State key laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, PR China.
State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, PR China.
Phytomedicine. 2024 Dec;135:156034. doi: 10.1016/j.phymed.2024.156034. Epub 2024 Sep 8.
Danggui Sini Decoction (DGSND) is a classic prescription for treating primary dysmenorrhea (PD), while, the ameliorating effects of DGSND on PD and its mechanisms are not yet fully understood.
The present study is devoted to investigate the protective effect of DGSND against PD and the possible mechanism from the perspective of metabolomics as well as lipidomics.
DGSND was characterized by UPLC-Q-TOF/MS. The PD rat model was induced by estradiol benzoate and oxytocin, and traditional pharmacology, including writhing times, latency time, biochemical index, organ index, and histopathology were performed to evaluated the efficacy of DGSND on PD. Urine metabolomics strategy combined with functional analysis was adopted to delineate the therapeutic effect of DGSND on PD rats and anchor the crucial pathway, and lipidomics analysis was further performed with the uterine tissue as the research object to elucidate the protective mechanism of DGSND from the perspective of lipid homeostasis. Finally, western blot analysis was used to validate the expression of key metabolic enzymes in lipid metabolism.
DGSND was effective in ameliorating writhing times, latency time, the value of prostaglandin F (PGF)/PGE, uterus index, and morphological changes of PD rats. Metabolic signature of PD rats was primarily characterized by the disturbance of steroid hormone metabolism, amino acid metabolism, and lipid metabolism. Functional analysis revealed the urine biomarkers of PD were most related with lipid abnormality. Further lipidomics analysis indicated DGSND exerted anti-PD effects by remodeling lipid homeostasis, which might be due to the significant correlations between different kinds of lipids, especially the extremely high correlation of phosphatidylethanolamine, phosphatidylcholine, and fatty acids. Moreover, the key metabolic enzymes expression of CK, PLA, LPCAT3, COX-2, and 5-LOX can be greatly downregulated by DGSND.
Our findings demonstrated a novel protective mechanism of DGSND against PD by regulating lipid homeostasis.
当归四逆汤（DGSND）是治疗原发性痛经（PD）的经典方剂，但其改善 PD 的作用及其机制尚不完全清楚。
本研究从代谢组学和脂质组学的角度探讨 DGSND 对 PD 的保护作用及其可能的机制。
采用 UPLC-Q-TOF/MS 对 DGSND 进行表征。采用苯甲酸雌二醇和缩宫素诱导 PD 大鼠模型，通过扭体次数、潜伏期、生化指标、器官指数和组织病理学等传统药理学方法评价 DGSND 对 PD 的疗效。采用尿代谢组学策略结合功能分析，阐明 DGSND 对 PD 大鼠的治疗作用，并确定关键途径，进一步以子宫组织为研究对象进行脂质组学分析，从脂质稳态的角度阐明 DGSND 的保护机制。最后，采用 Western blot 分析验证脂质代谢关键代谢酶的表达。
DGSND 能有效改善扭体次数、潜伏期、前列腺素 F（PGF）/PGE 值、子宫指数和 PD 大鼠的形态变化。PD 大鼠的代谢特征主要表现为甾体激素代谢、氨基酸代谢和脂质代谢紊乱。功能分析显示，PD 大鼠的尿生物标志物与脂质异常最相关。进一步的脂质组学分析表明，DGSND 通过重塑脂质稳态发挥抗 PD 作用，这可能与不同种类的脂质之间存在显著相关性有关，特别是磷脂酰乙醇胺、磷脂酰胆碱和脂肪酸之间的高度相关性。此外，DGSND 能显著下调 CK、PLA、LPCAT3、COX-2 和 5-LOX 等多种关键代谢酶的表达。
本研究结果表明，DGSND 通过调节脂质稳态发挥其对 PD 的保护作用。
