Chen Xiuli, Wu Hao, Li Peibo, Peng Wei, Wang Yonggang, Zhang Xiaoli, Zhang Ao, Li Jinliang, Meng Fenzhao, Wang Weiyue, Su Weiwei
Guangdong Engineering & Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Plant Resources, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Pharmaceuticals (Basel). 2024 Apr 8;17(4):475. doi: 10.3390/ph17040475.
Xiaochaihu granules (XCHG) are extensively used to treat fever. Nevertheless, the underlying mechanism remains elusive. This study aimed to explore the potential of XCHG in mitigating yeast-induced fever and the underlying metabolic pathways. The chemical composition of XCHG was ascertained using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS), followed by integrated network analysis to predict potential targets. We then conducted experimental validation using pharmacological assays and metabolomics analysis in a yeast-induced mouse fever model. The study identified 133 compounds in XCHG, resulting in the development of a comprehensive network of herb-compound-biological functional modules. Subsequently, molecular dynamic (MD) simulations confirmed the stability of the complexes, including γ-aminobutyric acid B receptor 2 (GABBR2)-saikosaponin C, prostaglandin endoperoxide synthases (PTGS2)-lobetyolin, and NF-κB inhibitor IκBα (NFKBIA)-glycyrrhizic acid. Animal experiments demonstrated that XCHG reduced yeast-induced elevation in NFKBIA's downstream regulators [interleukin (IL)-1β and IL-8], inhibited PTGS2 activity, and consequently decreased prostaglandin E2 (PGE2) levels. XCHG also downregulated the levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), corticotropin releasing hormone (CRH), and adrenocorticotrophin (ACTH). These corroborated the network analysis results indicating XCHG's effectiveness against fever in targeting NFKBIA, PTGS2, and GABBR2. The hypothalamus metabolomics analysis identified 14 distinct metabolites as potential antipyretic biomarkers of XCHG. In conclusion, our findings suggest that XCHG alleviates yeast-induced fever by regulating inflammation/immune responses, neuromodulation, and metabolism modules, providing a scientific basis for the anti-inflammatory and antipyretic properties of XCHG.
小柴胡颗粒（XCHG）被广泛用于治疗发热。然而，其潜在机制仍不清楚。本研究旨在探讨小柴胡颗粒减轻酵母诱导发热的潜力及其潜在的代谢途径。采用超快速液相色谱/四极杆-飞行时间串联质谱（UFLC-Q-TOF-MS/MS）确定小柴胡颗粒的化学成分，随后进行综合网络分析以预测潜在靶点。然后，我们在酵母诱导的小鼠发热模型中使用药理学试验和代谢组学分析进行实验验证。该研究在小柴胡颗粒中鉴定出133种化合物，构建了一个全面的草药-化合物-生物功能模块网络。随后，分子动力学（MD）模拟证实了复合物的稳定性，包括γ-氨基丁酸B受体2（GABBR2）-柴胡皂苷C、前列腺素内过氧化物合酶（PTGS2）-轮叶党参苷、以及NF-κB抑制剂IκBα（NFKBIA）-甘草酸。动物实验表明，小柴胡颗粒降低了酵母诱导的NFKBIA下游调节因子[白细胞介素（IL）-1β和IL-8]的升高，抑制了PTGS2活性，从而降低了前列腺素E2（PGE2）水平。小柴胡颗粒还下调了5-羟色胺（5-HT）、γ-氨基丁酸（GABA）、促肾上腺皮质激素释放激素（CRH）和促肾上腺皮质激素（ACTH）的水平。这些结果证实了网络分析结果，表明小柴胡颗粒在靶向NFKBIA、PTGS2和GABBR2方面对发热有效。下丘脑代谢组学分析确定了14种不同的代谢物作为小柴胡颗粒潜在的解热生物标志物。总之，我们的研究结果表明，小柴胡颗粒通过调节炎症/免疫反应、神经调节和代谢模块来减轻酵母诱导的发热，为小柴胡颗粒的抗炎和解热特性提供了科学依据。
