Isothiocyanate-Rich Moringa Seed Extract Activates SKN-1/Nrf2 Pathway in Caenorhabditis elegans

<i>Moringa oleifera</i> is a tropical tree that has its leaves, fruits, and seeds used as medicine and food. A standardized hydroalcoholic moringa seed extract (MSE) contains up to 40% of an isothiocyanate (MIC-1; moringin), a phytochemical known to have antioxidant and anti-inflammatory properties. Animal studies suggest that MSE may help with diseases, such as edema, colitis, obesity, and diabetes. In vitro studies have shown that MIC-1 activates the Nrf2 pathway, involved in detoxification and antioxidant pathways. To broaden the understanding of the molecular pathways regulated by MSE, we hypothesized that MSE improves the health span in <i>Caenorhabditis elegans</i> by activating the Nrf2 homolog (SKN-1). Our whole RNA-seq data showed that MSE at 0.1 mg/mL (100 µM MIC-1) regulated the expression of a total of 1555 genes, including genes related to <i>C. elegans</i> cuticle, molting cycle, and glutathione metabolism. MSE upregulated several glutathione S transferases (GST), involved in the detoxification of xenobiotics, and other SKN-1 downstream targets. MSE and MIC-1 upregulate <i>skn-1</i> expression and induce SKN-1 nuclear translocation, suggesting that they activate the SKN-1/Nrf2 pathway. Moreover, the regulation of glutathione metabolism is likely dependent on the SKN-1 pathway, as the <i>gst-4</i> upregulation by MSE was inhibited in <i>skn-1</i> knockout mutant. However, MSE decreased survivability and delayed growth rate, while purified MIC-1 increased the lifespan of <i>C. elegans</i>. This study shows that MIC-1 is responsible for SKN-1/Nrf2 activation by MSE; however, components other than MIC-1 within MSE likely cause detrimental effects in <i>C. elegans</i>.