title: Punicalagin Induces Nrf2/HO-1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS-Induced Oxidative Stress in RAW264.7 Macrophages.
abstract: 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.
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Xu
authors.affiliation: College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Li
authors.affiliation: College of Animal Science and Technology, Beijing University of Agriculture (BUA), Beijing 102206, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hou
authors.affiliation: College of Animal Science and Technology, Beijing University of Agriculture (BUA), Beijing 102206, China.
authors.forename: Deyin
authors.initials: D
authors.lastname: Li
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: He
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Changrong
authors.initials: C
authors.lastname: Wan
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Peng
authors.identifier: 0000-0002-9824-4964
authors.initials: P
authors.lastname: Yin
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Liu
authors.affiliation: College of Animal Science and Technology, Beijing University of Agriculture (BUA), Beijing 102206, China ; Beijing Key Laboratory for Dairy Cow Nutrition, Beijing 102206, China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Liu
authors.affiliation: CAU-BUA TCVM Teaching and Researching Team, College of Veterinary Medicine, China Agricultural University (CAU), No. 2 West Yuanmingyuan Road, Beijing 100193, China.
authors.forename: Jianqin
authors.identifier: 0000-0002-7941-573X
authors.initials: J
authors.lastname: Xu
mesh_terms: D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D047348:Hydrolyzable Tannins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C115642:punicalagin; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt