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Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in potentiate macrophages activation, causing excessive inflammation, tissue damage and sepsis.Our recent study has showed that Punicalagin (PUN) exhibits anti-inflammatory activity in Lipopolysaccharide (LPS)-stimulated macrophages.However,the potential anti-oxidant effects of PUN in macrophages remained unclear, revealing which will help understanding the mechanism underlying its properties inhibiting excessive macrophages activation.Hemeoxygenase—1 (HO—1) is reported to exhibit anti-oxidant activity in macrophages.Therefore,we hypothesized HO—1 as a potential target of PUN and tried to reveal its anti-oxidant mechanism in macrophages.Results demonstrated 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 demonstrated that PI3K/Akt pathway plays a critical role in the modulation of Nrf2/HO—1 protein expression as a upstream signaling molecular.In this study,via employing LY294002 (a specific PI3K/Akt inhibitor) and insulin (a PI3K/Akt activator),we found that inhibition of PI3K/ Akt signaling suppressed PUN-induced HO—1 expression and led to ROS accumulation in macrophages.In addition,we found PUN inhibited LPS—induced macrophages oxidative stress by reducing ROS generation,mediating superoxide dismutase (SOD) 1 mRNA expression and Nrf2/ HO—1 pathway participated in this inhibitory effect.These findings provide new perspectives for novel therapeutic approaches using anti-oxidant medicines and compounds for oxidative stress and excessive inflammatory diseases including tissue damage,sepsis and endotoxemic shock.