Nrf2: A central regulator of UV protection in the epidermis

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

“…NRF2 is constitutively expressed in keratinocytes of normal skin and is upregulated upon wounding and exposure to electrophiles (33). Following UVB irradiation, NRF2 activates the production and export of GSH by suprabasal keratinocytes, which subsequently protect basal keratinocytes in a paracrine manner (34). We show here that the loss of Krt16, whose expression in glabrous skin is normally limited to the suprabasal compartment, selectively affects GSH production.…”

“…Taken together, these findings imply that K16, whose expression can be stimulated by TGF-β in cultured keratinocytes (35), may be involved in a complex signaling network involving TGF-β, p21, RACK1, and NRF2 that ultimately affects redox balance in skin keratinocytes. The positive impact of K16 on TGF-β signaling may, under normal conditions, contribute to the suprabasal-to-basal gradient of NRF2 (and its target genes) brought to light by Schafer et al following UVB irradiation (34). This suggests that K16 is poised to be a key contributor to the unique cellular redox capabilities of the suprabasal compartment of epidermis in glabrous skin.…”

The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance

“…6,7 Genes regulated by Nrf2 have the capacity to prevent damage to DNA, proteins, and lipids and assist in the generation of new tissue. [8][9][10] Unlike in nonmalignant CD34 ϩ hematopoietic cells, Nrf2 is present in the nucleus of most patients with AML, where its pathway is primed for immediate activation, leading to cytoprotective and detoxification gene up-regulation in response to chemotherapeutic drugs, 2,11 and subsequently reduces apoptosis compared with AML cells with no nuclear Nrf2 expression.…”

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

“…An additional comprehensive understanding needs to be achieved regarding the way Nrf2-activating agents interact with normal and diseased cells [82]. Applying a topical dermal delivery system containing Nrf2-activating agents holds an additional rational; it was demonstrated that there is a gradient of Nrf2 expression and as a result higher ROS protection in higher epidermal layers than lower ones [12,234,235]. However, superbasal keratinocyte protection from ROS is crucial for maintaining skin integrity and homeostasis [12,235].…”

“…Applying a topical dermal delivery system containing Nrf2-activating agents holds an additional rational; it was demonstrated that there is a gradient of Nrf2 expression and as a result higher ROS protection in higher epidermal layers than lower ones [12,234,235]. However, superbasal keratinocyte protection from ROS is crucial for maintaining skin integrity and homeostasis [12,235]. Topical application of Nrf2-activating agents hopefully will supply an adequate solution resulting in activation of the Nrf2 pathway by exogenous and specific pharmacological intervention.…”