Abstract
BackgroundEvidence exists uncovering that SRY-box transcription factor 9 (SOX9) plays a role in ischemic brain injury (IBI). Thus, the current study was conducted to elucidate the specific role of SOX9 and the mechanism by which SOX9 influenced IBI.MethodsThe IBI-associated regulatory factors were searched by bioinformatics analysis. The rat model of IBI was generated using middle cerebral artery occlusion (MCAO) treatment. Neuronal cells were exposed to oxygen-glucose deprivation (OGD). The expressions of SOX9, forkhead box O3 (FOXO3), transcription of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), and IκB kinase α (IKKα) in OGD-treated neuronal cells were characterized using reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. The interaction among CITED2, IKKα, and FOXO3 was identified by chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays. Gain- and loss-of-function experiments were performed to verify the relationship among SOX9, FOXO3, CITED2, and IKKα and to investigate their functional effects on apoptosis and the inflammatory response of OGD-treated neuronal cells as well as neurological deficit and infarct area of the rat brain.ResultsSOX9, FOXO3, CITED2, and IKKα were highly expressed in OGD-treated neuronal cells. Silencing of SOX9 inhibited OGD-induced neuronal apoptosis and inflammatory response and reduced the neurological deficit and infarct area of the brain in the rats, which were caused by MCAO but were reversed by overexpressing FOXO3, CITED2, or IKKα.ConclusionTaken together, our study suggested that upregulation of SOX9 promoted IBI though upregulation of the FOXO3/CITED2/IKKα axis, highlighting a basic therapeutic consideration for IBI treatment.
Highlights
Intracranial lesions, trauma, or surgery-related injuries can activate immune inflammation and neuroendocrine responses so as to lead to ischemic brain injury (IBI) (Jiang et al, 2017)
Silencing of SRY-box transcription factor 9 (SOX9) inhibited oxygen-glucose deprivation (OGD)-induced neuronal apoptosis and inflammatory response and reduced the neurological deficit and infarct area of the brain in the rats, which were caused by middle cerebral artery occlusion (MCAO) but were reversed by overexpressing forkhead box O3 (FOXO3), carboxy-terminal domain 2 (CITED2), or IκB kinase α (IKKα)
Taken together, our study suggested that upregulation of SOX9 promoted IBI though upregulation of the FOXO3/CITED2/IKKα axis, highlighting a basic therapeutic consideration for IBI treatment
Summary
Intracranial lesions, trauma, or surgery-related injuries can activate immune inflammation and neuroendocrine responses so as to lead to ischemic brain injury (IBI) (Jiang et al, 2017). Ischemic injury is associated with high morbidity and mortality in various diseases such as ischemic stroke (Tang and Zhuang, 2019). Brain injury after focal cerebral ischemia is the most prevalent driver of stroke, which is caused by a variety of pathological processes such as inflammation and apoptosis (Du et al, 2010). Excessive physiological and pathological events such as inflammation and neuronal cell death associated with cerebral ischemia are regulated by multiple signaling pathways (Du et al, 2010). Evidence exists uncovering that SRY-box transcription factor 9 (SOX9) plays a role in ischemic brain injury (IBI). The current study was conducted to elucidate the specific role of SOX9 and the mechanism by which SOX9 influenced IBI
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