Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor

Abstract

The discovery that nuclear factor erythroid 2-related factor 2 (Nrf2) undergoes translocational oscillations from cytoplasm to nucleus in human cells with frequency modulation linked to activation of a stress-stimulated cytoprotective response raises the prospect that the Nrf2 works mechanistically analogous to a wireless sensor. Herein, we consider how this new model of Nrf2 oscillation resolves previous inexplicable experimental findings on Nrf2 regulation and why it is fit-for-purpose. Further investigation is required to assess how generally applicable the oscillatory mechanism is and if characteristics of this regulatory control can be found in vivo. It suggests there are multiple, potentially re-enforcing receptors for Nrf2 activation, indicating that potent Nrf2 activation for improved health and treatment of disease may be achieved through combination of Nrf2 system stimulants.

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

“…Herein we found that tRES also induces expression of Glo1 with high E max . Our recent studies (7,8) and those of others (31) suggest that this is achieved by preventing nuclear acetylation and inactivation of Nrf2 via increasing in situ activity of sirtuin-1. At low tRES concentrations, this occurs through inhibition of cAMP phosphodiesterases, activation of AMPK, and increased NAD + .…”

“…Activation of Nrf2 by dietary bioactive compounds is mostly studied through ARE-linked induction of NQO1 or HMOX1 expression. Small-molecule activators of Nrf2 increase expression of different ARE-linked gene subsets (6,7)-likely due to the ability of Nrf2 activators to recruit the requisite accessory proteins and increase nuclear concentration of functionally active Nrf2 to the level required for increased expression of the ARE-linked gene of interest (7,8). A specific functional screen for GLO1-ARE transcriptional activation was therefore required.…”

“…2B), which is likely due to inhibitory nuclear acetylation of Nrf2 blocking a high E max . Combination with tRES and HESP provides for faster nuclear translocation and decreased inactivation of Nrf2 (7,8,31). Use of HESP rather than related dietary glycoside hesperidin found in citrus fruits (34) is likely crucial: HESP has ;70-fold greater potency in Nrf2 activation and higher bioavailability than hesperidin (35).…”

“…HESP may activate Nrf2 through induction and activation of protein kinase A, upstream of fyn kinase, which drives Nrf2 translocational oscillations and ARE-linked gene expression (8,33). HESP is a partial agonist (Fig.…”

“…We described a functional regulatory antioxidant response element (ARE) in human GLO1 with basal and inducible expression upregulated by transcriptional factor nuclear factor E2-related factor 2 (Nrf2). Recent advances in Nrf2 regulation suggested that potent induction of Glo1 expression could be achieved by a synergistic combination of Nrf2 activators addressing different regulatory features (7,8). In this study, we sought to screen dietary bioactive compounds for Glo1 inducer activity in a functional reporter assay, confirm hits in cell culture, and evaluate an optimized Glo1 inducer formulation in a randomized, placebo-controlled crossover clinical trial for improved metabolic and vascular health in overweight and obese subjects.…”