DataSheet9_Mechanism and Protective Effect of Smilax glabra Roxb on the Treatment of Heart Failure via Network Pharmacology Analysis and Vitro Verification.ZIP

Smilax glabra Roxb (SGR) has been widely applied alone or in combination with other Chinese herbs in heart failure (HF), but its mechanism and protective effect have not been investigated. We aimed to explore the mechanism and protective effect of SGR on the treatment of HF. Network pharmacology analysis predicted that SGR was involved in the regulation of cell proliferation, oxidation–reduction process, apoptotic process, ERK1 and ERK2 cascade, MAPK cascade, etc. Its mechanism was mainly involved in the MAPK signaling pathway, calcium signaling pathway, cardiac muscle contraction, etc. Subsequently, SGR was proved to improve cellular viability, restore cellular morphology, suppress cellular and mitochondrial ROS production, improve H2O2-induced lysosome inhibition, attenuate mitochondrial dysfunction, and protect mitochondrial respiratory and energy metabolism in H9c2 cells. SGR activated the p38MAPK pathway by decreasing the mRNA expression of AKT, PP2A, NF-KB, PP2A, RAC1, and CDC42 and increasing the mRNA expression of Jun, IKK, and Sirt1. SGR also decreased the protein expression of ERK1, ERK2, JNK, Bax, and Caspase3 and increased the protein expression of p38MAPK and Bcl-2. In addition, Istidina at the highest degree was identified in SGR via the UHPLCLTQ-Orbitrap-MSn method, and it was suggested as anti-heart failure agents by targeting SRC with molecular docking analysis. In conclusion, SGR has a protective effect on HF through cellular and mitochondrial protection via multi-compounds and multi-targets, and its mechanism is involved in activating the p38 MAPK pathway. Istidina may be possible anti-HF agents by targeting SRC.

光叶菝葜（Smilax glabra Roxb，SGR）已被广泛单独或与其他中药配伍应用于心力衰竭（heart failure，HF）的治疗，但其具体作用机制与保护效应尚未得到研究阐明。本研究旨在探讨SGR用于治疗HF的作用机制与保护效果。网络药理学分析预测显示，SGR参与调控细胞增殖、氧化还原过程、细胞凋亡过程、ERK1与ERK2级联反应、MAPK级联反应等生物学过程，其潜在作用机制主要涉及MAPK信号通路、钙信号通路、心肌收缩等通路与生理过程。随后，实验证实SGR可在H9c2细胞中提升细胞活力、恢复细胞形态、抑制细胞及线粒体活性氧（ROS）生成，改善H₂O₂诱导的溶酶体功能抑制，减轻线粒体功能障碍，并保护线粒体呼吸与能量代谢。SGR可通过下调AKT、PP2A、NF-κB、PP2A、RAC1及CDC42的mRNA表达，上调Jun、IKK及Sirt1的mRNA表达，从而激活p38MAPK通路。SGR还可下调ERK1、ERK2、JNK、Bax及Caspase3的蛋白表达，上调p38MAPK与Bcl-2的蛋白表达。此外，本研究通过UHPLCLTQ-Orbitrap-MSn方法在SGR中鉴定出含量最高的组氨酸（Istidina），并通过分子对接分析提示其可通过靶向Src激酶（SRC）发挥抗心力衰竭作用。综上，SGR可通过多成分、多靶点的细胞与线粒体保护作用对HF发挥保护效应，其作用机制涉及激活p38 MAPK通路。组氨酸或可成为通过靶向SRC发挥抗HF作用的潜在候选药物。