The Therapeutic Mechanism of Schisandrol A and Its Metabolites on Pulmonary Fibrosis Based on Plasma Metabonomics and Network Analysis

Abstract

Background: Schisandrol A (Sch A) is the main active ingredient of Schisandra chinensis (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. Methods: 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). Results: 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. Conclusion: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.

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification

“…The ultra-high performance liquid chromatography coupled with tandem mass spectrometry metabolomics was used to explore the therapeutic mechanisms of schisandrol A against pulmonary fibrosis and revealed that TGF-β1-VIM-carnosine and TGF-β1-ID3creatine pathway were key pathways of Sch A modulating the metabolic disorders [137]. Serum metabolomics combined with UPLC/MS analyzed the effective substances and action mechanisms of Ziziphi Spinosae Semen extract for insomnia treatment [138].…”

Integrating Network Pharmacology and Experimental Validation to Explore the Pharmacological Mechanism of Astragaloside IV in Treating Bleomycin-Induced Pulmonary Fibrosis

“…Idiopathic pulmonary fibrosis (IPF) affects the lung parenchyma and is characterized by a decline in lung functions, abnormal deposition of extracellular matrix, and interstitial fibrosis that worsens with time. 1 , 2 The incidence of PF has been rising year after year in recent years; 3 however, IPF’s onset and progression have complex mechanisms that are still unknown. 4–6 In addition to the recognized risk factors for IPF, such as smoke, environmental elements, comorbidities, and viral infections, various other processes are associated with the disease.…”