Non-Electrophilic NRF2 ActivatorsPromote Wound Healingin Human KeratinocytesandDiabetic Miceand DemonstrateSelectiveDownstreamGene Targeting

ABSTRACT: The transcription factor NRF2 plays an important role in many biological processes and is a promising therapeutic target. NRF2 is highly expressed in the skin and is known to play a critical role in diabetic wound healing, a disease state with limited treatment options. However, many existing NRF2 activators display off-target effects due to their electrophilic mechanism, underscoring the need for alternative approaches. In this work, we investigated two recently described, non-electrophilic NRF2 activators, ADJ-310 and PRL-295, and demonstrated their efficacy in vitro and in vivo. Both ADJ-310 and PRL-295 maintained human keratinocyte cell viability at increasing concentrations and maintained or improved cell proliferation over time. Both compounds also increased cell migration, improving in vitro wound closure. ADJ-310 and PRL-295 enhanced the oxidative stress response in vitro, and RNA-sequencing data showed that PRL-295 activated NRF2 with a narrower transcriptomic effect than the widely used electrophilic NRF2 activator, CDDO-Me. In vivo, both ADJ-310 and PRL-295 improved wound healing in Leprdb/db diabetic mice. The non-electrophilic compounds ADJ-310 and PRL-295 are effective, innovative tools for the investigation of the function of NRF2 that directly address the need for alternative NRF2 activators. They offer a new approach to studying the role of NRF2 in human diseases and its potential as a therapeutic. Both non-electrophilic NRF2 activators promoted wound healing functions in human keratinocytes and improved wound healing in diabetic mice, demonstrating their efficacy both in vitro and in vivo. RNA sequencing showed that PRL-295 upregulated downstream target genes that favorably compared with those of CDDO-Me.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241267 | GEO | 2023/08/23

REPOSITORIES: GEO