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Cellular Metabolomics Revealed the Cytoprotection of Amentoflavone, a Natural Compound, in Lipopolysaccharide-Induced Injury of Human Umbilical Vein Endothelial Cells.

ABSTRACT: Amentoflavone is one of the important bioactive flavonoids in the ethylacetate extract of "Cebaiye", which is a blood cooling and hematostatic herb in traditional Chinese medicine. The previous work in our group has demonstrated that the ethylacetate extract of Cebaiye has a notable antagonistic effect on the injury induced by lipopolysaccharide (LPS) to human umbilical vein endothelial cells (HUVECs). The present investigation was designed to assess the effects and possible mechanism of cytoprotection of amentoflavone via metabolomics. Ultra-performance liquid chromatography/quadrupole time of flight-mass spectrometry (UPLC/QTOF-MS) coupled with multivariate data analysis was used to characterize the variations in the metabolites of HUVECs in response to exposure to LPS and amentoflavone treatment. Seven putative metabolites (glycine, argininosuccinic acid, putrescine, ornithine, spermidine, 5-oxoproline and dihydrouracil) were discovered in cells incubated with LPS and/or amentoflavone. Functional pathway analysis uncovered that the changes of these metabolites related to various significant metabolic pathways (glutathione metabolism, arginine and proline metabolism, ?-alanine metabolism and glycine, serine and threonine metabolism), which may explain the potential cytoprotection function of amentoflavone. These findings also demonstrate that cellular metabolomics through UPLC/QTOF-MS is a powerful tool for detecting variations in a range of intracellular compounds upon toxin and/or drug exposure.

SUBMITTER: Yao W

PROVIDER: S-EPMC5037791 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metronomic oral vinorelbine (VRL; Navelbine) was shown in clinical trials to yield sustainable antitumor activity possibly through antiangiogenic mechanisms. We investigated the effects of protracted low-dose VRL on human umbilical vein endothelial cells, compared with a conventional chemotherapy model. Human umbilical vein endothelial cell cultures were treated with different concentrations of VRL (0.001 nmol/l to 1 mmol/l) for 4, 24 and 96 h. The effects of different drug concentrations on cell growth, cell cycle, apoptosis and expression of the angiogenesis-modulating genes interleukin-8, cyclooxygenase-2, CD36 and peroxisome proliferator-activated receptor γ were assessed using the metronomic or conventional chemotherapy model. Apoptosis and cell-cycle effects were assessed by flow cytometry. Gene expression was measured at the transcript level by quantitative reverse transcriptase-PCR, protein expression by immunoblotting and levels of proteins secreted in the cell medium by enzyme-linked immunosorbent assay. Activation of the nuclear factor-κB pathway was investigated by immunoblot analysis of cytosolic and nuclear protein extracts. The half-maximal inhibitory concentrations (IC50) of VRL at 96 h were four orders lower compared with those after a 24-h exposure (1.23 nmol/l vs. 32 mmol/l for VRL). Drug concentrations at high nanomolar levels and above, which are relevant to conventional pulsatile dosing of VRL, induced a dose-dependent and nuclear factor-κB-related increase in proangiogenic interleukin-8 and cyclooxygenase-2 and a decrease in the thrombospondin-1 receptor CD36 and peroxisome proliferator-activated receptor γ at mRNA and protein levels. In contrast, the opposite was evident with protracted picomolar to low nanomolar concentrations (metronomic dosing). Our data provide experimental support for metronomic VRL by showing that a protracted low dose outperforms pulsed high-dose administration in inducing antiangiogenic effects in proliferating human endothelial cells.

Dataset Information

Cellular Metabolomics Revealed the Cytoprotection of Amentoflavone, a Natural Compound, in Lipopolysaccharide-Induced Injury of Human Umbilical Vein Endothelial Cells.

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