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Abstract：
Gushiling capsule (GSLC) is an effective traditional Chinese medicine for the treatment of glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). This study established the serum metabolite profiles of GSLC in rabbits and explored the metabolic mechanism and effect of GSLC on GIONFH. Seventy-five Japanese white rabbits were randomly divided into the control, model, and GSLC groups. The rabbits in the model group and the GSLC group received injection of prednisolone acetate. Meanwhile, rabbits in the GSLC group were treated by gavage at a therapeutic dose of GSLC once a day. The control group and the model group received the same volume of normal saline gavage. Three groups of serum samples were collected at different time points, and the changes in the metabolic spectrum were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The resulting data set was analyzed using multivariate statistical analysis to identify potential biomarkers related to GSLC treatment. The metabolic pathway was analyzed by MetaboAnalyst 4.0 and a heatmap was constructed using the HEML1.0.3.7 software package. In addition, histopathological and radiography studies were carried out to verify the anti-GIONFH effects of GSLC. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) score plots revealed a significant separation trend between the control group and the model group and the GSLC group (1-3 weeks), but there were no significant differences in the GSLC group (4-6 weeks). Orthogonal PLS-DA (OPLS-DA) score plots also revealed an obvious difference between the model and the GSLC groups (4-6 weeks). Ten potential metabolite biomarkers, mainly phospholipids, were identified in rabbit serum samples and demonstrated to be associated with GIONFH. Hematoxylin and eosin staining and magnetic resonance imaging indicated that the pathological changes in femoral head necrosis in the GSLC group were less than in the model group, which was consistent with the improved serum metabolite spectrum. GSLC regulated the metabolic disorder of endogenous lipid components in GIONFH rabbits. GSLC may prevent and treat GIONFH mainly by regulating phospholipid metabolism in vivo.
摘要：
固士灵胶囊(GSLC)是治疗糖皮质激素性股骨头坏死(GIONFH)的有效中药。本研究建立了兔GSLC的血清代谢产物谱，探讨了GSLC对GIONFH的代谢机制和作用。将75只日本大白兔随机分为对照组，模型，和GSLC组。模型组和GSLC组家兔注射醋酸泼尼松龙。同时,GSLC组的兔子每天一次以治疗剂量的GSLC进行灌胃治疗。对照组和模型组给予等量生理盐水灌胃。在不同时间点采集三组血清样本,采用超高效液相色谱-串联质谱(UPLC-MS/MS)分析代谢谱的变化。使用多变量统计分析分析所得数据集,以鉴定与GSLC治疗相关的潜在生物标志物。通过MetaboAnalyst4.0分析代谢途径，并使用HEML1.0.3.7软件包构建热图。此外,进行了组织病理学和影像学研究，以验证GSLC的抗GIONFH作用。主成分分析（PCA）和偏最小二乘判别分析（PLS-DA）得分图显示，对照组与模型组和GSLC组（1-3周）之间存在显着的分离趋势，但GSLC组(4-6周)无显著差异。正交PLS-DA(OPLS-DA)评分图也显示了模型与GSLC组(4-6周)之间的明显差异。十种潜在的代谢物生物标志物，主要是磷脂，在兔血清样本中鉴定，并证明与GIONFH相关。苏木精、伊红染色及磁共振成像显示GSLC组股骨头坏死病理变化较模型组减少,这与改善的血清代谢物谱一致。GSLC调节GIONFH兔内源性脂质成分的代谢紊乱。GSLC可能主要通过调节体内磷脂代谢来预防和治疗GIONFH。
