AI-3 is an Nrf2 activator. Users of Nrf2 activators report positive experiences.
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RESEARCH ARTICLE: (from pubmed.gov)
ACS Chem Biol. 2013 Aug 16;8(8):1764-74. doi: 10.1021/cb4000103. Epub 2013 Jun 17.
In vitro and in vivo characterization of a tunable dual-reactivity probe of the Nrf2-ARE pathway.
The cell utilizes the Keap1/Nrf2-ARE signaling pathway to detoxify harmful chemicals in order to protect itself from oxidative stress and to maintain its reducing environment. When exposed to oxidative stress and xenobiotic inducers, the redox sensitive Keap1 is covalently modified at specific cysteine residues. Consequently, the latent transcription factor Nrf2 is stabilized and translocates into the nucleus, where it transactivates the expression of detoxification genes through binding to the antioxidant response element (ARE). In the pursuit of potent and bioavailable activators of the ARE, we validated hits from a pathway-directed high-throughput screening campaign by testing them in cell culture and a reporter strain of a whole animal model, Caenorhabditis elegans. These studies allowed us to identify AI-3 as an ARE activator that induces cytoprotective genes in human cells and in worms, which also translated into in vivo activity in mice. AI-3 is an electrophilic ARE activator with two thiol sensitive sites toward a nucleophilic aromatic substitution, and SAR studies indicated the tunability of the system. Tandem LC-MS analysis revealed that AI-3 alkylates Keap1 primarily at Cys151, while AI-3 is reactive toward additional cysteine residues at higher doses in vitro and in vivo. The immediate effects of such alkylation included the disruption of Keap1-Cul3 (low [AI-3]) and/or Keap1-Nrf2 (high [AI-3]) interactions that both led to the stabilization of Nrf2. This further translated into the downstream Nrf2-ARE regulated cytoprotective gene activation. Collectively, AI-3 may become a valuable biological tool and may even provide therapeutic benefits in oxidative stress related diseases.
PMID: 23773140 [PubMed - indexed for MEDLINE] PMCID: PMC3753087 Free PMC Article
[INTERPRETATION: AI-3 is an antioxidant activator. When oxidative stress (cell damage) occurs, AI-3 causes Nrf2 to move to the cell nucleus and activate the body’s antioxidants to protect the cells. Nrf2 regulates activation of the genes that protect the body’s cells. It may be valuable for therapy for diseases related to cell damage caused by oxidants.]