Hyperuricemia (HUA) is a common metabolic disease that is an independent risk factor for comorbidities such as hypertension, chronic kidney disease, and coronary artery disease. The prevalence of HUA has increased over the last several decades with improved living standards and increased lifespans. Metabolites are considered the most direct reflection of individual physiological and pathological conditions, and represent attractive candidates to provide deep insights into disease phenotypes. Metabolomics, a technique used to profile metabolites in biofluids and tissues, is a powerful tool for identification of novel biomarkers, and can be used to provide valuable insights into the etiopathogenesis of metabolic diseases and to evaluate the efficacy of drugs. In this study, multi metabolomics-based analysis of the blood, urine, and feces of rats with HUA showed that HUA significantly altered metabolite profiles. Astragalus membranaceus (AM) and benbromomalone significantly mitigated these changes in blood and feces, but not in urine. Some crucial metabolic pathways including lipid metabolism, lipid signaling, hormones synthesis, unsaturated fatty acid (UFAs) absorption, and tryptophan metabolism, were seriously disrupted in HUA rats. In addition, AM administration exerted better treatment effects on HUA than benbromomalone. Furthermore, additional supplementation with UFAs and tryptophan may also induce therapeutic effects against HUA.

As the most abundant and bioactive constituent in vine tea (Ampelopsis grossedentata), dihydromyricetin possesses numerous biological activities. A rapid profiling and identification method for dihydromyricetin metabolites in rats after the oral administration has been established using ultra-highperformance liquid chromatography-Q-Exactive Orbitrap mass spectrometry coupled with multiple data-mining methods. Herein, an efficient analytical strategy characterized by a parallel reaction monitoring mode combining diagnostic fragment ions filtering techniques was developed for the comprehensive identification of dihydromyricetin metabolites in rat plasma, urine, and feces. And then, the biotransformation pathways of dihydromyricetin were further revealed. As a result, a total of 49 metabolites were finally identified by comparing diagnostic fragment ions, chromatographic retention times, neutral loss fragment ions, and accurate mass measurement with those of the dihydromyricetin reference standard. These metabolites were presumed to be dominantly generated through hydroxylation, dehydroxylation, methylation, reduction, sulfation, decarbonylation, glucuronidation, glucosylation, and their composite reactions. In a word, our present results not only supplied a solid foundation to better understand the action mechanism of dihydromyricetin, but also provided some models for the metabolism study of the other compounds in traditional Chinese medicines or natural plants.

Pterostilbene, a stilbene phytoalexin, is mainly obtained from blueberries and grape vines; however, its metabolic mechanisms were unclear in vivo. In the present study, three different methods were used to prepare biological samples, and then, an efficient strategy based on ultrahigh-performance liquid chromatography coupled with mass spectrometry was developed to screen and identify pterostilbene metabolites in rat urine, plasma, liver, and feces. In order to elucidate pterostilbene or its metabolites involved in vitro, this study was assessed by the liver microsome system. As a result, a total of 88 pterostilbene metabolites were characterized. Among them, 77 metabolites in vivo and 14 metabolites in vitro were found; 50 and 38 metabolites were observed in rat plasma and urine, while only 4 and 12 metabolites were detected in rat feces and liver, inferring that plasma and urine possessed more diverse types of pterostilbene metabolites; 41 metabolic products were obtained by solid-phase extraction, and 9 and 10 metabolites were screened by methanol precipitation and acetonitrile precipitation, respectively, indicating that solid-phase extraction could be adopted as the most acceptable method for pterostilbene metabolism. The results also demonstrated that pterostilbene mainly underwent glucosylation, dehydrogenation, hydrogenation, demethoxylation, sulfation, NAC binding, methylene ketogenic, acetylation, and methylation. In summary, this research provides an idea for the further study of drug metabolism.

Arctigenin is a phenylpropanoid dibenzylbutyro lactone lignan compound with multiple biological functions. Previous studies have shown that arctigenin have neuroprotective effects in Alzheimer’s disease (AD) models both in vivo and in vitro; however, its metabolism in vivo has not been studied. Most traditional analytical methods only partially characterize drug metabolite prototypes, so there is an urgent need for a research strategy that can fully characterize drug metabolites. In the present study, ions fishing with a serial five-membered lactone ring as a fishhook strategy based on ultrahigh-performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) was utilised to characterise the metabolism of arctigenin, and the establishment of this strategy also solved the challenge of creating a comprehensive metabolic profile of neolignan. Based on the proposed strategy, a total of 105 metabolites were detected and characterised, 76 metabolites of which were found in rats and 49 metabolites in liver microsomes. These metabolites were postulated to be produced through oxidation, reduction, hydrolysis, and complex reactions. Subsequently, network pharmacology was utilized to elucidate the mechanism of arctigenin and its main metabolites against Alzheimer’s disease, screening 381 potential targets and 20 major signaling pathways. The study on the comprehensive metabolism of arctigenin provides a holistic metabolic profile, which will help to better understand the mechanism of arctigenin in the treatment of Alzheimer’s disease (AD) and also provide a basis for the safe administration of arctigenin.