Proteins in Bone Health, Development and Disease in Environmental Illness

Proteins in Bone Health, Development and Disease in Environmental Illness

Flavonoids May Modulate BDNF and Amyloid In Alzheimer's ~!

"stimulating BDNF and reducing Aβ toxicity by natural flavonols provide a therapeutic implication for treatment of AD."


Hou, Y. et al. Anti-depressant natural flavonols modulate BDNF and beta amyloid in neurons and hippocampus of double TgAD mice. Neuropharmacology 58, 911-920 (2010). URL http://dx.doi.org/10.1016/j.neuropharm.2009.11.002.


Related:
Health and Environmental Illness Blog: Solvents, PAHs and BDNF as a Modulator of TrkB, Anxiety and Nrf2~!

Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness - see comments.

Solvents, PAHs and BDNF as a Modulator of TrkB, Anxiety and Nrf2~!

In other blogs, we have discussed how BDNF may play important roles for neuron health and therefore, may play an important role in environmental illnesses. This neutrophic factor is an important regulator in pathways of the cell. Older studies suggest it regulates the PI3K-Nrf2 pathway and Donovan explains that BDNF-TrkB are important for hippocampal regulation. This new studies further supports the role of BDNF in anxiety disorders and possibly others like PTSD. Other studies have shown that "chronic exposure to solvents has a number of health effects including abnormal EEG's, altered sense of smell, numbness or weakness in the extremities, emotional problems, including depressive tendencies, anxiety and social withdrawal. Also, frequent associations between the sense of well being and the cognitive functioning were reported by many authors. Hegazy et al suggests that some of the symptoms related to solvent exposure may be from downregulation of protein expression including BDNF and the activation of the AhR in response to some pollutants may influence BDNF expression as well. (Lin)  This has important implications overall, for the effects of solvent use and their hazards on the modulation of the antioxidant system in general. Taking these studies into account and others in recent months, it has been suggested that modulation through pharmacological or flavonoid therapy may provides benefits and correction of this pathway and be important for neurological disorders such as Parkinson's disease.

"11 base pair deletion in TrkB is significantly associated with increases in anxiety traits during childhood and the development of anxiety disorders in adulthood. We found that this deletion impaired transcription in some human cell lines"

Read more: CiteULike: A Deletion in Tropomyosin-Related Kinase B and the Development of Human Anxiety.:

Comment: In yesterdays blog, I noted how PAH may negatively effect autism genes and becomes an important consider also!


Related Tags: neurotrophins, BDNF, Nrf2


Ernst, C., Wanner, B., Brezo, J., Vitaro, F., Tremblay, R., and Turecki, G. (2010). A Deletion in Tropomyosin-Related Kinase B and the Development of Human Anxiety. Biological psychiatry.
http://www.citeulike.org/user/HEIRS/article/8364218
Nakaso, K., Nakamura, C., Sato, H., Imamura, K., Takeshima, T., and Nakashima, K. (2006). Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins. Biochemical and biophysical research communications, 339(3):915-922. http://www.citeulike.org/user/HEIRS/article/5770676?show_msg=already_posted
Donovan, M. H., Yamaguchi, M., and Eisch, A. J. (2008). Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus. Hippocampus, 18(5):435-439. http://www.citeulike.org/user/HEIRS/article/8364397
Hegazy, N. M., Abdel Gawad, N. B., Metwally, F. M., Ahmed, H. H., Abdel Raouf, E. R., Abrahim, K. S., and Sharaf, N. E. (2010). Neurotoxic effects of organic solvents in exposed workers: Altered expression of some biochemical markers. New York Science Journal, 3(11):171-176.
http://www.citeulike.org/user/HEIRS/article/8364905
Sheng, L., Ding, X., Ferguson, M., McCallister, M., Rhoades, R., Maguire, M., Ramesh, A., Aschner, M., Campbell, D., Levitt, P., and Hood, D. B. (2010). Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicological sciences : an official journal of the Society of Toxicology, 118(2):625-634. http://www.citeulike.org/group/6113/article/8357284

Lin, C.-H. H., Chen, C.-C. C., Chou, C.-M. M., Wang, C.-Y. Y., Hung, C.-C. C., Chen, J. Y., Chang, H.-W. W., Chen, Y.-C. C., Yeh, G. C. C., and Lee, Y.-H. H. (2009). Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons. Journal of neurochemistry, 111(3):777-789. http://www.citeulike.org/user/HEIRS/article/5817355?show_msg=already_posted
Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R. H., and Marini, A. M. (2005). The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. Journal of neurochemistry, 94(3):713-722.  http://www.citeulike.org/user/HEIRS/article/258195
Tuon, T., Valvassori, S. S., Lopes-Borges, J., Fries, G. R., Silva, L. A., Kapczinski, F., Quevedo, J., and Pinho, R. A. (2010). Effects of moderate exercise on cigarette smoke exposure-induced hippocampal oxidative stress values and neurological behaviors in mice. Neuroscience letters, 475(1):16-19. http://www.citeulike.org/user/HEIRS/article/6900487

Elevated Levels of Ammonia Impair the NO/cGMP Through Alterations of Cellular Transporters~!

In other blogs, I have suggested that alterations in the NO/cGMP pathway by environmental factors may influence environmental disease including CFS and MCS. Several recent studies have suggested a relationship between the NO/cGMP pathway and the activation of the Nrf2. Because the Nrf2 has a neuroprotective role on astrocytes and neurons, the failure of this pathway could contribute to neurological damage commonly associated with aging as well as, other neurological disorders. In this most recent study, the author provides more evidence that in cases of hyperammonemia, the No/cGMP pathway activity is decreased and therefore, may provide some explanation for damage resulting from high ammonia levels.

"reduced delivery of Arg due to enhanced y(+)LAT2-mediated exchange of extracellular Gln for intracellular Arg may contribute to the decrease of NO/cGMP pathway activity evoked in the brain by HA."

Zielińska, M., Ruszkiewicz, J., Hilgier, W., Fręśko, I., and Albrecht, J. (2010). Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y(+)LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochemistry international. http://www.citeulike.org/user/HEIRS/article/8341074
Sidoryk-Wegrzynowicz, M., Wegrzynowicz, M., Lee, E., Bowman, A., and Aschner, M. (2010). Role of Astrocytes in Brain Function and Disease. Toxicologic pathology.  http://www.citeulike.org/user/HEIRS/article/8341171

Blueberry Shows Potential Benefits Against Hepatic Fibrosis~!

"Blueberry can significantly inhibit the proliferation and activation of HSC and reduce the synthesis of extra-cellular matrix. It may have potential preventive and protective effects on hepatic fibrosis. The mechanism may be related to an elevated expression of HO-1 through the Nrf2 pathway."

CiteULike: [Effects of blueberry on the proliferation and activation of hepatic stellate cell and its mechanism.]:

The role of the antioxidant and longevity-promotin... [Curr Opin Clin Nutr Metab Care. 2010] - PubMed result

The role of the antioxidant and longevity-promotin... [Curr Opin Clin Nutr Metab Care. 2010] - PubMed result: "The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation."

Broccoli Compound Activates Heat Shock Proteins in Addition to Nrf2

"heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection."

Read more: CiteULike: Sulforaphane Activates Heat Shock Response and Enhances Proteasome Activity through Up-regulation of Hsp27:

Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and by disease processes.

CiteULike: Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and by disease processes.: "the emerging importance of master regulators of antioxidant defences such as Nrf2 and PGC-1α is revealing ways by which intrinsic defences may be manipulated to combat oxidative/nitrosative stress."

The nrf2 system as a potential target for the development of indirect antioxidants.

"critical role of Nrf2 has been demonstrated by various animal studies showing that mice with a targeted disruption of the nrf2 gene are prone to develop lesions in response to environmental toxicants/carcinogens, drugs, and inflammatory insults"

Read more: CiteULike: The nrf2 system as a potential target for the development of indirect antioxidants.:

The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics.

"Transcription factor Nrf2 regulates genes encoding drug-metabolising enzymes and drug transporters, as well as enzymes involved in the glutathione, thioredoxin and peroxiredoxin antioxidant pathways......."

Read more: CiteULike: The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics

Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity

"primary mouse hepatocytes extracted from Nrf2-deficient mouse was susceptible, and hepatocyte-specific conditional Keap1-deficient mouse was resistant to MeHg-induced cytotoxicity"

Read more: CiteULike: Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity:

Nrf2, HSP90 and CFS - More Evidence of Increased Risk w Certain Ancestries~!

Backgound: In recent weeks we have discussed many health problems that may occur with impaired Nrf2 functioning. Past studies have also suggested that SNPs in Nrf2 which may be population specific and may increase oxidative stress in those individuals. One such SNP has been shown to be present in the Native American population and another study has suggested that while the data is limited there seems to be a significantly higher risk of chronic fatigue syndrome in Native Americans and African-Americans. It has also be suggested that HSP90 activity may be used as a marker for CFS in a past study.

Niture from the University of Maryland demonstrates that HSP90 is involved in the activity of the Nrf2. He writes that Keap1 is an adaptor for Nrf2 and that HSP90 is a stabilizer for Keap1 under stress. He reports that HSP90 interacts with this adaptor to activate Nrf2. This suggests that Nrf2 activity may be closely associated with the development of CFS and leads one to assume that mechanisms that improve the activity of Nrf2 may be beneficial for therapeutics for CFS which may have a higher incidence rate for individuals with specific ancestries.  

Read more: HSP90


Thambirajah, A. A., Sleigh, K., Stiver, H. G., and Chow, A. W. (2008). Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Clinical and investigative medicine. Médecine clinique et experimentale, 31(6). http://www.citeulike.org/user/HEIRS/article/3725342
Niture, S. K. and Jaiswal, A. K. (2010). Hsp90 interaction with inrf2 (keap1) mediates stress-induced nrf2 activation. The Journal of biological chemistry. http://www.citeulike.org/user/HEIRS/article/7968348
Dinos, S., Khoshaba, B., Ashby, D., White, P. D. D., Nazroo, J., Wessely, S., and Bhui, K. S. S. (2009). A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. International journal of epidemiology. http://www.citeulike.org/group/6033/article/4289419

Characterization of Developmental neurotoxicity of As, Cd and Pb mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions — Toxicol Sci

: "together, these observations are the first to show that mixture of As, Cd and Pb has the capacity to induce synergistic toxicity in astrocytes that may compromise the BBB, and may cause behaviroal dysfunction in developing rats."


Read more: Characterization of Developmental neurotoxicity of As, Cd and Pb mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions — Toxicol Sci

SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity

SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity

Mycotoxin Downregulates Nrf2 -Causes Brain Oxidative Stress

CiteULike: Brain oxidative stress after dermal and subcutaneous exposure of T-2 toxin in mice.: "T-2 toxin exposure resulted in down regulation of transcription factor Nrf2 and its downstream target genes of phase II detoxifying enzymes NQO1, Gclc, Gclm and hemeoxygenase-1. Results of our study show that percutaneously and subcutaneously applied T-2 toxin can cause brain oxidative damage possibly after crossing blood-brain barrier by altering its permeability."

Nrf2 and DJ1 are consistently upregulated in inflammation in MS

Nrf2 and DJ1 are consistently upregulated in infla... [Free Radic Biol Med. 2010] - PubMed result: "our findings suggest that persistent Nrf2-mediated transcription occurs in active MS lesions, but that this endogenous response is insufficient to prevent ROS-induced cellular damage, which is abundant in inflammatory MS lesions."

Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation

Seems to me that the findings from this author are pretty important....:)

"up-regulation of HO-1 in astrocytes is associated with down-regulation of iNOS expression and thereby NO production, an effect that involves the p38 MAPK signaling pathway, which suggests that this glial cell response could play an important protective role against oxidative stress in the brain."

"Sheng, W., Hu, S., Nettles, A., Lokensgard, J., Vercellotti, G., and Rock, R. (2010). Hemin inhibits no production by il-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 mapk activation. Journal of Neuroinflammation, 7(1):51+."

Read more: CiteULike: Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation:

Cell signaling mediated by nitrated cyclic guanine nucleotide.

"8-Nitro-cGMP activated the Nrf2 signaling pathway by triggering dissociation of Keap1, via S-guanylation of its highly nucleophilic cysteine sulfhydryls. We also determined that S-guanylation of Keap1 was involved in cytoprotective actions of NO and 8-nitro-cGMP by inducing oxidative stress response genes such as heme oxygenase-1"


Read more: CiteULike: Cell signaling mediated by nitrated cyclic guanine nucleotide.:

Meth Labs, Wood Treatments, Pesticides and Ammonia Toxicity on Astrocytes~!

Astrocytes: (astroglia) : are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a principal role in the repair and scarring process of the brain and spinal cord following traumatic injuries. (Wipedia: Astrocytes)

This study would suggest that any condition that impairs the antioxidant system which has a primary role in protecting astrocytes against damage (ie Nrf2)  would augment the toxicity of ammonia whether it be produced endogenously or from exogenous exposures. Young children, the elderly and those with impaired immune systems would also be more at risk. Products that contain ammonia or have it as an "inert" ingredient or exposures from hazardous environments such as methamphetamine labs pose an elevated risk for the above populations because they would be more susceptible to ammonia toxicity.

"This study demonstrated that in rats with HA or HE ammonia specifically promote GSH synthesis and export from astrocytes and increase its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity."

Hilgier, W., Wegrzynowicz, M., Ruszkiewicz, J., Oja, S. S., Saransaari, P., and Albrecht, J. (2010). Direct exposure to ammonia and hyperammonemia increase the extracellular accumulation and degradation of astroglia-derived glutathione in the rat prefrontal cortex. Toxicological sciences : an official journal of the Society of Toxicology, 117(1):163-168. http://www.citeulike.org/user/HEIRS/article/7292948?show_msg=already_posted
 
 

Positive correlation between PPAR{gamma}/PGC-1{alp... [Acta Biochim Biophys Sin (Shanghai). 2010] - PubMed result

Comment: Recent studies suggest Nrf2 may regulate to PPAR-gamma to a degree.

"activation of the PPARgamma/PGC-1alpha pathway may protect against COPD progression by upregulating gamma-GCS and relieving oxidative stress."

Read more: Positive correlation between PPAR{gamma}/PGC-1{alp... [Acta Biochim Biophys Sin (Shanghai). 2010] - PubMed result: