Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Drug Des Devel Ther. 2023 Feb 15;17:477-496. doi: 10.2147/DDDT.S391503. eCollection 2023.
Schisandrol A (Sch A) is the main active ingredient of (Turcz.) Baill. Our previous study showed that Sch A has anti-pulmonary fibrosis (PF) activity, but its metabolic-related mechanisms of action are not clear.
Here, we explored the therapeutic mechanisms of Sch A on PF by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) metabolomics approach and network analysis. The metabolites of Sch A in mice (bleomycin + Sch A high-dose group) plasma were identified based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS).
32 metabolites were detected reversed to normal level after treating bleomycin (BLM)-induced PF mice with Sch A. The 32 biomarkers were enriched in energy metabolism and several amino acid metabolisms, which was the first report on the therapeutic effects of Sch A on PF through rescuing the disordered energy metabolism. The UPLC-Q-TOF/MS analysis identified 17 possible metabolites (including isomers) of Sch A in mice plasma. Network analysis revealed that Sch A and 17 metabolites were related to 269 genes, and 1109 disease genes were related to PF. The construction of the Sch A/metabolites-target-PF network identified a total of 79 intersection genes and the TGF-β signaling pathway was determined to be the main signaling pathway related to the treatment of PF by Sch A. The integrated approach involving metabolomics and network analysis revealed that the TGF-β1-ID3-creatine pathway, TGF-β1-VIM-carnosine pathway were two of the possible pathways Sch A regulated to modulate metabolic disorders, especially energy metabolism, and the metabolite of Sch A M5 was identified as a most likely active metabolite.
The results suggested the feasibility of combining metabolomics and network analysis to reflect the effects of Sch A on the biological network and the metabolic state of PF and to evaluate the drug efficacy of Sch A and its related mechanisms.
五味子醇甲（Sch A）是五味子（Turcz.）Baill. 的主要活性成分。我们之前的研究表明，Sch A 具有抗肺纤维化（PF）活性，但它的代谢相关作用机制尚不清楚。
本研究采用超高效液相色谱-串联质谱（UPLC-MS/MS）代谢组学方法和网络分析，探讨 Sch A 治疗 PF 的治疗机制。基于超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF/MS）鉴定了 Sch A 处理博来霉素（BLM）诱导的 PF 小鼠（Sch A 高剂量组）血浆中的代谢物。
用 Sch A 处理 BLM 诱导的 PF 小鼠后，有 32 种代谢物恢复到正常水平。这 32 种生物标志物富集于能量代谢和几种氨基酸代谢，这是首次报道 Sch A 通过恢复紊乱的能量代谢来治疗 PF。UPLC-Q-TOF/MS 分析鉴定出 17 种可能的 Sch A 代谢物（包括异构体）在小鼠血浆中。网络分析显示，Sch A 和 17 种代谢物与 269 个基因相关，与 PF 相关的疾病基因有 1109 个。Sch A/代谢物-靶标-PF 网络的构建共确定了 79 个交集基因，其中 TGF-β 信号通路被确定为 Sch A 治疗 PF 的主要信号通路。代谢组学和网络分析相结合的方法表明，Sch A 调节的 TGF-β1-ID3-肌酸途径、TGF-β1-VIM-牛磺酸途径是 Sch A 调节代谢紊乱，尤其是能量代谢的可能途径之一，鉴定出 Sch A 的代谢物 M5 可能是最可能的活性代谢物。
研究结果表明，代谢组学和网络分析相结合的方法可以反映 Sch A 对生物网络和 PF 代谢状态的影响，评估 Sch A 的药效及其相关机制是可行的。
