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Identification of Piperlongumine as Potent Inhibitor of Necroptosis

PURPOSE: 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...

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Autores principales: He, Xiaoyan, Li, Min, Ye, Zhi, You, Xiaoling, Wang, Jia, Xiao, Xin, Zhu, Guofeng, Wei, Jun, Zha, Yunhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178306/
https://www.ncbi.nlm.nih.gov/pubmed/37188283
http://dx.doi.org/10.2147/DDDT.S397971
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author He, Xiaoyan
Li, Min
Ye, Zhi
You, Xiaoling
Wang, Jia
Xiao, Xin
Zhu, Guofeng
Wei, Jun
Zha, Yunhong
author_facet He, Xiaoyan
Li, Min
Ye, Zhi
You, Xiaoling
Wang, Jia
Xiao, Xin
Zhu, Guofeng
Wei, Jun
Zha, Yunhong
author_sort He, Xiaoyan
collection PubMed
description PURPOSE: 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). METHODS: 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. RESULTS: Among the compounds investigated, piperlongumine significantly rescued cell viability. The half maximal effective concentration (EC(50)) 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 (IC(50)) 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. CONCLUSION: 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.
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spelling pubmed-101783062023-05-13 Identification of Piperlongumine as Potent Inhibitor of Necroptosis He, Xiaoyan Li, Min Ye, Zhi You, Xiaoling Wang, Jia Xiao, Xin Zhu, Guofeng Wei, Jun Zha, Yunhong Drug Des Devel Ther Original Research PURPOSE: 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). METHODS: 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. RESULTS: Among the compounds investigated, piperlongumine significantly rescued cell viability. The half maximal effective concentration (EC(50)) 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 (IC(50)) 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. CONCLUSION: 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. Dove 2023-05-08 /pmc/articles/PMC10178306/ /pubmed/37188283 http://dx.doi.org/10.2147/DDDT.S397971 Text en © 2023 He et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
He, Xiaoyan
Li, Min
Ye, Zhi
You, Xiaoling
Wang, Jia
Xiao, Xin
Zhu, Guofeng
Wei, Jun
Zha, Yunhong
Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title_full Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title_fullStr Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title_full_unstemmed Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title_short Identification of Piperlongumine as Potent Inhibitor of Necroptosis
title_sort identification of piperlongumine as potent inhibitor of necroptosis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178306/
https://www.ncbi.nlm.nih.gov/pubmed/37188283
http://dx.doi.org/10.2147/DDDT.S397971
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