Background
Thiazolidinediones (TZD) were reported to protect against ischemia-reperfusion (I/R) injury. Their protective actions are considered to be PPAR-γ (peroxisome proliferator-activated receptor γ)-dependent. However, it is unclear how PPAR-γ activation confers resistance to I/R.
Methods and Results
We evaluated the effects of rosiglitazone or PPAR-γ overexpression on cerebral infarction in a rat model and investigated the anti-apoptotic actions in N2-A neuroblastoma cell model. Rosiglitazone or PPAR-γ overexpression significantly reduced infarct volume. The protective effect was abrogated by PPAR-γ siRNA. In mice with knockin of a PPAR-γ domain negative mutant, infarct volume was enhanced. Proteomic analysis reveals that brain 14-3-3ε was highly upregulated in rats treated with rosiglitazone. 14-3-3ε upregulation was abrogated by PPAR-γ siRNA or antagonist. Promoter analysis and chromatin immunoprecipitation reveal that rosiglitazone induced PPAR-γ binding to specific regulatory elements on 14-3-3ε promoter and thereby increased 14-3-3ε transcription. 14-3-3ε siRNA abrogated the anti-apoptotic actions of rosiglitazone or PPAR-γ overexpression while 14-3-3ε recombinant proteins rescued brain tissues and N2-A cells from ischemia-induced damage and apoptosis. Elevated 14-3-3ε enhanced binding of phosphorylated Bad, and protected mitochondrial membrane potential.
Conclusions
Ligand-activated PPAR-γ confers resistance to neuronal apoptosis and cerebral infarction by driving 14-3-3ε transcription. 14-3-3ε upregulation enhances sequestration of phosphorylated Bad and thereby suppresses apoptosis.
Three new cyclobutanoid amides with trans-trans-trans configurations, piperarborenine C, piperarborenine D and piperarborenine E, and a new furanoid lignan, (+)-arborone, together with twelve known compounds, were isolated from the stems of Piper arborescens. The structures of these new compounds were determined by means of spectral analyses. Piperarborenine C, (+)-diayangambin, piplartine, piperolactam B, piperolactam C, aristolactam BIII, goniothalactam, and methyl trans-3,4,5-trimethoxycinnamate possessed anti-platelet aggregation activity in vitro. Among them, piplartine showed the most potent anti-platelet aggregation activity induced by collagen and showed an IC50 value of 21.5 microM. Piperarborenines A - E, piperarborenine, aristololactam BIII and goniothalactam showed significant cytotoxic activity (IC50 values < 4 microg/mL) against P-388, HT-29 and A549 cell lines in vitro.
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