马鞭草苷通过促进宿主免疫稳态来预防冠状病毒肺炎：其作用机制的证据

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-30 DOI:10.1016/j.phymed.2025.156820

Qiyue Sun , Ronghua Zhao , Shuran Li , Weiqin Zhou , Jingsheng Zhang , Bo Pang , Shilan Ding , Lei Bao , Zihan Geng , Rui Xie , Dan Xie , Xiaolan Cui , Shanshan Guo , Jing Sun

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引用次数: 0

摘要

冠状病毒在世界范围内引起了高死亡率的病毒性肺炎。其发病机制的特点是由免疫稳态失调引起的高炎症反应。马鞭草苷是一种从马鞭草中提取的环烯醚萜苷，因其具有抗氧化、抗炎和抗病毒的特性而广泛应用于中医临床。目的研究马鞭草苷对冠状病毒肺炎的体内外药理作用及其机制。方法建立冠状病毒肺炎小鼠模型和巨噬细胞损伤模型，包括小鼠肺泡巨噬细胞系（MH-S）细胞和原代巨噬细胞，初步证实马鞭草苷的抗病毒作用。然后使用时间分辨蛋白质组学来揭示蛋白质组学变化并确定冠状病毒治疗的潜在治疗靶点。随后，采用流式细胞术和Western blot检测马鞭草苷对NOD-、LRR-和pyrin结构域蛋白3 （NLRP3）炎症小体通路的影响。此外，通过分子对接、表面等离子体共振（SPR）、免疫荧光染色、RNA干扰（RNAi）、抑制线粒体自噬等实验，验证了马尾马苷对磷酸酶和张力素同源性诱导的激酶1 (PINK1) / E3泛素连接酶Parkin （Parkin）通路的靶向调节作用。结果马鞭草苷减轻人冠状病毒229E （HCoV-229E）感染巨噬细胞的细胞损伤和炎症反应，改善小鼠肺部炎症反应。蛋白质组学分析强调了核苷酸结合寡聚结构域（NOD）样受体信号传导和线粒体自噬途径在冠状病毒肺炎中的作用。马尾草苷与PINK1和Parkin蛋白强结合，增加线粒体膜电位（MMP），降低线粒体活性氧（mtROS）水平，降低线粒体通透性过渡孔（MPTP）的开放，维持线粒体质量，促进线粒体自噬通量，上调PINK1、Parkin和微管相关蛋白1A/ 1b -轻链3BII （LC3BII）的表达。此外，马尾马苷在体内和体外均抑制NLRP3炎性体的激活，下调白细胞介素-1β (IL-1β)、半胱氨酸天冬氨酸特异性蛋白酶1 （caspase-1）和气皮蛋白D （GSDMD）的表达。此外，用线粒体自噬抑制剂和RNAi治疗可以减弱马鞭草苷对NLRP3激活的抑制作用，证实了PINK1/Parkin/NLRP3通路参与了马鞭草苷的保护作用。结论马鞭草苷增强PINK1/ parkin介导的线粒体自噬，抑制NLRP3的激活，从而促进免疫稳态，减轻hcov - 229e诱导的炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action

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Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action

Background

Coronavirus has caused high-mortality viral pneumonia worldwide. The pathogenesis is characterized by hyperinflammatory reactions resulting from immune homeostasis dysregulation. Verbenalin, an iridoid glucoside derived from Verbena officinalis L., is widely used in Traditional Chinese Medicine (TCM) clinical practice for its antioxidant, anti-inflammatory and antiviral properties.

Purpose

This study aimed to investigate the pharmacological effects and underlying mechanisms of verbenalin on coronavirus pneumonia both in vivo and in vitro.

Methods

A coronavirus pneumonia mouse model and macrophage injury models, including mouse alveolar macrophage cell line (MH-S) cells and primary macrophages, were established to initially confirm the antiviral effects of verbenalin. Time-resolved proteomic were then employed to uncover proteomic changes and identify potential therapeutic targets for coronavirus treatment. Subsequently, flow cytometry and Western blot were employed to investigate verbenalin's effects on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Additionally, the targeting regulation of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) / E3 ubiquitin ligase Parkin (Parkin) pathway by verbenalin was validated through molecular docking, surface plasmon resonance (SPR), immunofluorescent staining, RNA interference (RNAi), and mitophagy inhibition both in vivo and in vitro.

Results

Verbenalin reduced cell injury and inflammation in Human coronavirus 229E (HCoV-229E)-infected macrophages and improved lung inflammation in mice. Proteomics analysis highlighted the roles of nucleotide-binding oligomerization domain (NOD)-like receptor signaling and mitophagy pathways in coronavirus pneumonia. Verbenalin bound strongly to PINK1 and Parkin proteins, increased mitochondrial membrane potential (MMP), decreased mitochondrial reactive oxygen species (mtROS) levels, reduced the opening of mitochondrial permeability transition pore (MPTP), maintained mitochondrial mass, promoted mitophagy flux, upregulated the expression of PINK1, Parkin, and microtubule-associated protein 1A/1B-light chain 3BII (LC3BII). Additionally, verbenalin inhibited the activation of the NLRP3 inflammasome and downregulated the expression of Interleukin-1 beta (IL-1β), cysteine aspartate-specific protease 1 (caspase-1), and gasdermin D (GSDMD) both in vivo and in vitro. Furthermore, treatment with a mitophagy inhibitor and RNAi attenuated the inhibitory effects of verbenalin on NLRP3 activation, confirming the involvement of the PINK1/Parkin/NLRP3 pathway in verbenalin's protective effects.

Conclusion

Verbenalin enhances PINK1/Parkin-mediated mitophagy to suppress NLRP3 activation, thereby promoting immune homeostasis and mitigating HCoV-229E-induced inflammation.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.