國家衛生研究院 NHRI:Item 3990099045/8894
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    题名: Insulin Receptor Substrate-1 activation mediated p53 downregulation protects against Hypoxic-Ischemia in the neonatal brain
    作者: Tu, YF;Jiang, ST;Chow, YH;Huang, CC;Ho, CJ;Chou, YP
    贡献者: Division of Vaccine Research and Development
    摘要: This study determined if dietary restriction (DR) protects against hypoxic-ischemia (HI) in the neonatal brain via insulin receptor substrate-1 (IRS-1)/Akt pathway-mediated downregulation of p53 in the neurovascular unit. On postnatal (P) day 7, HI was induced in rat pups grouped from P1 into normal litter size (NL, 12 pups/dam) and increased litter size (DR, 18 pups/dam). In vivo IRS-1 anti-sense oligonucleotide and IRS-1 overexpressed recombinant adenovirus were given, and neurovascular damage was assessed. In vitro models of oxygen-glucose deprivation (OGD) examined the inhibition and overexpression of IRS-1 on p53 and cell death in neurons and endothelial cells. Compared to NL pups, DR pups had significantly higher IRS-1, p-IRS-1, and pAkt levels, decreased p53, more tight junction proteins, reduced blood-brain barrier (BBB) damage after HI, and less infarct volumes at P21. Immunofluorescence revealed that IRS-1 was upregulated in the endothelial cells and neurons of DR pups. IRS-1 downregulation in DR pups reduced p-Akt, increased p53, worsened BBB damage, and increased brain injury, whereas IRS-1 overexpression in NL pups upregulated p-Akt, decreased p53, attenuated BBB damage, and decreased brain injury. In vitro, IRS-1 downregulation aggravated cell death in neurons and endothelial cells and is associated with decreased p-Akt and increased p53. In contrast, IRS-1 overexpression reduced cell death in endothelial cells with increased p-Akt and decreased p53. In conclusion, DR reduces neurovascular damage after HI in the neonatal brain through an IRS-1/Akt-mediated p53 downregulation, suggesting that IRS-1 signaling is a therapeutic target for hypoxic brain injury in neonates.
    日期: 2016-08
    關聯: Molecular Neurobiology. 2016 Aug;53(6):3658-3669.
    Link to: http://dx.doi.org/10.1007/s12035-015-9300-5
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0893-7648&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000379707600013
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84933557029
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