Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages

• Published in: Mediators of Inflammation Vol. 2015; no. 2015; pp. 705 - 715-167
• Main Authors: Xu, Jianqin, Liu, Fenghua, Yin, Peng, Wan, Changrong, He, Shasha, Li, Deyin, Hou, Xiaolin, Li, Hongquan, Xu, Xiaolong, Liu, Mingjiang
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Limiteds 01.01.2015; Hindawi Publishing Corporation; Hindawi Limited; Wiley
• Subjects: Agriculture; Animal sciences; Antioxidants; Cell Line; Cytokines; Defense mechanisms; Enzymes; Free radicals; Gene expression; Genetic aspects; Genetic regulation; Health aspects; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Hydrolyzable Tannins - pharmacology; Inflammation; Kinases; Macrophages; Macrophages - drug effects; Macrophages - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Observations; Oxidative stress; Oxidative Stress - drug effects; Phenols; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Polyphenols; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Studies; Tumor necrosis factor-TNF; Veterinary medicine; Zoology
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2015/380218

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.