Wang, Rui, Paul, Valerie J., and Luesch, Hendrik. 2013. "Seaweed extracts and unsaturated fatty acid constituents from the green alga Ulva lactuca as activators of the cytoprotective Nrf2-ARE pathway." Free Radical Biology and Medicine 57:141-153. https://doi.org/10.1016/j.freeradbiomed.2012.12.019
Increased amounts of reactive oxygen species (ROS) have been implicated inmany pathological conditions, including cancer. The major machinery that the cell employs to neutralize excess ROS is through the activation of the antioxidant response element (ARE) that controls the activation of many phase II detoxification enzymes. The transcriptional factor that recognizes the ARE,Nrf2, can be activated by a variety of small molecules, most of which contain an α,β-unsaturated carbonyl system. In the pursuit of chemopreventive agents from marine organisms, we built, fractionated, and screened a library of thirtyfield-collected eukaryotic algae from Florida. Anedible green alga, Ulva lactuca, yielded multiple active fractions by ARE-luciferase reporter assay. We isolated three monounsaturated fatty acid (MUFA) derivativesas active components, including a new keto-type C18 fatty acid (1), the corresponding shorter chain C16 acid (2), and an amide derivative (3) of the C18 acid.Their chemical structures were elucidatedby NMR and mass spectrometry. All three contain the conjugated enone motif between C7–C9, which is thought to be responsible for the ARE activity.Subsequent biological studies focused on C18 acid(1), the most active and abundant ARE activator isolated. C18 acid (1) induced the expression of ARE-regulated cytoprotective genes, including NAD(P)H:quinoneoxidoreductase 1 (NQO1), hemeoxygenase 1 (HO1), thioredoxinreductase 1 (TXNRD1), both subunits of the glutamate-cysteine ligase (GCLC, catalytic subunit and GCLM, modifier subunit), and cystine/glutamate exchange transporter (SLC7A11),in IMR-32 human neuroblastoma cells. Its cellular activity requires the presence of Nrf2 and PI3K function, based on RNA interference and pharmacological inhibitor studies, respectively. Treatment with C18 acid (1) only led to Nrf2 activation, but not the increase in production of NRF2mRNA. To test its ARE activity and cytoprotective potential in vivo, we treated mice with a single dose of an U. lactucafraction that was enriched with C18 acid (1), which showed similar ARE-activating effects as observed in vitro. This could be owing to this fraction's ability to stabilize Nrf2 through inhibition of Keap1-mediated Nrf2 ubiquitination and the subsequent accumulation and nuclear translocation of Nrf2. The induction of many ARE-driven antioxidant genes in vivoand most prominently in the heart agreed with the commonly recognized cardioprotective properties of MUFAs. A significant increase in Nqo1 transcript levels was also found in other mouse tissues such as the brain, lung, and stomach. Collectively, this study provides new insight as to why consumption of dietary seaweed may have health benefits, and the identified compounds add to the list of chemopreventive dietary unsaturated fatty acids.