Oxidative stress and inflammation are common to many pathological conditions. Cellular defense mechanisms protect oxidative stress, but can become overwhelmed following injury and inflammation. NF-κB and Nrf2 are major transcription factors that are involved in regulating proinflammatory and antioxidant genes, respectively. Currently, numerous studies have shown that many natural dietary compounds can potently modulate various molecular targets, leading to prevention of inflammation and oxidative stress via regulation of NF-κB and Nrf2.
In the first study, we evaluated the therapeutic potential of Prunella vulgaris var. lilacina (Pru) to improve oxidative stress and inflammation.
A Pru extract examined for its abilities to scavenge free radicals and inhibit inflammatory reactions. The Pru extract showed significantly inhibit the free radical production. And Pru extract also exhibited high anti-inflammatory activities, inducing inhibition of nitric oxide and prostaglandin E2 production as well as inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α mRNA expression in response to lipopolysaccharide stimulation. Moreover, the Pru extract significantly inhibited the production of ROS. In summary, Pru extract possessed pharmacological activity and might be useful for developing antioxidant or anti-inflammatory agents.
Recent evidence has suggested crosstalk between NF-κB and Nrf2 under oxidative stress. These two pathways are proposed to inhibit each other at their transcription level via protein-protein interactions or through secondary messenger effects. However, definitive evidence of direct Nrf2 inhibition of NF-κB signaling has not yet been explored. Therefore, in second study, we examined that whether Nrf2 inhibited NF-κB signaling directly or another molecules were involved in interaction of two pathways. As a results, we identified MafK, a novel transcriptional regulator that modulates NF-κB activity MafK knockdown reduced NF-κB activation, whereas MafK overexpression enhanced NF-κB function. MafK mediated p65 acetylation by CBP upon LPS stimulation, thereby facilitating recruitment of p65 to NF-κB promoters such as IL-8 and TNFα. And we also observed MafK-depleted mice showed prolonged survival with a reduced hepatic inflammatory response after LPS and D-GalN injection. Thus, our findings reveal a novel mechanism by which MafK controls NF-κB activity via CBP-mediated p65 acetylation.
Besides, in the third study, since Pru extract has antioxidant, anti-inflammatory activities, we confirmed an influence on the MafK expression by major compounds(rosmarinic acid, oleanolic acid, ursolic acid and caffeic acid) of Pru extract. As a result, oleanolic acid significantly decreased the MafK expression, and decreased MafK-mediated p65 acetylation.
Taken together, we identify the role of MafK as a novel modulator for the NF-κB via CBP-mediated p65 acetylation in vitro and in vivo. We also reveal the natural material "Prunella vulgaris var. lilacina" as a MafK modulator. Thus, these findings suggest potential therapeutic applications of the NF-κB pathway, and NF-κB inhibitors are promising drug candidates for the treatment of oxidative stress-induced diseases.