<br>Pimpinellin 通过促进 RNF146 介导的 PARP1 泛素化改善巨噬细胞炎症,Phytotherapy Research

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Pimpinellin 通过促进 RNF146 介导的 PARP1 泛素化改善巨噬细胞炎症
Phytotherapy Research ( IF 6.1 ) Pub Date : 2024-02-07 , DOI: 10.1002/ptr.8135
Liuye Yang _{1,

2} , Meng Du _{1,

2,

3,

4} , Kaiyuan Liu _{1,

2} , Pengchao Wang _{1,

2} , Jingbo Zhu _{1,

2} , Fengcen Li ₁ , Ze Wang ₅ , Kai Huang _{1,

2,

3,

4} , Minglu Liang _{1,

3,

4}

Affiliation

巨噬细胞炎症在脓毒症的发生和进展过程中发挥着核心作用，而parthanatos对巨噬细胞的调节最近已被确定为抗炎治疗的新策略。本研究旨在探讨 pippinellin 对 LPS 诱导的脓毒症的治疗潜力和机制。通过蛋白质印迹或免疫组织化学检测 PARP1 和 PAR 激活。通过流式细胞术和蛋白质印迹评估细胞死亡。使用 Seahorse XFe24 细胞外通量分析仪测量细胞代谢。 C57、PARP1 敲除和 PARP1 条件敲入小鼠用于 LPS 引起的脓毒症模型，以评估 pimpinellin 的作用。在这里，我们发现pimpinellin可以特异性抑制LPS诱导的巨噬细胞PARP1和PAR活化。体外研究表明，pimpinellin可以通过抑制PARP1的过度表达来抑制巨噬细胞中炎症细胞因子的表达和信号通路的激活。此外，pimpinellin 还提高了 LPS 治疗小鼠的存活率，从而预防 LPS 诱导的败血症。进一步的研究证实，在 PARP1 过表达小鼠中，LPS 诱导的脓毒症可被 pippinellin 减弱，并且 PARP1 敲除消除了 pippinellin 对 LPS 诱导的脓毒症的保护作用。进一步研究发现pimpinellin可以通过RNF146促进泛素介导的PARP1降解。这是第一项证明 pimpinellin 通过促进泛素介导的 PARP1 降解来抑制过度炎症反应的研究。

"点击查看英文标题和摘要"

Pimpinellin ameliorates macrophage inflammation by promoting RNF146-mediated PARP1 ubiquitination

Macrophage inflammation plays a central role during the development and progression of sepsis, while the regulation of macrophages by parthanatos has been recently identified as a novel strategy for anti-inflammatory therapies. This study was designed to investigate the therapeutic potential and mechanism of pimpinellin against LPS-induced sepsis. PARP1 and PAR activation were detected by western blot or immunohistochemistry. Cell death was assessed by flow cytometry and western blot. Cell metabolism was measured with a Seahorse XFe24 extracellular flux analyzer. C57, PARP1 knockout, and PARP1 conditional knock-in mice were used in a model of sepsis caused by LPS to assess the effect of pimpinellin. Here, we found that pimpinellin can specifically inhibit LPS-induced macrophage PARP1 and PAR activation. In vitro studies showed that pimpinellin could inhibit the expression of inflammatory cytokines and signal pathway activation in macrophages by inhibiting overexpression of PARP1. In addition, pimpinellin increased the survival rate of LPS-treated mice, thereby preventing LPS-induced sepsis. Further research confirmed that LPS-induced sepsis in PARP1 overexpressing mice was attenuated by pimpinellin, and PARP1 knockdown abolished the protective effect of pimpinellin against LPS-induced sepsis. Further study found that pimpinellin can promote ubiquitin-mediated degradation of PARP1 through RNF146. This is the first study to demonstrate that pimpinellin inhibits excessive inflammatory responses by promoting the ubiquitin-mediated degradation of PARP1.

更新日期：2024-02-07

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