Safflower Alleviates Pulmonary Arterial Hypertension by Inactivating NLRP3: A Combined Approach of Network Pharmacology and Experimental Verification

IF 1.9 4区 医学 Q3 RESPIRATORY SYSTEM Clinical Respiratory Journal Pub Date : 2024-08-18 DOI:10.1111/crj.13826
Shibiao Ding, Jinyu Cui, Luning Yan, Chuhui Ru, Fei He, Aifeng Chen
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Abstract

Introduction

Traditional Chinese medicinal plant, safflower, shows effective for treating pulmonary arterial hypertension (PAH), yet the underlying mechanisms remain largely unexplored. This study is aimed at exploring the potential molecular mechanisms of safflower in the treatment of PAH.

Methods

Network pharmacology approach and molecular docking were applied to identify the core active compounds, therapeutic targets, and potential signaling pathways of safflower against PAH. Meanwhile, high-performance liquid chromatography (HPLC) assay was performed to determine the core compounds from safflower. Further, the mechanism of action of safflower on PAH was verified by in vivo and in vitro experiments.

Results

A total of 15 active compounds and 177 targets were screened from safflower against PAH. Enrichment analysis indicated that these therapeutic targets were mainly involved in multiple key pathways, such as TNF signaling pathway and Th17 cell differentiation. Notably, molecular docking revealed that quercetin (core compound in safflower) displayed highest binding capacity with NLRP3. In vivo, safflower exerted therapeutic effects on PAH by inhibiting right ventricular hypertrophy, inflammatory factor release, and pulmonary vascular remodeling. Mechanistically, it significantly reduced the expression of proangiogenesis-related factors (MMP-2, MMP-9, Collagen 1, and Collagen 3) and NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1) in PAH model. Similarly, these results were observed in vitro. Besides, we further confirmed that NLRP3 inhibitor had the same therapeutic effect as safflower in vitro.

Conclusion

Our findings suggest that safflower mitigates PAH primarily by inhibiting NLRP3 inflammasome activation. This provides novel insights into the potential use of safflower as an alternative therapeutic approach for PAH.

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红花通过激活 NLRP3 缓解肺动脉高压:网络药理学与实验验证相结合的方法
简介中国传统药用植物红花对治疗肺动脉高压(PAH)有显著疗效,但其潜在机制仍有待探索。本研究旨在探索红花治疗 PAH 的潜在分子机制:方法:采用网络药理学方法和分子对接法鉴定红花治疗 PAH 的核心活性化合物、治疗靶点和潜在信号通路。同时,采用高效液相色谱法(HPLC)测定了红花中的核心化合物。此外,还通过体内和体外实验验证了红花对 PAH 的作用机制:结果:共从红花中筛选出 15 种活性化合物和 177 个针对 PAH 的靶点。富集分析表明,这些治疗靶点主要涉及多个关键通路,如 TNF 信号通路和 Th17 细胞分化。值得注意的是,分子对接显示槲皮素(红花中的核心化合物)与 NLRP3 的结合能力最强。在体内,红花通过抑制右心室肥大、炎症因子释放和肺血管重塑,对 PAH 发挥了治疗作用。从机理上讲,红花能明显减少 PAH 模型中促血管生成相关因子(MMP-2、MMP-9、胶原蛋白 1 和胶原蛋白 3)和 NLRP3 炎性体成分(NLRP3、ASC 和 Caspase-1)的表达。同样,在体外也观察到了这些结果。此外,我们还进一步证实了 NLRP3 抑制剂在体外具有与红花相同的治疗效果:我们的研究结果表明,红花主要通过抑制 NLRP3 炎性体的激活来缓解 PAH。结论:我们的研究结果表明,红花主要通过抑制 NLRP3 炎性体的活化来缓解 PAH,这为红花作为 PAH 替代疗法的潜在用途提供了新的见解。
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来源期刊
Clinical Respiratory Journal
Clinical Respiratory Journal 医学-呼吸系统
CiteScore
3.70
自引率
0.00%
发文量
104
审稿时长
>12 weeks
期刊介绍: Overview Effective with the 2016 volume, this journal will be published in an online-only format. Aims and Scope The Clinical Respiratory Journal (CRJ) provides a forum for clinical research in all areas of respiratory medicine from clinical lung disease to basic research relevant to the clinic. We publish original research, review articles, case studies, editorials and book reviews in all areas of clinical lung disease including: Asthma Allergy COPD Non-invasive ventilation Sleep related breathing disorders Interstitial lung diseases Lung cancer Clinical genetics Rhinitis Airway and lung infection Epidemiology Pediatrics CRJ provides a fast-track service for selected Phase II and Phase III trial studies. Keywords Clinical Respiratory Journal, respiratory, pulmonary, medicine, clinical, lung disease, Abstracting and Indexing Information Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Embase (Elsevier) Health & Medical Collection (ProQuest) Health Research Premium Collection (ProQuest) HEED: Health Economic Evaluations Database (Wiley-Blackwell) Hospital Premium Collection (ProQuest) Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) ProQuest Central (ProQuest) Science Citation Index Expanded (Clarivate Analytics) SCOPUS (Elsevier)
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