Yumi Abiko

Humans are exposed to environmental heavy metals such as methylmercury, manganese, cobalt, cadmium and arsenic throughout their lifespan. A growing body of evidence has demonstrated strong associations between environmental pollutants and human health. Redox toxicity is considered to be one of the main mechanisms of chemical-induced pathology. The nuclear factor erythroid 2-related factor 2 (NRF2) has attracted much attention as a sensor of oxidative stress and a positive regulator of antioxidants in recent years. However, the role of NRF2 in the environmental heavy metal toxicity has not been systematically investigated. Here, we summarize the function of NRF2 in response to environmental heavy metals and its regulation through KEAP1-dependent and KEAP1-independent pathways. Finally, we shed light on the epigenetic regulation of NRF2, including DNA methylation, histone acetylation, noncoding RNAs and N6-methyladenosine modification. In brief, alterations in NRF2 upon exposure to environmental heavy metals are regulated by both genetic and epigenetic aspects, and, in turn, may participate in the etiology of various diseases.

Graphical Intake of a variety of vegetables and fruit is found to be effective in promoting health; one of the reasons for this is activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper protein. Nrf2 is activated by chemical modification of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator for this transcription factor, and specific phosphorylation of Nrf2, resulting in upregulation of its downstream gene products for antioxidant proteins, phase-II xenobiotic-metabolizing enzymes, and phase-III transporters. This type of activation plays a role in adaptive response and protection against oxidative and electrophilic stress. Multiple phytochemicals, such as curcumin, sulforaphane, and (E)-2-alkenals, have been identified as Nrf2 activators and may reduce the adverse health effects of oxidants and electrophiles. In this review, we introduce plant components that are known as Nrf2 activators and associated phytochemical-mediated reduction of risk from chemicals which cause oxidative and electrophilic stress. We also discuss the capture and inactivation of methylmercury, an electrophile, by sulfane sulfur atoms contained in garlic.

Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO_1-3H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO₃H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.