Atherosclerosis (AS) is a chronic disorder of large arteries that is a major risk factors of high morbidity and mortality. Oxidative modification LDL is one of the important contributors to atherogenesis. Macrophages take up ox-LDL and convert into foam cells, which is the hallmark of AS. To advance the understanding of the metabolic perturbation involved in ox-LDL induced macrophage-derived foam cells and discover the potential biomarkers of early AS, a global metabolomics approach was applied based on UHPLC-QTOF/MS. Multivariate statistical analyses identified five metabolites (25-azacholesterol, anandamide, glycocholate, oleoyl ethanolamide, and 3-oxo-4, 6-choladienoate) for distinguishing foamy macrophages from controls. Among the six main metabolic pathways, the unsaturated fatty acid, especially arachidonic acid metabolism, contributed importantly to early AS. A new biomarker, anandamide (AEA), whose synthesis and metabolism in macrophages are disturbed by overloaded ox-LDL, results in metabolic obstruction. This study is the first to investigate the metabolic disturbance in macrophage-derived foam cells induced by ox-LDL and screen potential biomarkers and metabolic pathways associated with early AS. Our findings provide a new insight in the underlying pathophysiological mechanisms and also help to identify novel targets for the intervention of AS.
Objective: Investigate the active ingredients and underlying hypolipidemic mechanisms of Danhe granule (DHG). Methods: The lipid-lowering effect of DHG was evaluated in hyperlipidemic hamsters induced by a high-fat diet. The ingredients absorbed into the blood after oral administration of DHG in hamsters were identified by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). A systems pharmacology approach incorporating target prediction and network construction, gene ontology (GO) enrichment and pathway analysis was performed to predict the active compounds and map the compounds-targets-disease network. Real-time polymerase chain reaction (RT-PCR) and Western blot were utilized to analyze the mRNA and protein expression levels of predicted targets. Results: DHG remarkably lowered the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and arteriosclerosis index (AI), at the same time, elevated the levels of serum high-density lipoprotein cholesterol (HDL-c) and HDL-c/TC ratio in hyperlipidemic hamsters. Sixteen ingredients absorbed into blood after oral administration of DHG were identified as the possible components interacted with targets. Moreover, 65 potential targets were predicted after targets intersection and compounds-targets-disease network mapping. Then, compounds-targets-pathways network mapping revealed that six active compounds (emodin, naringenin, etc.) compounds could interact with 10 targets such as sterol regulatory element binding protein (SREBP) 1c, SREBP-2 and peroxisome proliferation-activated receptor (PPAR) a, regulate three lipid metabolism-related pathways including SREBP control of lipid synthesis pathway, PPAR signaling pathway and nuclear receptors in lipid metabolism and toxicity pathway, and further affect lipid metabolic processes including fatty acid biosynthesis, low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake, bile acid biosynthesis, and cholesterol efflux. Experimental results indicated that DHG significantly increased SREBP-2, LDLR, PPARa, liver X receptor alpha (LXRa),
The key in vivo metabolites of a drug play an important role in its efficacy and toxicity. However, due to the low content and instability of these metabolites, they are hard to obtain through in vivo methods. Electrochemical reactions can be an efficient alternative to biotransformation in vivo for the preparation of metabolites. Accordingly, in this study, the metabolism of Z-ligustilide was investigated in vitro by electrochemistry coupled online to mass spectrometry. This work showed that five oxidation products of the electrochemical reaction were detected and that two of the oxidation products (senkyunolide I and senkyunolide H) were identified from liver microsomal incubation as well. Furthermore, after intragastric administration of Z-ligustilide in rats, senkyunolide I and senkyunolide H were detected in the rat plasma and liver, while 6,7-epoxyligustilide, a key intermediate metabolite of Z-ligustilide, was difficult to detect in vivo. By contrast, 6,7-epoxyligustilide was obtained from the electrochemical reaction. In addition, for the first time, 6 mg of 6,7-epoxyligustilide was prepared from 120 mg of Z-ligustilide. Therefore, electrochemical reactions represent an efficient laboratory method for preparing key drug metabolites.
Rhodiola crenulata (R. crenulata), is a famous traditional Chinese medicine, with observable effects such as anti-high-altitude illness and fatigue resistance. Nevertheless, comprehensive and systematic structural identification of its components remains a challenge. In this study, a pseudotargeted analytical method, involving key fragment filtering by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and ultra-high performance liquid chromatography-linear ion trap-Orbitrap mass spectrometry, was developed for rapid detection and identification of the chemical constituents of R. crenulata. The process consists of three steps: (i) acquiring sufficient mass spectral data, (ii) constructing a key fragments schedule and discovering the substructures rapidly by pseudotargeted key fragment filtering, and (iii) further identification of the compound structures based on accurate masses, fragment ions, related literatures, and authentic standards. As a result, 104 compounds were identified and divided into five categories, among which three potentially new and 59 ones were reported for the first time in R. crenulata. These results indicated that the major types of components are flavanols and gallic acid derivatives, organic acids, alcohols and their glycosides, flavonoids and their glycosides. This study enhances the understanding of R. crenulata and provides a reference for rapid and comprehensive identification of constituents in other herbal medicines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.