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Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition.

ABSTRACT: In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (1?8), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. All the compounds (1?8) showed a significant inhibition to bacterial NA with IC₅₀ values of 0.17?106.3 µM. In particular, the prenyl group on the flavonoids played a critical role in bacterial NA inhibition. Epimedokoreanin B (compound 1, IC₅₀ = 0.17 µM) with two prenyl groups on C8 and C5' of luteolin was 500 times more effective than luteolin (IC₅₀ = 85.6 µM). A similar trend was observed on compound 2 (IC₅₀ = 0.68 µM) versus dihydrokaempferol (IC₅₀ = 500.4 µM) and compound 3 (IC₅₀ = 12.6 µM) versus apigenin (IC₅₀ = 107.5 µM). Kinetic parameters (K_m, V_max, and K_ik/K_iv) evaluated that all the compounds apart from compound 5 showed noncompetitive inhibition. Compound 5 was proven to be a mixed type inhibitor. In an enzyme binding affinity experiment using fluorescence, affinity constants (K_SV) were tightly related to inhibitory activities.

SUBMITTER: Choi HM

PROVIDER: S-EPMC6359343 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition.

Choi Hong Min HM Kim Jeong Yoon JY Li Zuo Peng ZP Jenis Janar J Ban Yeong Jun YJ Baiseitova Aizhamal A Park Ki Hun KH

Molecules (Basel, Switzerland) 20190116 2

In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (1⁻8), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. ...[more]

PMID: 30654565

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Project description:Epimedii Folium is widely used worldwide as an herbal supplement, and the risk of its induced liver damage has emerged in recent years. Our preliminary study has found that, among several Epimedii Folium species specified in the Chinese Pharmacopoeia, Epimedium koreanum Nakai has a more severe propensity for hepatotoxicity. However, the mechanism of hepatotoxicity of Epimedium koreanum Nakai is still unclear. In this study, untargeted metabolomics was performed to analyze the serum and liver tissue to explore the mechanism of hepatotoxicity of Epimedium koreanum Nakai. The results of experiments in vivo showed that, after 28 days of exposure to Epimedium koreanum Nakai ethanol extract (EEE), the liver weight, levels of AST, ALP, TBIL, etc. in serum of rats in the EEE group were significantly increased, as well as severe cytoplasmic vacuolation appeared in the liver tissue, which suggested that EEE has significant hepatotoxicity. Subsequently, the results of metabolomics revealed significant changes in the metabolic profile in the liver and serum of rats after EEE exposure, in which metabolites in serum such as flavin mononucleotide, phenylacetylglycine, glutathione, l-tryptophan, and sphingomyelin were able to accurately identify liver injury caused by EEE and could be used as serum markers to reflect EEE-induced liver injury. The KEGG pathway enrichment analysis revealed that EEE caused extensive effects on rats' metabolic pathways. Some of the most affected pathways included glutathione metabolism, glutamate metabolism pathway, primary bile acid biosynthesis pathway, and sphingolipid metabolism pathway, which were all directed to the biological process of ferroptosis. Then, the main markers related to ferroptosis in the liver were examined, and the results demonstrated that the content of malondialdehyde was significantly increased, the activity of superoxide dismutase was significantly reduced, the ferroptosis inhibitory proteins GPX4 and System xc - were significantly downregulated, and the ferroptosis-promoting protein ACSL4 was significantly up-regulated. Judging from these results, we concluded that the mechanism of hepatotoxicity of Epimedium koreanum Nakai was probably related to the induction of ferroptosis in hepatocytes.

Project description:Introduction: The root of Cratoxylum cochinchinense has been widely used as Chinese folk medicine to cure fevers, burns, and abdominal complications because it contains various bioactive metabolites such as xanthones, triterpenes, and flavonoids. In this study, we estimated bacterial neuraminidase inhibition with a series of xanthones from C. cochinchinense. BNA has connected to various biological functions such as pathogenic bacteria infection inflammatory process after infection and biofilm formation. Methods: The identification of xanthones (1-6) bearing geranyl and prenyl groups was established by spectroscopic data using UV, IR, NMR, and HREIMS. BNA inhibitory modes of isolated xanthones were investigated by Double-reciprocal plots. Moreover, the competitive inhibitor was evaluated the additional kinetic modes determined by kinetic parameters (k 3, k 4, and K i app). The molecular docking (MD) and molecular dynamics simulations (MDS) studies also provided the critical information regarding the role of the geranyl and prenyl groups against BNA inhibition. Results: A series of xanthones (1-6) appended prenyl and geranyl groups on the A-ring were isolated, and compounds 1-3 were shown to be new xanthones. The analogues within this series were highly inhibited with excellent affinity against bacterial neuraminidase (BNA). A subtle change in the prenyl or geranyl motif affected the inhibitory potency and behavior significantly. For example, the inhibitory potency and binding affinity resulting from the geranyl group on C4: xanthone 1 (IC50 = 0.38 μM, KA = 2.4434 × 105 L·mol-1) were 100-fold different from those of xanthone 3 (IC50 = 35.8 μM, KA = 0.0002 × 105 L·mol-1). The most potent compound 1 was identified as a competitive inhibitor which interacted with BNA under reversible slow-binding inhibition: K i app = 0.1440 μM, k 3 = 0.1410 μM-1s-1, and k 4 = 0.0203 min-1. The inhibitory potencies (IC50) were doubly confirmed by the binding affinities (KA). Discussion: This study suggests the potential of xanthones derived from C. cochinchinense as promising candidates for developing novel BNA inhibitors. Further research and exploration of these xanthones may contribute to the development of effective treatments for bacterial infections and inflammatory processes associated with BNA activity.

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Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition.

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Effectiveness of Prenyl Group on Flavonoids from <i>Epimedium koreanum</i> Nakai on Bacterial Neuraminidase Inhibition.

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