Mercury Induces Oxidative Stress, Altering Nrf2 Microglial~!

"Consistent with the nuclear translocation of Nrf2, quantitative real-time PCR revealed a concentration-dependent increase in the messenger RNA level of Ho-1, Nqo1, and xCT 30 min post MeHg exposure, whereas Nrf2 knockdown greatly reduced the upregulation of these genes. Furthermore, we observed increased microglial death upon Nrf2 knockdown by the small hairpin RNA approach. Taken together, our study has demonstrated that microglial cells are exquisitely sensitive to MeHg and respond rapidly to MeHg by upregulating the Nrf2-mediated antioxidant response."

CiteULike: Methylmercury Induces Acute Oxidative Stress, Altering Nrf2 Protein Level in Primary Microglial Cells:

HO/CO and NO Regulate Oxytocin - Anxiety and Autism Implications?

Considering the relationship of oxytocin to behaviors such as fear, aggression and attachment, this study may have significant implications for PTSD as well as social problems such as violence and neglect. Also, it presents a question of whether a decline in the antioxidant system may also positively or negatively have an influence because it regulates HO-1.

Blockade of HO inhibited both basal and osmotically stimulated OT release, and induced a marked increase in NOS activity. These results indicate the involvement of CO in the regulation of NOS activity. The present data demonstrate that hypothalamic OT release induced by osmotic stimuli is modulated, at least in part, by interactions between NO and CO.

CiteULike: Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro.: "Gomes, D. A. A., Giusti-Paiva, A., Ventura, R. R. R., Elias, L. L. K. L., Cunha, F. Q. Q., and Antunes-Rodrigues, J. (2010). Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro. Bioscience reports, 30(5):351-357."

Pathway Impairment that Regulates Stress Response Could Lead to A Variety of Environmental Diseases

A recent study determined that caffeine can be a preventative against some of the health effects in Parkinson's disease caused by pesticides. The following pathway is a good representation of the NO/cGMP pathway that is more than likely effected by caffeine in these conditions and can account for some of the locomoter problems in PD. As one can see, expression of other proteins including BDNF rely on its activity. In other blogs, we have noted that BDNF is altered in environmental illnesses including CFS and may account for mood changes that occur with the condition. Proper signaling of the NO/cGMP pathway is important for a number of health conditions because the pathways are consistently activated by a number of different xenobiotics and environmental cues.

Alterations in the functioning of Nrf2 and other conditions like excretory defects that increase ammonia levels with negatively impact this system. While NO is an important component of this pathway - the actual dysfunction is not related to peroxynitrite, although oxidative stress to some may increase dysfunction though loss of NO signalling. Madhusoodanan explains that in this case, "nitric oxide is a short lived free radical species synthesized by NOS. The physiological role of NO depends on its local concentration as wells as the availability of downstream targets. At low levels, activation of guanalyl cyclase is the major event by NO. The resulting elevation of cGMP serves as an regulator of many events." I suggest that many environmental diseases including CFS and MCS are probably due more to the impairments of NO/cGMP which is also negatively effected by endogenous gases including ammonia and the impairment of the system results in astrocyte damage. Because Nrf2 is also neuroprotective --- alterations in Nrf2 will contribute to neural injury. Also, cGMP inhibits the protein GSK-3b which is an off/on switch for Nrf2. Studies have demonstrated that Nrf2 regulates the antioxidant complexes of HO-1/CO which modulates CRF (which can be activated by odors) and CO activates cGMP. These pathways seem to strongly suggest that Nrf2 ultimately may influence the regulation of the stress response from environmental cues. In any case, HO-1/CO does modulate the CRF system which can be activated by response cytokines such as Il-1.

Recent studies show that increasing Nrf2 may be beneficial in limiting neural injury and in this case, I would say it probably would too. The article discusses hormetic responses that we have also discussed at length and as Mattson describes "recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors." This of course may act on activities involved in methylation.



Notes:

• Diabetes exacerbates functional deficiency of NO/cGMP in ED

Madhusoodanan, K. and Murad, F. (2007). No-cgmp signaling and regenerative medicine involving stem cells. Neurochemical Research, 32(4):681-694.
http://www.citeulike.org/user/HEIRS/article/1245237
Chan, M.-H., Chien, T.-H., Lee, P.-Y., and Chen, H.-H. (2004). Involvement of no/cgmp pathway in toluene-induced locomotor hyperactivity in female rats. Psychopharmacology, 176(3):435-439.
http://www.citeulike.org/user/HEIRS/article/7170771
van Staveren, W. (2001). The effects of phosphodiesterase inhibition on cyclic gmp and cyclic amp accumulation in the hippocampus of the rat. Brain Research, 888(2):275-286.
http://www.citeulike.org/user/HEIRS/article/7170748
Kachroo, A., Irizarry, M. C., and Schwarzschild, M. A. (2010). Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration. Experimental neurology, 223(2):657-661.
http://www.citeulike.org/user/HEIRS/article/6835294
Mattson, M. P., Son, T. G., and Camandola, S. (2007). Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose-response : a publication of International Hormesis Society, 5(3):174-186.
http://www.citeulike.org/user/HEIRS/article/3812627
Angulo, J., González-Corrochano, R., Cuevas, P., Fernández, A., Fuente, J. L. M., Rolo, F., Allona, A., and Sáenz de Tejada, I. (2009). Diabetes exacerbates the functional deficiency of no/cgmp pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. The journal of sexual medicine. http://www.citeulike.org/user/HEIRS/article/7170872

Yang, R., Wang, J., Chen, Y., Sun, Z., Wang, R., and Dai, Y. (2008). Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. J Androl, 29(5):586-591. http://www.citeulike.org/user/HEIRS/article/7170883
Nisoli, E. and Carruba, M. O. (2006). Nitric oxide and mitochondrial biogenesis. J Cell Sci, 119(14):2855-2862.http://www.citeulike.org/user/HEIRS/article/7170901