Punicalagin Induces Nrf2HO-1 Expression via Upregulation of PI3KAKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages

Abstract EN

Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in potentiating macrophage activation, causing excessive inflammation, tissue damage, and sepsis.

Recently, we have shown that punicalagin (PUN) exhibits anti-inflammatory activity in LPS-stimulated macrophages.

However, the potential antioxidant effects of PUN in macrophages remain unclear.

Revealing these effects will help understand the mechanism underlying its ability to inhibit excessive macrophage activation.

Hemeoxygenase-1 (HO-1) exhibits antioxidant activity in macrophages.

Therefore, we hypothesized that HO-1 is a potential target of PUN and tried to reveal its antioxidant mechanism.

Here, PUN treatment increased HO-1 expression together with its upstream mediator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2).

However, specific inhibition of Nrf2 by brusatol (a specific Nrf2 inhibitor) dramatically blocked PUN-induced HO-1 expression.

Previous research has demonstrated that the PI3K/Akt pathway plays a critical role in modulating Nrf2/HO-1 protein expression as an upstream signaling molecule.

Here, LY294002, a specific PI3K/Akt inhibitor, suppressed PUN-induced HO-1 expression and led to ROS accumulation in macrophages.

Furthermore, PUN inhibited LPS-induced oxidative stress in macrophages by reducing ROS and NO generation and increasing superoxide dismutase (SOD) 1 mRNA expression.

These findings provide new perspectives for novel therapeutic approaches using antioxidant medicines and compounds against oxidative stress and excessive inflammatory diseases including tissue damage, sepsis, and endotoxemic shock.