Feng Zhang1, Yan Hu2, Xiaomei Xu2, Xiaohan Zhai2, Guangzhi Wang1, Shili Ning1, Jihong Yao2, Xiaofeng Tian3. 1. Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China. 2. Department of Pharmacology, Dalian Medical University, Dalian, China. 3. Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address: txfdl@hotmail.com.
Abstract
BACKGROUND: This study investigated the role of Sirtuin 1 (SIRT1)/forkhead box O3 (FOXO3) pathway, and a possible protective function for Icariin (ICA), in intestinal ischemia-reperfusion (I/R) injury and hypoxia-reoxygenation (H/R) injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were pretreated with different doses of ICA (30 and 60 mg/kg) or olive oil as control 1 h before intestinal I/R. Caco-2 cells were pretreated with different concentrations of ICA (25, 50, and 100 μg/mL) and then subjected to H/R-induced injury. RESULTS: The in vivo results demonstrated that ICA pretreatment significantly improved I/R-induced tissue damage and decreased serum tumor necrosis factor α and interleukin-6 levels. Changes of manganese superoxide dismutase, Bcl-2, and Bim were also reversed by ICA, and apoptosis was reduced. Importantly, the protective effects of ICA were positively associated with SIRT1 activation. Increased SIRT1 expression, as well as decreased acetylated FOXO3 expression, was observed in Caco-2 cells pretreated with ICA. Additionally, the protective effects of ICA were abrogated in the presence of SIRT1 inhibitor nicotinamide. This suggests that ICA exerts a protective effect upon H/R injury through activation of SIRT1/FOXO3 signaling pathway. Accordingly, the SIRT1 activator resveratrol achieved a similar protective effect as ICA on H/R injury, whereas cellular damage resulting from H/R was exacerbated by SIRT1 knockdown and nicotinamide. CONCLUSIONS: SIRT1, activated by ICA, protects intestinal epithelial cells from I/R injury by inducing FOXO3 deacetylation both in vivo and in vitro These findings suggest that the SIRT1/FOXO3 pathway can be a target for therapeutic approaches intended to minimize injury resulting from intestinal dysfunction.
BACKGROUND: This study investigated the role of Sirtuin 1 (SIRT1)/forkhead box O3 (FOXO3) pathway, and a possible protective function for Icariin (ICA), in intestinal ischemia-reperfusion (I/R) injury and hypoxia-reoxygenation (H/R) injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were pretreated with different doses of ICA (30 and 60 mg/kg) or olive oil as control 1 h before intestinal I/R. Caco-2 cells were pretreated with different concentrations of ICA (25, 50, and 100 μg/mL) and then subjected to H/R-induced injury. RESULTS: The in vivo results demonstrated that ICA pretreatment significantly improved I/R-induced tissue damage and decreased serum tumor necrosis factor α and interleukin-6 levels. Changes of manganese superoxide dismutase, Bcl-2, and Bim were also reversed by ICA, and apoptosis was reduced. Importantly, the protective effects of ICA were positively associated with SIRT1 activation. Increased SIRT1 expression, as well as decreased acetylated FOXO3 expression, was observed in Caco-2 cells pretreated with ICA. Additionally, the protective effects of ICA were abrogated in the presence of SIRT1 inhibitor nicotinamide. This suggests that ICA exerts a protective effect upon H/R injury through activation of SIRT1/FOXO3 signaling pathway. Accordingly, the SIRT1 activator resveratrol achieved a similar protective effect as ICA on H/R injury, whereas cellular damage resulting from H/R was exacerbated by SIRT1 knockdown and nicotinamide. CONCLUSIONS:SIRT1, activated by ICA, protects intestinal epithelial cells from I/R injury by inducing FOXO3 deacetylation both in vivo and in vitro These findings suggest that the SIRT1/FOXO3 pathway can be a target for therapeutic approaches intended to minimize injury resulting from intestinal dysfunction.
Authors: Laura W Hansen; Adam Khader; Weng-Lang Yang; Jose M Prince; Jeffrey M Nicastro; Gene F Coppa; Ping Wang Journal: Shock Date: 2016-04 Impact factor: 3.454