Proteins in Bone Health, Development and Disease in Environmental Illness

Proteins in Bone Health, Development and Disease in Environmental Illness

Central tetrahydrobiopterin concentration in neurodevelopmental disorders.

Hmmm, I would say considering that Nrf2 helps to maintain coupling of NO via tetrahydrobiopterin....the resources of methionine, proper functionings of the pathway and methylation status of the pathways involved may throw a really big wrench into things....and could account for a number of conditions including those in autism and other environmental illnesses including multiple chemical sensitivity or idiopathic intolerance.

"citrulline-to-methionine was found to correlate with the cerebrospinal fluid BH(4) concentration (r = -0.67, p < 0.05). Both citrulline and methionine are substrates in inflammation and oxidative stress pathways - two pathways that utilize BH(4) and are abnormally activated in autism. These data suggests that central BH(4) concentration may be related to systemic inflammation and oxidative stress pathways."

Read more: CiteULike: Central tetrahydrobiopterin concentration in neurodevelopmental disorders.:

Further Reading:

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

Additional Citation:

• Frye, R. E., Huffman, L. C., and Elliott, G. R. (2010). Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 7(3):241-249.
  http://www.citeulike.org/user/HEIRS/article/7557630

Plant compound resveratrol shown to suppresses inflammation, free radicals in humans

"BUFFALO, N.Y. -- Resveratrol, a popular plant extract shown to prolong life in yeast and lower animals due to its anti-inflammatory and antioxidant properties, appears also to suppress inflammation in humans, based on results from the first prospective human trial of the extract conducted by University at Buffalo endocrinologists."

Read more:Plant compound resveratrol shown to suppresses inflammation, free radicals in humans:

Effects of Acute Psychological Stress on Glucose Metabolism and Subclinical Inflammation in PTSD

CiteULike: Effects of Acute Psychological Stress on Glucose Metabolism and Subclinical Inflammation in Patients with Post-traumatic Stress Disorder: "Nowotny, B., Cavka, M., Herder, C., Löffler, H., Poschen, U., Joksimovic, L., Kempf, K., Krug, A. W., Koenig, W., Martin, S., and Kruse, J. Effects of acute psychological stress on glucose metabolism and subclinical inflammation in patients with post-traumatic stress disorder. Hormone and Metabolic Research."

Absence of TLR2 Protect Against Insulin Resistace from High Fat Diet~!

According to the author, this study presents evidence TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.

HEIRS Health Research Blog: Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2

PROPENSITY TO HIGH FAT DIET-INDUCED OBESITY IN RATS IS ASSOCIATED WITH CHANGES IN THE GUT MICROBIOTA AND GUT INFLAMMATION.

Consumption of a high fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.

"De La Serre, C. B. B., Ellis, C. L., Lee, J., Hartman, A. L., Rutledge, J. C., and Raybould, H. E. (2010). Propensity to high fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. American journal of physiology. Gastrointestinal and liver physiology."CiteULike: PROPENSITY TO HIGH FAT DIET-INDUCED OBESITY IN RATS IS ASSOCIATED WITH CHANGES IN THE GUT MICROBIOTA AND GUT INFLAMMATION.:

C-Reactive Protein Alters Protein Interactions W/ eNOS.

"negative protein-protein interactions of eNOS were able to partly explain the CRP-induced decreases in the activity of this critical enzyme, which caused endothelial dysfunction."

CiteULike: C-Reactive Protein Adversely Alters the Protein-Protein Interaction of the Endothelial Isoform of Nitric Oxide Synthase.:

PTSD may raise diabetes risk in service members

It's possible that the stress response associated with PTSD could contribute to widespread inflammation in the body and lower sensitivity to the blood-sugar-regulating hormone insulin, which could lead to diabetes, researchers say.

PTSD may raise diabetes risk in service members Reuters: "PTSD may raise diabetes risk in service members"

Reduced NO-cGMP Signaling Contributes to Vascular Inflammation and Insulin Resistance Induced by High-Fat Feeding

Reduced signaling via the NO-cGMP pathway is a mediator of vascular inflammation and insulin resistance during overnutrition induced by high-fat feeding. Therefore, phosphodiesterase-5, soluble guanylyl cyclase, and other molecules in the NO-cGMP pathway (eg, protein kinase G) constitute potential targets for the treatment of vascular dysfunction in the setting of obesity.

CiteULike: Reduced NO-cGMP Signaling Contributes to Vascular Inflammation and Insulin Resistance Induced by High-Fat Feeding: "Rizzo, N. O., Maloney, E., Pham, M., Luttrell, I., Wessells, H., Tateya, S., Daum, G., Handa, P., Schwartz, M. W., and Kim, F. (2010). Reduced no-cgmp signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol, 30(4):758-765."

Regulatory T Cells and Inflammation in the Intestinal Tract

Background: It has been proposed that environmental pollutants may dysregulate Treg suppressive function and may therefore contribute to environmental illness.

"The enterocolitis in the Il10–/– mice is largely attributed to dysfunctional Tregs. As in many other models of intestinal inflammation, the inflammatory response in the intestinal mucosa in this model of colitis depends on luminal bacteria and/or their inflammatory components....In addition, this author reported that mice that were null for both IL10 and TLR4 have increased inflammation and is similar to the findings of increased inflammation from Helicobacter in Il10 -/- and TLR4 -/- animals. These findings suggest a positive role of TLR4 on the regulatory function of Tregs in intestinal inflammation."


González-Navajas, J. M., Fine, S., Law, J., Datta, S. K., Nguyen, K. P., Yu, M., Corr, M., Katakura, K., Eckman, L., Lee, J., and Raz, E. (2010). Tlr4 signaling in effector cd4+ t cells regulates tcr activation and experimental colitis in mice. Journal of Clinical Investigation.
http://www.citeulike.org/user/HEIRS/article/6488590?show_msg=already_posted

Selected Update: Tumour immunology: Inflammatory transformation

Selected Update: Tumour immunology: Inflammatory transformation: "URL: Selected Update: Tumour immunology: Inflammatory transformation

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Interleukin-1 is essential for systemic inflammatory bone loss

Interleukin-1 is essential for systemic inflammatory bone loss: "URL: Interleukin-1 is essential for systemic inflammatory bone loss

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Link Between Pain Thresholds, Inflammation And Sleep Problems In Arthritis Patients

"Recent advances in anti-inflammatory therapy, many RA patients continue to suffer from pain. A new study found that inflammation is associated with heightened pain sensitivity at joint sites, whereas increased sleep problems are associated with heightened pain sensitivity at both joint and non-joint sites." Click here.

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

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Surgeons Discover a Visceral Fat Hormone That Could Protect Against Life-threatening Sepsis

"A study exhibited at the conference showed that low levels of the hormone adiponectin placed animals at a profoundly high risk of death from a septic insult." Click here to read more.....

Ptsd is associated with an excess of inflammatory immune activities

Gill writes, high lelels of inflammatory cytokines have been linked to PTSD vulnerability in trauma victims which the evidence suggests may be due to dysregulation of cortisol. The inflammatory decline may be responsible for health decline in patients with PTSD and treating the PTSD may decrease the risk for further negative health-related consequences. For more see the citation below.






Gill, J. M., Saligan, L., Woods, S., and Page, G. (2009). Ptsd is associated with an excess of inflammatory immune activities. Perspectives in Psychiatric Care, 45(4):262-277. http://www.citeulike.org/group/6880/article/5843242

Tnf-a, Inflammation and Bone Loss and Stopping it With Another Protein

Experimental approach may reverse rheumatoid arthritis and osteoporosis

Fighting Loss Of Muscle Function In Obesity

Fighting Loss Of Muscle Function In Obesity

Vitamin Research: Lipoic acid synthase (lasy): a novel role in inflammation, mitochondrial function, and insulin resistance

Padmalayam, I., Hasham, S., Saxena, U., and Pillarisetti, S. (2009). Lipoic acid synthase (lasy): a novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes, 58(3):600-608. http://www.citeulike.org/group/6096/article/4859046

Diabetes Medications Don't Lower Inflammation

Diabetes Medications Don't Lower Inflammation