Polyphenols have unique cellular effects that are distinct from antioxidant function in Toll-like receptor 4–mediated inflammation in RAW264.7 macrophage-like cells

Plant polyphenols are bioactive compounds touted for their antioxidant effects, and this is often the primary attribute used to explain their health benefits. However, we hypothesize that polyphenols have molecular properties independent of antioxidant function. The objective of this study was to investigate whether polyphenols had distinct molecular effects compared to pure antioxidants. RAW 264.7 macrophages were pretreated with either TEMPOL, a superoxide scavenger, N-acetyl cysteine, a hydroxyl radical and hydrogen peroxide scavenger, or polyphenol extracts from blackberry, blueberry, raspberry, strawberry, kale, and baru nut. After 1 hour of pretreatment, cells were treated with lipopolysaccharides (100 ng/mL) for an additional 6 hour. Antioxidants and polyphenol extracts elicited antioxidant effects in vitro; however, polyphenols regulated redox proteins in a distinct, protective manner, whereas antioxidants, TEMPOL, and N-acetyl cysteine, did not. Additionally, distinct effects were observed in downstream Toll-like receptor 4 signaling and transcriptional activity of inflammatory proteins. We conclude that polyphenols have unique molecular effects that are independent of just their free radical scavenging capacity. This work advances our molecular understanding of how polyphenols act to target inflammation.