Acute Oxidative Stress Can Paradoxically Suppress Human NRF2 Protein Synthesis by Inhibiting Global Protein Translation.

The NRF2 transcription factor is a master regulator of the cellular oxidant/electrophile response and a drug target for the prevention/treatment of chronic diseases. A major mechanism of NRF2 activation is its escape from rapid degradation, and newly synthesized NRF2 induces cytoprotective protein expression through its cognate antioxidant response elements (AREs). However, oxidative stress can also inhibit global protein translation, thereby potentially inhibiting NRF2 protein accumulation.

Solving the Problem of Assessing Synergy and Antagonism for Non-Traditional Dosing Curve Compounds Using the DE/ZI Method: Application to Nrf2 Activators.

Multi-drug combination therapy carries significant promise for pharmacological intervention, primarily better efficacy with less toxicity and fewer side effects. However, the field lacks methodology to assess synergistic or antagonistic interactions for drugs with non-traditional dose response curves. Specifically, our goal was to assess small-molecule modulators of antioxidant response element (ARE)-driven gene expression, which is largely regulated by the Nrf2 transcription factor.