Angong Niuhuang Pills(AGNHP) are effective in clearing heat, removing the toxin, and eliminating phlegm for resuscitation. Clinically, it is widely used to treat various diseases such as febrile convulsion due to heat attacking pericardium, but its therapeutic effects on heart failure(HF) have not been well recognized. In this study, the profiles of differential metabolites regulated by AGNHP were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). The underlying mechanism of AGNHP against HF was illustrated based on the integrated analysis of pharmacological data and metabolic molecular network. The HF model was induced by isoproterenol in mice. After oral administration of AGNHP for one week, cardiac functions in HF mice were evaluated by echocardiography, and serum samples of mice were collected for metabolomics analysis. Eight differential metabolites of AGNHP against HF were screened out through partial least square discriminant analysis(PLS-DA) and input into MetaboAnalyst for the analysis of metabolic pathways. Moreover, the critical metabolic pathways regulated by AGNHP were enriched according to the potential targets of major compounds in AGNHP. After AGNHP treatment, the recovered index of relative content of some metabolites underwent cross-scale fusion analysis with therapeutic efficacy data, followed by "compound-reaction-enzyme-gene" network analysis. It is inferred that the anti-HF effects of AGNHP may be attributed to the metabolism of arachidonic acid, amino acid, glycerophospholipid, and linoleic acid. The cross-scale polypharmacological analysis method developed in this study provides a new method to interpret scientific principles of AGNHP against HF with modern technologies.

中文翻译：

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基于跨尺度多药理学研究的安宫牛黄丸对心力衰竭的影响[J].

安宫牛黄丸(AGNHP)具有清热解毒、化痰开窍的功效。临床上广泛用于治疗热攻心包引起的热性惊厥等多种疾病，但其对心力衰竭（HF）的治疗作用尚未得到很好的认识。本研究采用超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF-MS）鉴定了AGNHP调控的差异代谢物谱。基于药理数据和代谢分子网络的综合分析，阐明了 AGNHP 对抗 HF 的潜在机制。HF模型由小鼠异丙肾上腺素诱导。口服 AGNHP 一周后，通过超声心动图评估 HF 小鼠的心脏功能，收集小鼠血清样本进行代谢组学分析。通过偏最小二乘判别分析(PLS-DA)筛选出八种AGNHP对HF的差异代谢物，输入MetaboAnalyst进行代谢途径分析。此外，根据 AGNHP 中主要化合物的潜在靶点，丰富了 AGNHP 调节的关键代谢途径。AGNHP处理后，部分代谢物相对含量恢复指标与疗效数据进行跨尺度融合分析，随后进行“复合-反应-酶-基因”网络分析。推测 AGNHP 的抗 HF 作用可能与花生四烯酸、氨基酸、甘油磷脂和亚油酸的代谢有关。