Tang Yelin, Zhang Wenxin, Wu Liqin, Bai Bin, Zheng Bin, Li Mengying, Tang Yue, Zhu Xiaona, Zhang Yali, Wang Yi, Zhang Bing
Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325600, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Biochem Biophys Res Commun. 2023 Jan 29;642:118-127. doi: 10.1016/j.bbrc.2022.11.092. Epub 2022 Dec 5.
Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target.
In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance, ELISA and immunoprecipitation assay.
It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines, and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization.
As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
急性肺损伤（ALI）是一种致命的急性炎症性疾病，临床上治疗选择有限。胡椒碱（PL）是从荜茇中分离出的一种生物碱，据报道具有多种药理活性（如抗炎活性）。然而，PL对脂多糖（LPS）诱导的ALI的影响及其抗炎靶点尚不清楚。本文旨在评估PL在LPS诱导的ALI中的作用及其潜在机制和靶点。
在体内，通过气管内注射LPS诱导ALI，以评估PL的保护作用，并通过组织病理学变化进行评估。在体外，通过酶联免疫吸附测定（ELISA）、逆转录定量聚合酶链反应（RT-qPCR）、转录因子富集分析、蛋白质免疫印迹法（Western blotting）和免疫荧光测定法研究PL的抗炎活性和机制。使用计算机对接、表面等离子体共振、ELISA和免疫沉淀测定法分析PL与髓样分化蛋白2（MD2）的结合亲和力。
本文报道PL治疗可减轻LPS诱导的小鼠肺损伤、炎症细胞浸润和炎症反应。在培养细胞中，PCR阵列显示PL显著抑制LPS诱导的炎性细胞因子、趋化因子和I型干扰素的基因表达，同时抑制转化生长因子β激活激酶1（TAK1）和TANK结合激酶1（TBK1）信号通路。值得注意的是，PL能够直接与MD2结合，抑制MD2/Toll样受体4（TLR4）复合物形成以及TLR4二聚化。
本研究表明，PL通过抑制TAK1和TBK1信号通路的激活直接与MD2结合，从而阻断细胞因子表达，进而发挥其肺保护活性。因此，PL可能是治疗LPS诱导的ALI的潜在候选药物。
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