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Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the “redox modulatory site.”33 Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone. Src kinase enhances NMDA receptor currents.34 Reelin modulates NMDA function through Src family kinases and DAB1,35 significantly enhancing LTP in the hippocampus. CDK5 regulates the amount of NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.36,37
Clinical Effects of Pollution
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 5, 2017
William J. Rea, Kalpana D. Patel
SRC kinase enhances NMDA receptor currents.125 Reelin modulates NMDA function through Src family kinases and DAB1,126 significantly enhancing LTP in the hippocampus. CDK5 regulates the amount of NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.127,128
Epigenetic modifications associated with pathophysiological effects of lead exposure
Published in Journal of Environmental Science and Health, Part C, 2019
Madiha Khalid, Mohammad Abdollahi
Tauopathy belongs to a class of neurodegenerative diseases characterized by high levels of tau proteins in the brain, though an appropriate amount of tau proteins is required for stabilizing microtubules.236 Several animal studies have reported the risks of tauopathies associated with developmental Pb exposure via inducing tau phosphorylation and aberrant miRNAs expression.75,237,238 Postnatal 0.2% Pb exposure in transgenic mice carrying human tau gene showed hyperphosphorylated internal and external brain capsules along phosphorylated tau at sites Ser396 protein at PND20/30 (P < 0.001), increased total tau protein at PND20/40 (P = 0.01) and cyclin-dependent kinase 5 (CDK5) protein at PND40/60 (P < 0.001). Increased miR-34c expression was observed between PND20/50 (P = 0.037).237 Similarly, in another study with the same postnatal 0.2% Pb exposure level in mice demonstrated varied miRNAs expression levels over time. At PND20, transient increase in miR-106b (1.5fold) was found unsustainable while, a significant decrease in miR-34c (1.6fold) was found to be sustainable throughout animal life. Moreover, decreased expression of miR-124 was observed at PND700 (2fold), while increased expression was observed of miR-29b at PND20 (1.6fold).76 Among miRNAs whose expression changed with exposure to Pb, miR-34c is known to target microtubule-associated protein tau (MAPT) mRNA and tends to downregulate its expression,239 miR-106b is known to regulate APP expression during brain development and neuronal differentiation and its decreased expression was reported among AD patients76,240 and both miR-124 and -29 b are known to target Sp1 mRNA.76 Overexpression of miR-29b is linked to a significant reduction in DNMT1/3A/3B. It suppresses cell proliferation via targeting Sp1 and PTEN-AKT signaling pathways.241–245 Moreover, significantly increased Sp1 mRNA levels among AD patients have been reported.246 Another miRNA sensitive to Pb exposure, miR-148a, is known to regulate DNMT1 expression.247,248 miR-132 targets MeCP2 mRNA and its downregulation will cause a translational block on MeCP2, which has a pivotal role in normal nerve cell function.249,250 Aforementioned evidence suggests that Pb is capable of inducing aberrant expression of different miRNAs, thereby negatively affecting tight regulations between epigenetic mechanisms, disrupting normal expression of tau protein, and contributing to tauopathies.