(Z)-Ligustilide alleviates intervertebral disc degeneration by suppressing nucleus pulposus cell pyroptosis via Atg5/NLRP3 axis.

IF 8 2区 生物学 Q1 BIOLOGY
Jiale Wang, Chunyang Fan, Yao Zhang, Di Hua, Zhongwei Ji, Wei He, Yongkang Deng, Dechun Geng, Xiexing Wu, Haiqing Mao
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引用次数: 0

Abstract

Intervertebral disc degeneration (IVDD) represents one of the most prevalent degenerative disorders, significantly impairing quality of life and overall health. The inflammatory cascade and dysregulated degradation of the extracellular matrix (ECM) triggered by pyroptosis are considered key mechanisms underlying the pathogenesis of IVDD. Research has highlighted the potential of Chuanxiong Rhizoma (CX), a traditional Chinese medicine, in exerting anti-pyroptotic effects; nevertheless, the exact mechanisms and pathways through which it modulates inflammation, as well as its potential role in the context of IVDD, remain unknown. Network pharmacology analysis was initially employed to identify the principal components and targets of Chuanxiong Rhizoma (CX) in the treatment of IVDD, ultimately selecting LIG as the key active ingredient responsible for its therapeutical effect. To explore the therapeutic effects of LIG on IVDD, we established a rat acupuncture model to simulate IVDD in vivo. Additionally, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to induce NPC degeneration model in vitro. In vitro experiments revealed that LIG treatment promotes the expression of anabolic markers such as Collagen II and Aggrecan while inhibiting the expression of catabolic markers MMP9 and MMP13 in nucleus pulposus cells (NPCs). Furthermore, LIG was also shown to inhibit cell pyroptosis and the secretion of inflammatory cytokines, which was mediated by NLRP3/caspase-1/GSDMD-N activation. Molecular docking and co-immunoprecipitation further demonstrated that LIG acts as a ligand for the Atg5 protein, inhibiting its degradation and promoting its interaction with the NLRP3 protein, ultimately leading to the suppression of pyroptosis activation in NPCs. It was also found that knocking down Atg5 reverses the protective effects of LIG and exacerbates pyroptosis-mediated inflammation in IVDD. In addition, in vivo experiments also showed that LIG delayed acupuncture-mediated IVDD development. Therefore, this paper confirmed that LIG has the ability to protect NPCs against pyroptosis through Atg5/NLRP3 axis and exert its therapeutic application to ameliorate disc degeneration in vivo. This may shed new insights into the role of LIG in IVDD treatment and offer a mechanistic basis for targeting NLRP3-mediated pyroptosis.

(Z)- liguslide通过Atg5/NLRP3轴抑制髓核细胞热下垂,减轻椎间盘退变。
椎间盘退变(IVDD)是最常见的退行性疾病之一,严重影响生活质量和整体健康。由焦亡引发的炎症级联和细胞外基质(ECM)降解失调被认为是IVDD发病的关键机制。研究强调了中药川芎根(CX)在发挥抗焦亡作用方面的潜力;然而,它调节炎症的确切机制和途径,以及它在IVDD背景下的潜在作用,仍然未知。通过网络药理学分析,初步确定川芎治疗IVDD的主要成分和作用靶点,最终确定LIG为其治疗IVDD的关键活性成分。为了探讨LIG对IVDD的治疗作用,我们建立了大鼠针刺模型,模拟体内IVDD。此外,我们采用脂多糖(LPS)和三磷酸腺苷(ATP)体外诱导鼻咽癌变性模型。体外实验表明,LIG处理可促进髓核细胞(NPCs)合成代谢标志物如Collagen II和Aggrecan的表达,同时抑制分解代谢标志物MMP9和MMP13的表达。此外,LIG还被证明可以抑制NLRP3/caspase-1/GSDMD-N激活介导的细胞焦亡和炎症细胞因子的分泌。分子对接和共免疫沉淀进一步证明,LIG作为Atg5蛋白的配体,抑制其降解,促进其与NLRP3蛋白的相互作用,最终抑制npc的焦亡活化。研究还发现,敲低Atg5会逆转LIG的保护作用,并加剧IVDD中焦热介导的炎症。此外,体内实验也表明,LIG延缓了针灸介导的IVDD的发生。因此,本文证实了LIG能够通过Atg5/NLRP3轴保护npc免于焦亡,并在体内发挥其治疗应用,改善椎间盘退变。这可能为LIG在IVDD治疗中的作用提供新的见解,并为靶向nlrp3介导的焦亡提供机制基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
15.10
自引率
8.80%
发文量
2907
审稿时长
3.2 months
期刊介绍: Science China Life Sciences is a scholarly journal co-sponsored by the Chinese Academy of Sciences and the National Natural Science Foundation of China, and it is published by Science China Press. The journal is dedicated to publishing high-quality, original research findings in both basic and applied life science research.
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