Disease

Study Reveals How Genes Interact With Environment To Cause Disease: "Study Reveals How Genes Interact With Environment To Cause Disease"











Learn more about gene biology.

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Flu-Induced Stress Response Necessary for Resistance to Secondary Illness

Flu-induced stress response is critical for resistance to secondary infection

ScienceDaily (2010-02-19) -- A new study reveals how infection with the influenza virus impacts the way that the immune system responds to subsequent infections. The research provides a new understanding of the physiological and pathological consequences of the flu. ... > read full article

Nrf2, Transition Metals and Quinones-- Implications for Diseases Involving Metals and Oxygen

To our knowledge, we provide the first experimental evidence that the para- and ortho-hydroquinones themselves are unable to activate Nrf2 directly and that their corresponding quinones react with Keap1 and are the direct activators of Nrf2. In addition, we show that in the presence of Cu2+, the catechol estrogens 2-hydroxyestradiol, 4-hydroxyestradiol, 4-hydroxyestrone, as well as dopamine, are potent Nrf2 activators.

 Further,

"hydroquinones will not stimulate Nrf2-mediated gene induction in the absence of transition metals and oxygen. These findings are of particular importance for certain human conditions in which the levels of transition metals are increased, such as Wilson's disease (genetic mutation in the copper transporter resulting in copper accumulation) or patients with cancer (who have increased plasma and tumor copper levels), and especially in tissues that are exposed to relatively high concentrations of oxygen, such as the lung, the brain, and the alveolar epithelium of the breast."

Wang, X. J., Hayes, J. D., Higgins, L. G., Wolf, C. R., and Dinkova-Kostova, A. T. (2010). Activation of the nrf2 signaling pathway by copper-mediated redox cycling of para- and ortho-hydroquinones. Chemistry & Biology, 17(1). http://www.citeulike.org/user/HEIRS/article/6699335

Immune Differences Between Mice Strains Determine Susceptibility to Cigarettte Smoke

Snippet: Strain A and B showed differences in baseline production of ROS and H2O2 and also glutathione, Nrf2, heme oxygenase 1 and GPX2. This was associated with reduced HDAC2 expression, activation of NF-kappaB and higher basal levels of TNF-alpha and IL-6. CSE induced a decrease in HDAC2 protein levels strains, however, the level of HDAC2 was significantly lower in strain A than in strain B. (Names of mouse strains have been changed for purpose of simplicity.)
Comment: One can assume from this there is significant potential for different people (because of their genetic makeup that results in different expression of antioxidant and immune genes) to be more prone to the health consequences of cigarette smoke. This has important implication for health conditions including but not limited to conditions like COPD, asthma and also other conditions like MCS.

For further reading: Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

Blog Tags: Nrf2 , HO-1 , Tnf-a, Il-6



CiteULike: Reactivity of Mouse Alveolar Macrophages to Cigarette Smoke is Strain Dependent.: "Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology."

Hyperammonemia: eMedicine Neurology

Hyperammonemia: eMedicine Neurology: "Hyperammonemia, along with acidosis, ketosis, and a low bicarbonate level, is suggestive of an organic acidemia. In addition, hyperglycinemia and hypoglycemia also are seen in some organic acidemias. Hyperammonemia, in addition to acidosis, ketosis, and increased lactate and citrulline, indicates pyruvate carboxylase deficiency."

Hyperammonemia: eMedicine Neurology

Hyperammonemia: eMedicine Neurology: "Hyperammonemia"

Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease

Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease: "URL: Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease

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Down Regulation of Adipose Glutathione S-Transferase Leads to Increased Protein Carbonylation, Oxidative Stress and Mitochondrial Dysfunction.

Down Regulation of Adipose Glutathione S-Transferase Leads to Increased Protein Carbonylation, Oxidative Stress and Mitochondrial Dysfunction.: "URL: Down Regulation of Adipose Glutathione S-Transferase Leads to Increased Protein Carbonylation, Oxidative Stress and Mitochondrial Dysfunction.

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SIRT1 on the brain: Sirtuin controls behavior under CR

SIRT1 on the brain: Sirtuin controls behavior under CR: "URL: SIRT1 on the brain: Sirtuin controls behavior under CR

"

Production of Interleukin-10 in serum and erythropoietin sensitivity in ESRD patients on hemodialysis.

Production of Interleukin-10 in serum and erythropoietin sensitivity in ESRD patients on hemodialysis.: "URL: Production of Interleukin-10 in serum and erythropoietin sensitivity in ESRD patients on hemodialysis.

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Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness

As we have noted the Nrf2 regulates a number of genes including those that are important for mitochondrial biogenesis and other homeostatic functions and the expression of it can be effected by age, injury, oxidative stress, nutrition and other behavioral factors. As Dhar shows, the NRF-1 transcription factor upregulated by Nrf2 and important for PGC-1a activation and mitochondrial biogenesis has been shown to co-regulate a number of different genes including that for NR1, NR2b and Cox1. The Nr2b is a subunit of the NMDA which has been implicated in nociception of MCS upon upregulation (Pall) as well as, has been implicated in having involvement in other environmental illnesses including fibromyalgia. Its involvement also provides important implications for conditions of learning and cognitive difficulties that usually are co-morbid with these conditions. There does seem to be some debate on whether NMDA is upregulated or down-regulated and it may be that specific situations influence this. Yonden previously demonstrated that the downregulation of the NR2b receptor occurs with addition of experimental ammonia and concluded that downregulation of the NMDA contributes to severity of hepatic encephalopathy. This also supports our opinion that Nrf2 may influence environmental conditions including MCS and others because it is important for regulation of NRF1. It also provides supporting evidence that other health conditions where mitochondrial dysfunction is a factor, may also be influenced by the expression of Nrf2 because NRF1's role in mitochondrial biogenesis.

HEIRS Tags: NR2B, NRF1, hyperammonia,
For Further Reading: Nrf2, Ornithine Transferase, Autism and Maternal Age -- A Possible Link?

CiteULike: Coupling of Energy Metabolism and Synaptic Transmission at the Transcriptional Level: Role of Nuclear Respiratory Factor 1 in Regulating both Cytochrome c Oxidase and NMDA Glutamate Receptor Subunit Genes: "Dhar, S. S. and Wong-Riley, M. T. T. (2009). Coupling of energy metabolism and synaptic transmission at the transcriptional level: Role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and nmda glutamate receptor subunit genes. J. Neurosci., 29(2):483-492."
Yonden, Z., Aydin, M., Kilbas, A., Demirin, H., Sutcu, R., and Delibas, N. (2010). Effects of ammonia and allopurinol on rat hippocampal nmda receptors. Cell biochemistry and function. http://www.citeulike.org/user/HEIRS/article/6567065
Pall, Martin.  (2007). Explaining Ünexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479

CiteULike: Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection

CiteULike: Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection: "Yamamoto, N., Izumi, Y., Matsuo, T., Wakita, S., Kume, T., Takada-Takatori, Y., Sawada, H., and Akaike, A. (2010). Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection. Journal of Neuroscience Research, 9999(9999):NA+."

Study shows correlation between mitochondrial biogenesis and G6PDH

Recent study shows correlation between G6PDH and mtDNA replication. This
may account for low developmental competance in these animals. Marker changes
include those for COX1, NRF1 and tFAM.

CiteULike: Transcript expression of mitochondria related genes is correlated with bovine oocyte selection by BCB test.: "Opiela, J., Lipiński, D., Słomski, R., and Katska-Ksiazkiewicz, L. (2010). Transcript expression of mitochondria related genes is correlated with bovine oocyte selection by bcb test. Animal reproduction science, 118(2-4):188-193."

Epigenetic signals differ across alleles

Epigenetic signals differ across alleles: "Epigenetic signals differ across alleles"

Protein Important for Mitochondrial Biogenesis Cooperates With HO-1 To Increase Stress Resistance In Endothelial Cells

ConclusionWe have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.

CiteULike: PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress: "Ali, F., Ali, N. S., Bauer, A., Boyle, J. J., Hamdulay, S. S., Haskard, D. O., Randi, A. M., and Mason, J. C. (2010). Ppardelta and pgc1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc Res, 85(4):701-710."

Hot pepper relief: New category of painkillers on the way?

Hot pepper relief: New category of painkillers on the way?

Green Tea Compounds May Have Therapeutic Benefits For Autoimmune Disease..

Summary: "findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease."

Reference Blog Tags: EGCG
CiteULike: Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells.: "Peairs, A., Dai, R., Gan, L., Shimp, S., Rylander, M. N., Li, L., and Reilly, C. M. (2010). Epigallocatechin-3-gallate (egcg) attenuates inflammation in mrl/lpr mouse mesangial cells. Cellular & molecular immunology."



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Ammonia Enzymes, Immune Cells & X-Linked Mutations In Autoimmunity and Disease

Background: We have suggested that environmental illnesses may involve the loss of suppression of regulatory T cells and that several different proteins may be involved which changes the dynamics or "immunological footprint" of these conditions in each individual. Previously we mentioned how high ammonia levels may account for some of the symptoms associated with multiple chemical sensitivity. We also noted recently how alterations in ornithine enzymes may effect ammonia levels and the Nrf2 gene regulator has some control over its expression. The following article discusses findings related to how a mutation in ornithine transcarbamalase may influence the immune system and play a role in autoimmune type disease. Interestingly, the author points out the condition is X-linked which might account for higher number of females presenting with them because males usually die in utero and do not live but a few days after birth. There is usually a large sexual dimorphism in the prevalence of many environmental diseases. As Li explains, there may be a number of factors that contribute to autoimmune disease which may include estrogenic production as well as, vulnerable phenotypes may be more susceptible to metals exposure which may accelerate some individuals to reactive phenotypes. (Li)

The author writes, "Antigen expression in the thymus leads to the deletion of self-reactive T cells and generation of regulatory lymphocytes, including regulatory T cells(Treg) and NKT cells. We show an Ornithine transcarbamylase(OTC) mutation causes ineffective presentation of self antigens in the thymus. As such, deletion of self reactive T cells is compromised and production of Treg and NKT cells is reduced in the OTC mutant mice. More importantly the heterozygous mice have increased susceptibility to autoimmune diseases, including the generation of autoantibodies and more severe EAE." Further, "OTC mutant mice, the production of Treg in the thymus is reduced, which is correlated with the impaired antigen presentation due to hyperammonemia."


Comment: This article is a good representation of why only qualified medical professionals that understand the multitude of genetic conditions and environmental conditions that activate them should be treating them. There is no evidence thus far, that a "therapeutic recipe" is effective at treating all of them.


Chang, X. (2006). X linked foxp3 & otc in immune tolerance and autoimmunity. Ohio State University. http://www.citeulike.org/user/HEIRS/article/6650098
Li, J., Stein, T. D., and Johnson, J. A. (2004). Genetic dissection of systemic autoimmune disease in nrf2 deficient mice. Physiological Genomics.
http://www.citeulike.org/user/HEIRS/article/6604948

Allergen exposure increases Th2-cytokines and FOXP3 expression in asthmatic lungs

MedWire News - Respiratory - Allergen exposure increases Th2-cytokines and FOXP3 expression in asthmatic lungs: "Allergen exposure increases Th2-cytokines and FOXP3 expression in asthmatic lungs"

Depressed Mice Reveal Critical Chemical Pathway for Treatment - DukeHealth.org

Depressed Mice Reveal Critical Chemical Pathway for Treatment - DukeHealth.org: "Depressed Mice Reveal Critical Chemical Pathway for Treatment"

The Rise of Antioxidant Signaling-The Evolution and Hormetic Actions of Nrf2.

The Rise of Antioxidant Signaling-The Evolution and Hormetic Actions of Nrf2.: "URL: The Rise of Antioxidant Signaling-The Evolution and Hormetic Actions of Nrf2.

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Kimberly Kramer
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Nrf2, Ornithine Transferase, Autism and Maternal Age -- A Possible Link?

Recently a report was published of a link between autism and maternal age. While some may criticize that such admissions are worthless, I beg to differ. The Nrf2 antioxidant system which controls a battery of protective genes also controls an enzyme called ornithine aminotransferase which protects against ammonia. High ammonia levels have been implicated as a possible cause for some types of autism. There are behavioral conditions that may improve levels of Nrf2 expression including diet and exercise. While this may be premature, it should be worth more study from autism experts.

Past HEIRS Environmental Illness Research Blogs of Interest:

• Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.
• Mitochondrial MAO Enzyme May Contribute to Oxidative Stress in Hyperammonemia!
• Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.
• Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
• Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish
• Neutrophic Factors Protect Against High Ammonia Levels
• Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease
• Nrf2 and Cigarette Smoke ---A Possible Link to B12 Deficiency.......?
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment.
• Effect of Acute Exposure to Ammonia on Glutamate Transport in Glial Cells Isolated From the Salamander Retina -- Mort et al. 86 (2): 836 -- Journal of Neurophysiology
• Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats
• Ammonia, ASIC Channels and Mental Health
• Ammonia and Its Relationship To Environmental Illness
• Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and CRF systems
• Effects of ammonia and allopurinol on rat hippocampal NMDA receptors.
• Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness
• ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

HEIRS Library Tags: PGC-1a, Nrf2,
    Other Blog Tags: PGC-1a, Nrf2,

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Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002). Identification of nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res, 62(18):5196-5203. http://www.citeulike.org/user/HEIRS/article/3728059?show_msg=already_posted
University of California - Davis - Health System (2010, February 8). Link between advanced maternal age and autism confirmed. ScienceDaily. Retrieved February 9, 2010, from http://www.sciencedaily.com/releases/2010/02/100208102411.htm
Holmes, Amy, MD. Heavy Metal Detoxification and Metallothionein Promotion. Autism Treatments. The Healing Center Online. Retrieved on February 10, 2010.

Alterations of BDNF, Behavior Hormones in PTSD, Fibromyalgia and Other Environmental Illnesses

Many experts believe that the functions of the hypothalamus are dysrupted in environmental illness. We recently blogged about how hypothalamus-stimulated signaling of  BDNF levels are altered in a number of environmental illnesses. In fibromyalgia they are increased while in other are they are lower. A more recent report has indeed supported the fact that BDNF levels are increased in fibromyalgia. Also, they have demonstrated that this hormone is elevated shortly after trauma in PTSD and evens out over time. Interestingly, these findings were independant of severity, psychiatric history and treatments with medication. Because BDNF has been implicated in learning and memory the higher levels of this protein may contribute to the pathology of PTSD and considering they are elevated in fibromyalgia, one may suspect they also contribute to the pathology of fibromyalgia also. Of course, further evidence is warranted but these findings are interesting none-the-less.

Note:

• Orexin is another signaling peptide of the hypothalamus and it has been demonstrated that altered levels are consistent with fibromyalgia, chronic fatigue syndrome, PTSD and panic attacks. We have discussed this hormone in other blogs and explained, it dictates a number of different animal behaviors and is sexually dimorphic and plays a role in sickness behavior.  In addition, there is an important connection between orexins and BDNF. Dopamine are regulators of orexins and low levels are also associated with Parkinson's disease.
• BDNF is mediated by GSk-3b which is implicated in a number of psychological disorders and can be activated by environmental exposures. (Mai)

For further Reading:

• Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

Reference Library Tags: orexin, narcolepsy, chronic fatigue syndrome, PTSD, BDNF
                HEIRS Blogs: orexins, BDNF, chronic fatigue syndrome, sickness syndrome, fibromyalgia,  PTSD,


Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today.  http://www.citeulike.org/user/HEIRS/article/6640584
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/user/HEIRS/article/6463668
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. http://www.citeulike.org/user/HEIRS/article/4967509
Stanley, S., Wynne, K., McGowan, B., and Bloom, S. (2005). Hormonal regulation of food intake. Physiol. Rev., 85(4):1131-1158. http://physrev.physiology.org/cgi/content/full/85/4/1131/F2
Mai, L., Jope, R. S., and Li, X. (2002). Bdnf-mediated signal transduction is modulated by gsk3β and mood stabilizing agents. Journal of Neurochemistry, 82(1):75-83. http://www.citeulike.org/user/HEIRS/article/6621876

PTSD, Environment and Gene Variants in COMT

A new study reports that variants in the gene for catechol-O-methyltransferase (COMT) Val158Met and the amount of "traumatic load" influences the likelihood of PTSD and other reports show that COMT may be located both in the glia and certain neurons. The toxic destruction  of dopamine neurons in striatum does not result in loss of COMT and therefore, striatal dopaminergic neurons do not contain a high level of this protein. In areas where COMT neurons are present such as the prefrontal cortex, variants may influence the dopamine signaling and increase the length of time for this neural transmitters elimination. These findings provide a foundation for understanding the difference in cognitive performance including executive functioning, of COMT variants as well as, their association with mental health disorders. (Yavich)

Notes:

• We suggested in an earlier blog that because hyperammonemia may influence cellular pathways associated with PTSD -- conditions that influence endogenous levels of ammonia from exogenous environmental factors or alterations in metabolism may have implications on development of this disorder.
• "COMT catalyzes the methylation of various endobiotic and xenobiotic substances preventing quinone formation and redox cycling, and therefore might protect DNA from oxidative damage."  Availability and variants of this protein therefore may influence the biological effect related to toxic exposures. (Hung) 

References:

• Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish.

Kolassa, I.-T. T., Kolassa, S., Ertl, V., Papassotiropoulos, A., and De Quervain, D. J.-F. J. (2010). The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase val(158)met polymorphism. Biological psychiatry, 67(4):304-308. http://www.citeulike.org/user/HEIRS/article/6250832
Hung, R. J., Boffetta, P., Brennan, P., Malaveille, C., Gelatti, U., Placidi, D., Carta, A., Hautefeuille, A., and Porru, S. (2004). Genetic polymorphisms of mpo, comt, mnsod, nqo1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis, 25(6):973-978. http://www.citeulike.org/user/HEIRS/article/6643978
Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003

Mitochondrial MAO Enzyme May Contribute to Oxidative Stress in Hyperammonemia!

brain mitochondrial MAO-A is regulated by the function of NMDA receptors. The enzyme can contribute to the oxidative stress associated with hyperammonemic conditions such as encephalopathy and Alzheimer’s disease.

CiteULike: Brain monoamine oxidase A in hyperammonemia is regulated by NMDA receptors: "Kosenko, E. and Kaminsky, Y. (2009). Brain monoamine oxidase a in hyperammonemia is regulated by nmda receptors. Central European Journal of Biology, 4(3):321-326."

Discovery of pathway in learning impairment caused by liver disease may lead to drug treatment

Discovery of pathway in learning impairment caused by liver disease may lead to drug treatment: "Discovery of pathway in learning impairment caused by liver disease may lead to drug treatment
Main Category: Mental Health"

Sleep deprivation may alter memory formation.

Sleep deprivation inhibits expression of NADPH-d a... [Cells Tissues Organs. 2003] - PubMed result: "Sleep deprivation inhibits expression of NADPH-d and NOS while activating microglia and astroglia in the rat hippocampus."

Hyperbaric oxygen exposure improves blood glucose ... [Diabetes Technol Ther. 2010] - PubMed result

Hyperbaric oxygen exposure improves blood glucose ... [Diabetes Technol Ther. 2010] - PubMed result: "Hyperbaric oxygen exposure improves blood glucose level and muscle oxidative capacity in rats with type 2 diabetes"

Chemical Used to Clean Car Parts Shows Stong Link to Parkinson's

Trichloroethylene is a risk factor for parkinsonism: "Trichloroethylene is a risk factor for parkinsonism"

Substance in Wine and Grape Skins Reduces Chronic Intestinal Inflammation

CiteULike: Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice.: "Sánchez-Fidalgo, S., Cárdeno, A., Villegas, I., Talero, E., and la Lastra, C. A. d. A. (2010). Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice. European journal of pharmacology."

CiteU Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.

CiteULike: Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.: "Hermenegildo, C., Montoliu, C., Llansola, M., Muñoz, M. D., Gaztelu, J. M., Miñana, M. D., and Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic gmp pathway in cerebellar neurons in culture and in the rat in vivo. The European journal of neuroscience, 10(10):3201-3209."

Neutrophic Factors Protect Against High Ammonia Levels

CNTF protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved.: "Cagnon, L. and Braissant, O. (2009). Cntf protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiology of disease, 33(1):133-142."

Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

A number of noxious fumes and toxins are produced in the manufacturing process of the illegal drug methamphetamine and in recent months there have been a number of broadcasts on dangers associated with "meth lab homes". If you have missed these broadcasts it may interest you to know that 1 pound of meth produces 6 pounds of toxic chemicals. If you're not in the market for renting or buying a home, you might not be concerned by this now but these chemicals end up in the soil, air and water that surround the manufacturing site or are dumped along the roadside from mobile labs. Chemicals produced indoors from meth labs absorb into any porous material including carpets, clothing, blankets, food products, paint, flooring etc and get distributed onto all surfaces through air flow, ventilation and duct work and tracked into "clean" environments by contaminated shoes. Cars that house mobile labs are also a lifetime hazard because upholstery is porous and absorbs toxins.  

Most people are familiar with the fact that one of the most common chemicals associated with meth lab exposure is ammonia that can be toxic at certain amounts. Of course, the level of what determines the effects of toxicity is going to depend on the concentration, the route of exposure, the duration and metabolic characteristics of those exposed. Different people have different levels of detoxification that ultimately determines how serious the exposure to ammonia or to any chemical will be and there are a number of factors that influence this including genetics. One author explains ammonia toxicity can occur as a result of "alterations of ammonia metabolism including enzyme issues within the urea cycle, Reyes Syndrome and liver failure and the effects of these conditions may lead to brain edema and severe neurological impairment. Generally, it is now known that ammonia crosses the blood-brain barrier and interacts with a number of cellular processes including neurotransmission and brain metabolism." (Butterworth)

 For several years now, health experts have been aware that the illegal use of  methamphetamine may lead to long-lasting health consequences including dental disease and mental health problems in addition to those associated with addiction. Another consequence is an increased risk for Parkinson's disease for those who abuse methamphetamine, later in life. While there are a number of reasons for this, there are two that stand out in importance in addition to ammonia-inducing mitochondria dysfunction. The first is because of the vulnerability of certain neurons including those that regulate dopamine to the toxic effects of ammonia. There are also "lasting decrements in something called the dopamine transporter" and the elevation of oxidative stress by dopamine which damages tissues and causes neural injury. Luckily, under normal circumstances and at normal concentrations and when all things are working properly these kinds of toxic processes can be neutralized through the activities of antioxidants but meth labs are not considered normal circumstances and produce ammonia levels at much higher levels than normal.  

Unfortunately and as noted above, a number of physiological conditions influence how toxins are detoxified and levels of antioxidants may be reduced as a consequence of genetic polymorphisms, injury or the natural processes associated with aging. As far as antioxidant production in PD, the antioxidant system Nrf2 has been found to modulate the severity of toxicity associated with drugs and other toxic exposures. In experimental models, the loss of the expression of Nrf2  results in a greater loss of the dopamine transporter and much greater oxidative stress and greater neural damage.  While this process is more complex than what is explained here, the main point is expression of the Nrf2 is necessary to reduce the kinds of toxicity implicated in PD. (McCann) Nrf2 also regulates the production of certain cofactors necessary that are used in mitochondrial biogenesis which further influences neurological health. Oxidative stress at optimal levels is important for activation of different protective mechanisms including Nrf2 but too much is just too much to continue homeostasis (Widmer) and these conditions significantly complicate methods for treatment. Alterations in functions of antioxidant systems influence a number of diseases and specifically, dysfunction of the Nrf2 system has been implicated in several including cancer, respiratory diseases like COPD and autoimmune diseases.

  

Notes:

• Interestingly, it has been suggested that cigarette manufacturers add ammonia to cigarettes to make it more addictive because it enhances the effects of nicotine. This is achieved by "the addition of ammonia in the manufacturing process which helps convert bound nicotine molecules in tobacco smoke into free nicotine molecules and commonly known as "freebasing." This process is similar to that of freebasing cocaine, the end result is an enhanced effect of the drug on the user. This becomes a real problem upon cigaratte exposure for those who may have inborn errors for ammonia detoxificaton or genetic alteractions in other protective pathways such as Nrf2. (Martin)
• It takes a number of months before a baby's detoxification system is developed and so exposures to toxins in the womb and after birth can take a tremendous toll on the "little ones".
• Alterations in metabolic pathways that influence the excretion of ammonia are negatively influenced by heavy metals. One can be exposed to them from exposure to methamphatamine or meth precursors.
• Elevated levels of ammonia have been implicated in health conditions such as autism and may contribute to different types of brain injury.
• Because physical activity improves neural function and toxic exposure may negatively influence olfaction which also dictates behavior --- there is potential for increase atrophy and damage. Olfactory deficits present themselves often years before PD motor deficits appear.  
• Sleep deprivation from drug abuse has potential to speed mitochodrial dysfunction and shut off the antioxidant system. (Kresiun) Hyperammonemia alters expression of orexins which have a responsibility in control of sleep wake cycles and as a result may alter circadian rhythm and hormone function. (Ahabach) Specific dopamine signals regulate orexins and studies show the loss of orexin neurons is correlated to disease severity of PD. (Bubser, Thannickal)

Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428: "McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., and Ricaurte, G. A. (1998). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from positron emission tomography studies with [11c]win-35,428. J. Neurosci., 18(20):8417-8422." http://www.citeulike.org/user/HEIRS/article/6639032
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