The drug combination of biapenem (BIPM) and xuebijing injection (XBJ) is commonly applied for the treatment of sepsis in China. However, the potential synergistic mechanism is still enigmatic. There have been no studies focused on the plasma metabolome alterations in sepsis after the intervention of this combination. In this work, an untargeted metabolomics approach was performed by liquid chromatography-mass spectrometry coupled with multivariate statistical analysis to provide new insights into the synergistic effect of BIPM in combination with XBJ. We characterized the metabolic phenotype of sepsis and described metabolic footprint changes in septic rats responding to XBJ and BIPM individually and in combination, in addition to histopathological and survival evaluation. A total of 91 potential biomarkers of sepsis were identified and 32 disturbed metabolic pathways were constructed. Among these biomarkers, 36 metabolites were reversely regulated by XBJ, mainly including glycerophospholipids, sphingolipids, free fatty acids (FFAs), bile acids and acylcarnitines; 42 metabolites were regulated by BIPM, mainly including amino acids, glycerophospholipids, and acylcarnitines; 72 metabolites were regulated after XBJ-BIPM combination treatment, including most of the 91 potential biomarkers. The results showed that the interaction between XBJ and BIPM indeed exhibited a synergistic effect by affecting some key endogenous metabolites, 15 metabolites of which could not be regulated when XBJ or BIPM was used alone. Compared with Model group, 13, 22, and 27 metabolic pathways were regulated by XBJ, BIPM, and XBJ-BIPM combination, respectively. It suggested that many more endogenous metabolites and metabolic pathways were significantly regulated after combination treatment compared with XBJ or BIPM monotherapy. Metabolisms of lipids, amino acids, acylcarnitines, and bile acids were common pathways involved in the synergistic action of XBJ and BIPM. This study was the first to employ metabolomics to Frontiers in Pharmacology | www.frontiersin.org elucidate the synergistic effect and decipher the underlying mechanisms of BIPM in combination with XBJ against sepsis. The results provide some support for clinical application of antibiotics in combination with traditional Chinese medicines and have important implications for the treatment of sepsis in clinic.

Introduction:Ginkgo biloba L. leaf extract (GBLE) has been reported to be effective for alleviating cognitive and memory impairment in Alzheimer’s disease (AD). Nevertheless, the potential mechanism remains unclear. Herein, this study aimed to explore the neuroprotective effects of GBLE on AD and elaborate the underlying therapeutic mechanism.Methods: Donepezil, the most widely prescribed drug for AD, was used as a positive control. An integrated metabolomics and lipidomics approach was adopted to characterize plasma metabolic phenotype of APP/PS1 double transgenic mice and describe the metabolomic and lipidomic fingerprint changes after GBLE intervention. The Morris water maze test and immunohistochemistry were applied to evaluate the efficacy of GBLE.Results: As a result, administration of GBLE significantly improved the cognitive function and alleviated amyloid beta (Aβ) deposition in APP/PS1 mice, showing similar effects to donepezil. Significant alterations were observed in metabolic signatures of APP/PS1 mice compared with wild type (WT) mice by metabolomic analysis. A total of 60 markedly altered differential metabolites were identified, including 28 lipid and lipid-like molecules, 13 organic acids and derivatives, 11 organic nitrogen compounds, and 8 other compounds, indicative of significant changes in lipid metabolism of AD. Further lipidomic profiling showed that the differential expressed lipid metabolites between APP/PS1 and WT mice mainly consisted of phosphatidylcholines, lysophosphatidylcholines, triglycerides, and ceramides. Taking together all the data, the plasma metabolic signature of APP/PS1 mice was primarily characterized by disrupted sphingolipid metabolism, glycerophospholipid metabolism, glycerolipid metabolism, and amino acid metabolism. Most of the disordered metabolites were ameliorated after GBLE treatment, 19 metabolites and 24 lipids of which were significantly reversely regulated (adjusted-p<0.05), which were considered as potential therapeutic targets of GBLE on AD. The response of APP/PS1 mice to GBLE was similar to that of donepezil, which significantly reversed the levels of 23 disturbed metabolites and 30 lipids.Discussion: Our data suggested that lipid metabolism was dramatically perturbed in the plasma of APP/PS1 mice, and GBLE might exert its neuroprotective effects by restoring lipid metabolic balance. This work provided a basis for better understanding the potential pathogenesis of AD and shed new light on the therapeutic mechanism of GBLE in the treatment of AD.