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Figure 3: Mechanisms underlying the biological effects of polyphenols. Polyphenols and their in vivo metabolites activate cellular stress-response pathways resulting in the upregulation of neuroprotective genes. For example, both PKC and ERK can activate the nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then translocates to the nucleus and binds to the antioxidant response element (ARE) in genes that encode cytoprotective proteins such as antioxidant enzymes (AOE) and phase 2 (Ph2) enzymes. The transcription factor cAMP-response-element-binding protein (CREB) is also activated by ERK, which induces the expression of brain-derived neurotrophic factor (BDNF), a mediator of neurohormesis. In addition, polyphenols can also regulate the transcription factor NF-κB, which can mediate adaptive cellular stress responses by reducing the expression of inflammatory cytokines. Activated SIRT1 may also inhibit NF-κB and so can reduce the cellular stress response. Another important pathway activated by metabolic and oxidative stress involves transcription factors of the forkhead (FoxO) family, which modulate genes that encode antioxidant enzymes and other stress-response proteins.