丹参酮IIA通过减少VEGFR2/PI3K/ akt驱动的线粒体破坏依赖性凋亡来减轻败血症诱导的肺损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-14 DOI:10.1016/j.phymed.2025.156957

Delida Aidebaike , Hailong Gong , Yun Xia , Guoqing Jing , Huifan Liu , Huimin Zhou , Die Wu , Jing Zuo , Cheng Yang , Xing Wang , Yingyue Dong , Jie Yan , Xue Chen , Zihan Lei , Junjie Liang , Xiaojing Wu , Xuemin Song

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Tanshinone IIA (TanIIA), a bioactive molecule extracted from <em>Salvia miltiorrhiza</em>, demonstrates potential in regulating inflammatory pathways and enhancing cellular resilience.</div></div><div><h3>Purpose</h3><div>This study comprehensively examined the therapeutic mechanisms of TanIIA in SILI by an integrated methodology that incorporates network pharmacology, molecular docking, and comprehensive experimental validation.</div></div><div><h3>Methods</h3><div>Network pharmacology and WGCNA analysis of GSE239388 revealed possible treatment targets for TanIIA. Computational analysis utilizing molecular docking techniques and molecular dynamics simulations validated a stable intermolecular connection between TanIIA and the vascular endothelial growth factor receptor 2.</div><div>TanIIA's therapeutic effectiveness was evaluated in vivo using septic mouse model. BEAS-2B cells treated with LPS in vitro were employed to elucidate the underlying mechanisms. 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引用次数: 0

摘要

脓毒症诱导的肺损伤（SILI）以过度炎症和细胞凋亡为特征，由于缺乏靶向治疗，造成了相当大的治疗问题。丹参酮IIA （tan参酮IIA）是一种从丹参中提取的生物活性分子，具有调节炎症途径和增强细胞恢复能力的潜力。目的采用网络药理学、分子对接和综合实验验证相结合的方法，全面探讨TanIIA对SILI的治疗机制。方法对GSE239388进行网络药理学和WGCNA分析，揭示其可能的治疗靶点。利用分子对接技术和分子动力学模拟的计算分析验证了TanIIA与血管内皮生长因子受体2之间稳定的分子间连接。采用脓毒症小鼠模型对TanIIA的治疗效果进行体内评价。利用体外LPS处理的BEAS-2B细胞来阐明其潜在机制。采用Western blotting、qRT-PCR、免疫组织化学、流式细胞术和线粒体功能检测来评估基因表达、细胞凋亡和线粒体功能。结果vegfr2被确定为TanIIA在SILI中的关键治疗靶点。在clp诱导的脓毒症小鼠中，TanIIA治疗显著提高了存活率，减轻了肺组织病理学损伤，降低了促炎细胞因子水平。在机制上，TanIIA抑制VEGFR2-PI3K-AKT信号通路，保持线粒体完整性并抑制细胞凋亡。使用lps处理的BEAS-2B上皮细胞获得了进一步的验证，加强了最初的发现。结论taniia通过特异性靶向VEGFR2，抑制PI3K/AKT信号通路，对SILI具有保护作用，有助于维持线粒体稳态，减少细胞凋亡。

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Tanshinone IIA attenuates sepsis-induced lung injury by reducing VEGFR2/PI3K/AKT-driven mitochondrial disruption dependent apoptosis

Background

Sepsis-induced lung injury (SILI) is marked by excessive inflammation and apoptosis, posing considerable therapeutic problems owing to the scarcity of targeted therapy. Tanshinone IIA (TanIIA), a bioactive molecule extracted from Salvia miltiorrhiza, demonstrates potential in regulating inflammatory pathways and enhancing cellular resilience.

Purpose

This study comprehensively examined the therapeutic mechanisms of TanIIA in SILI by an integrated methodology that incorporates network pharmacology, molecular docking, and comprehensive experimental validation.

Methods

Network pharmacology and WGCNA analysis of GSE239388 revealed possible treatment targets for TanIIA. Computational analysis utilizing molecular docking techniques and molecular dynamics simulations validated a stable intermolecular connection between TanIIA and the vascular endothelial growth factor receptor 2.

TanIIA's therapeutic effectiveness was evaluated in vivo using septic mouse model. BEAS-2B cells treated with LPS in vitro were employed to elucidate the underlying mechanisms. Western blotting, qRT-PCR, immunohistochemistry, flow cytometry, and mitochondrial function assays were performed to evaluate gene expression, apoptosis, and mitochondrial functionality.

Results

VEGFR2 was identified as a critical therapeutic target of TanIIA in SILI. Treatment with TanIIA significantly enhanced survival rates, mitigated lung histopathological damage, and decreased levels of pro-inflammatory cytokines in CLP-induced septic mice. Mechanistically, TanIIA suppressed the VEGFR2-PI3K-AKT signaling pathway, preserving mitochondrial integrity and inhibiting apoptosis. Additional validation was obtained using LPS-treated BEAS-2B epithelial cells, reinforcing the initial findings.

Conclusion

TanIIA provides protective effects against SILI by specifically targeting VEGFR2 and inhibiting the PI3K/AKT signaling pathway, which helps maintain mitochondrial homeostasis and reduces apoptosis.

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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.