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Abstract
Purpose: To investigate the effect of FOXO4 on cerebral ischemia/reperfusion (CIR) injury and the underlying mechanism.Methods: An in vitro ischemia/reperfusion (IR) model was achieved using oxygen-glucose deprivation/reoxygenation (OGD/R). Expression of RNA and protein was determined using quantitative real time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell viability and apoptosis were determined using MTT assay and flow cytometry, respectively. Commercial kits were used to measure lactate dehydrogenase (LDH), reactive oxygen species (ROS), chloramphenicol acetyltransferase (CAT), malondialdehyde (MDA), and superoxide dismutase (SOD).Results: Following OGD/R, FOXO4 mRNA and protein expressions were upregulated in SH-SY5H human neuroblastoma cells. ODG/R reduced cell proliferation and increased the proportion of apoptotic cells, and these effects were inhibited by knockdown of FOXO4 (p < 0.05). Levels of cleaved caspase 3 and cleaved poly(ADP-ribose) polymerases (PARPs) were increased after ODG/R and these increaseswere inhibited by FOXO4 knockdown. ROS content and levels of LDH and MDA were increased after ODG/R and decreased by knockdown of FOXO4 (p < 0.05). Levels of CAT and SOD were reduced after ODG/R, and this reduction was reversed by knockdown of FOXO4 (p < 0.05).Conclusion: The results demonstrate that knockdown of FOXO4 promotes cell proliferation and inhibits cellular apoptosis via reduction of oxidative stress after CIR injury, indicating a new therapeutic target for the treatment of CIR injury.
 Keywords: FOXO4, Neuronal survival, Oxidative stress, Cerebral ischemia/reperfusion injury
Highlights
Cerebral ischemia/reperfusion (CIR) injury occurs when blood supply to the brain is suspended and subsequently restored [1].Cerebral IR injury induces brain dysfunction, which contributes to high mortality and disability [2,3]
After oxygen-glucose deprivation/reoxygenation (OGD/R), expression of FOXO4 mRNA was significantly upregulated in SH-5Y5H cells compared with the control group (Figure 1 A)
reactive oxygen species (ROS) content was increased after OGD/R, and downregulation of FOXO4 reduced OGD/R-induced ROS production, indicating that FOXO4 controlled ROS generation in CIR injury, which is consistent with observations in myocardial IR injury and renal IR injury
Summary
Cerebral ischemia/reperfusion (CIR) injury occurs when blood supply to the brain is suspended and subsequently restored [1]. Cerebral IR injury induces brain dysfunction, which contributes to high mortality and disability [2,3]. Oxidative stress has been reported to occur in almost all cases of CIR injury, resulting in excessive production of reactive oxygen species (ROS) [5,6]. Excessive ROS may cause cell death and tissue necrosis by inducing DNA damage, lipid peroxidation, cytoskeletal structural injury, and chemotaxis [5]. Among the PARPs, PARP-1 has been reported to regulate inflammation in central nervous system disorders, including CIR injury [8]. Overactivation of PARP-1 has been detected in the brain after brain ischemia and cardiac arrest in response to oxidative DNA damage [9]. Ischemic injury was prevented in a PARP knockout mouse model compared with wild-type mice, indicating that inhibition of PARP is a potential new therapeutic strategy for CIR injury [10]
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