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• W4376641304 endingPage "1394" @default.
• W4376641304 startingPage "1387" @default.
• W4376641304 abstract "Excessive necroptosis contributes to the pathogenesis of several inflammatory and neurodegenerative diseases. Here, using a high-throughput screening approach, we investigated the anti-necroptosis effects of piperlongumine, an alkaloid isolated from the long pepper plant, in vitro and in a mouse model of systemic inflammatory response syndrome (SIRS).A natural compound library was screened for anti-necroptosis effects in cellular. The underlying mechanism of action of the top candidate piperlongumine was explored by quantifying the necroptosis marker phosphorylated receptor-interacting protein kinase 1 (p-RIPK1) by Western blotting. The anti-inflammatory effect of piperlongumine was assessed in a tumor necrosis factor α (TNFα)-induced SIRS model in mice.Among the compounds investigated, piperlongumine significantly rescued cell viability. The half maximal effective concentration (EC50) of piperlongumine for inhibiting necroptosis was 0.47 μM in HT-29 cells, 6.41 μM in FADD-deficient Jurkat cells, and 2.33 µM in CCRF-CEM cells, while the half maximal inhibitory concentration (IC50) was 95.4 µM in HT-29 cells, 93.02 µM in FADD-deficient Jurkat cells, and 161.1 µM in CCRF-CEM cells. Piperlongumine also significantly inhibited TNFα-induced intracellular RIPK1 Ser166 phosphorylation in cell lines and significantly prevented decreases in body temperature and improved survival in SIRS mice.As a potent necroptosis inhibitor, piperlongumine prevents phosphorylation of RIPK1 at its activation residue Ser166. Piperlongumine thus potently inhibits necroptosis at concentrations safe enough for human cells in vitro and inhibits TNFα-induced SIRS in mice. Piperlongumine has potential clinical translational value for the treatment of the spectrum of diseases associated with necroptosis, including SIRS." @default.
• W4376641304 created "2023-05-17" @default.
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• W4376641304 date "2023-05-01" @default.
• W4376641304 modified "2023-10-14" @default.
• W4376641304 title "Identification of Piperlongumine as Potent Inhibitor of Necroptosis" @default.
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• W4376641304 doi "https://doi.org/10.2147/dddt.s397971" @default.
• W4376641304 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37188283" @default.
• W4376641304 hasPublicationYear "2023" @default.
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