Artesunate is a widely used drug in clinical treatment of malaria. The aim of this study was to investigate the therapeutic mechanism of artesunate on malaria using an integrated strategy of network pharmacology and serum metabolomics. The mice models of malaria were established using 2 × 10 7 red blood cells infected with Plasmodium berghei ANKA injection. Giemsa and hematoxylin-eosin (HE) staining were used to evaluate the efficacy of artesunate on malaria. Next, network pharmacology analysis was applied to identify target genes. Then, a metabolomics strategy has been developed to find the possible significant serum metabolites and metabolic pathways induced by artesunate. Additionally, two parts of the results were integrated to confirm each other. Giemsa and HE staining results showed that artesunate significantly inhibited the proliferation of Plasmodium and reduced liver and spleen inflammation. Based on metabolomics, 18 differential endogenous metabolites were identified as potential biomarkers related to the artesunate for treating malaria. These metabolites were mainly involved in the relevant pathways of biosynthesis of unsaturated fatty acids; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; and phenylalanine, tyrosine, and tryptophan biosynthesis. The results of the network pharmacology analysis showed 125 potential target genes related to the treatment of malaria with artesunate. The functional enrichment was mainly associated with lipid and atherosclerosis; pathways of prostate cancer and proteoglycans in cancer; and PI3K-Akt, apoptosis, NF-κB, Th17 cell, and AGE-RAGE signaling pathways. These findings were partly consistent with the findings of the metabolism. Our results further suggested that artesunate could correct the inflammatory response caused by malaria through Th17 cell and NF-κB pathways. Meanwhile, our work revealed that cholesterol needed by Plasmodium berghei came directly from serum. Cholesterol and palmitic acid may be essential in the growth and reproduction of Plasmodium berghei . In summary, artesunate may have an effect on anti-malarial properties through multiple targets.
Mulberroside A is a polyhydroxylated stilbene active component of Morus alba L. Studies have shown that it has antitussive, antiasthmatic, tyrosinase and antioxidation activities. However, little is known about the metabolism of it in vitro and in vivo. In our study, an integrated strategy on the basis of UHPLC-Q-Exactive Plus Orbitrap MS and network pharmacology was established to comprehensively research the metabolic characteristic of mulberroside A for the first time. Plasma, urine, feces and liver tissues of rats in the blank group and drug group were collected after intragastric administration of mulberroside A at a dose of 150 mg/kg, and rat liver microsomes were cultured for in vitro metabolism experiment. The biological samples were processed by different methods and analyzed in positive and negative ion modes using UHPLC-Q-Exactive Plus Orbitrap MS. A total of 72 metabolites were finally identified based on the accurate molecular mass, retention time, MS/MS spectra and related literatures combined with the Compound Discoverer 3.1. The metabolic pathways were mainly hydrolysis, glucuronidation, hydrogenation, sulfation, hydroxylation, methylation and their composite reactions. In addition, a network pharmacology method was used to predict the mechanism of action of mulberroside A and its metabolites. In the end, 7 metabolites with high gastrointestinal absorption and drug-likeness and 167 targets were screened by Swiss ADME and Swiss Target Prediction. 1702 items of GO analysis and 158 related signaling pathways of KEGG were enriched using Metascape. This study established a novel integrated strategy based on UHPLC-Q-Exactive Plus Orbitrap MS and network pharmacology, which could systematically analyze the metabolism behavior of mulberroside A in vivo and in vitro of rats and provide basis for the further research of mulberroside A.
Neobavaisoflavone is an important isoflavone component isolated from Psoraleae Fructus. It is used extensively worldwide because of its antibacterial, antioxidant, anti-inflammatory, anticancer, and anti-osteoporotic activities. However, there is no systematic and comprehensive research on the metabolism of neobavaisoflavone in vivo and in vitro. The study aimed to analyze the metabolic characteristics and mechanism of neobavaisoflavone for the first time. Firstly, biological samples were pretreated by the solid-phase extraction (SPE) method, methanol precipitation, and acetonitrile precipitation. Secondly, the samples were analyzed on UHPLC-Q-Exactive Plus Orbitrap MS. Thirdly, metabolites were tentatively identified based on retention time, parallel reaction monitoring strategy, diagnostic product ions, and neutral loss fragments. A total of 72 metabolites of neobavaisoflavone were tentatively identified, including 28 in plasma, 43 in urine, 18 in feces, six in the liver, and four in the liver microsome. The results suggested that neobavaisoflavone mainly underwent glucuronidation, sulfation, hydroxylation, methylation, cyclization, hydration, and their composite reactions in vivo and in vitro. In addition, nine active components with high bioavailability and 191 corresponding targets were predicted by the Swiss Drug Design database. The 1806 items of GO and 183 KEGG signaling pathways were enriched. These results showed that metabolites expanded the potential effects of neobavaisoflavone. The present study would provide the scientific basis for the further exploitation and application of neobavaisoflavone.
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