背景:中国传统药用植物,红花,显示有效治疗肺动脉高压(PAH),然而,潜在的机制在很大程度上仍未被探索。本研究旨在探讨红花治疗PAH的潜在分子机制。
方法:采用网络药理学方法和分子对接方法对核心活性化合物进行鉴定,治疗目标,以及红花抗PAH的潜在信号通路。同时,进行高效液相色谱(HPLC)测定以确定红花的核心化合物。Further,通过体内外实验验证了红花对PAH的作用机制。
结果:从红花中筛选出了总共15种活性化合物和177种靶标。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(红花核心化合物)与NLRP3的结合能力最高。在体内,红花通过抑制右心室肥厚发挥对PAH的治疗作用,炎症因子释放,和肺血管重塑。机械上,它显着降低了促血管生成相关因子(MMP-2,MMP-9,Collagen1和Collagen3)和NLRP3炎症小体成分(NLRP3,ASC,和Caspase-1)在PAH模型中。同样,这些结果是在体外观察到的。此外,我们进一步证实NLRP3抑制剂在体外具有与红花相同的治疗效果。
结论:我们的研究结果表明,红花主要通过抑制NLRP3炎性体激活来减轻PAH。这为红花作为PAH的替代治疗方法的潜在用途提供了新的见解。
BACKGROUND: 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.
CONCLUSIONS: 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.