<p>A pathway to activate the <i>iNOS</i> gene and the action of FRLFE are schematically depicted. The bold arrows indicate the decreases caused by FRLFE in this study. The proinflammatory cytokine IL-1β binds to its receptor (type I IL-1 receptor, IL1R1) to activate NF-κB through the IκB kinase (IKK) signaling pathway <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093818#pone.0093818-Takimoto1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093818#pone.0093818-Lawrence1" target="_blank">[25]</a>. Activated IKK phosphorylates IκB-α, resulting in the degradation of IκB-α. A circled P denotes protein phosphorylation. Active NF-κB enters into the nucleus, binds to the <i>iNOS</i> gene promoter (κB sites), and activates transcription. FRLFE inhibits the phosphorylation of IκB-α and the nuclear translocation of NF-κB, resulting in a decrease in the nuclear levels of NF-κB. Because NF-κB also regulates the transcription of the iNOS asRNA, FRLFE reduces the level of iNOS asRNA, which interacts with and stabilizes the iNOS mRNA <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093818#pone.0093818-Matsui1" target="_blank">[17]</a>. Furthermore, FRLFE may interfere with the iNOS mRNA–asRNA interaction at a posttranscriptional level. Therefore, FRLFE significantly decreases the level of iNOS mRNA.</p
