Neurochemistry international
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Alzheimer's disease (AD) is a neurodegenerative and progressive disorder. The hallmark of pathological AD is amyloid plaque which is the accumulation of amyloid β (Aβ) in extracellular neuronal cells and neurofibrillary tangles (NFT) in neuronal cells, which lead to neurotoxicity via reactive oxygen species (ROS) generation related apoptosis. Loss of synapses and synaptic damage are the best correlates of cognitive decline in AD. ⋯ Additionally, di-O-demethylcurcumin treatment also reduced the expression of ER stress protein markers, including protein kinase RNA like endoplasmic reticulum kinase (PERK) phosphorylation, eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation, inositol-requiring enzyme 1 (IRE1) phosphorylation, X-box-binding protein-1 (XBP-1), activating transcription factor (ATF6), C/EBP homologous protein (CHOP), and cleaved caspase-12 protein. CHOP and cleaved caspase-12 protein are the key mediators of apoptosis. Our data suggest that di-O-demethylcurcumin is a candidate protectant against neuronal death through its suppression of the apoptosis mediated by mitochondrial death and ER stress pathway.
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We previously found that TIGAR (TP53-induced glycolysis and apoptosis regulator) was upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. The present study sought to investigate the regulatory mechanisms of TIGAR upregulation in animal and cellular models of stroke. The animal and cellular models of ischemia/reperfusion were produced by transient middle cerebral artery occlusion and reperfusion (tMCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. ⋯ The transcription factor SP1 was induced by ischemia/reperfusion ahead of TIGAR upregulation. Inhibiting SP1 with mithramycin A or silencing SP1 with siRNA blocked the ischemia-induced TIGAR upregulation. These results suggest that ROS and hormones regulating blood glucose metabolism play a role in ischemia/reperfusion-induced TIGAR upregulation.