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Atherosclerosis is a chronic inflammatory disease of arterial wall, and circulating monocyte adhesion to endothelial cells is a crucial step in the pathogenesis of atherosclerosis. Epithelial-stromal interaction 1 (EPSTI1) is a novel gene, which is dramatically induced by epithelial-stromal interaction in human breast cancer. EPSTI1 expression is not only restricted to the breast but also in other normal tissues. In this study we investigated the role of EPSTI1 in monocyte-endothelial cell adhesion and its expression pattern in atherosclerotic plaques. We showed that EPSTI1 was dramatically upregulated in human and mouse atherosclerotic plaques when compared with normal arteries. In addition, the expression of EPSTI1 in endothelial cells of human and mouse atherosclerotic plaques is significantly higher than that of the normal arteries. Furthermore, we demonstrated that EPSTI1 promoted human monocytic THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs) via upregulating VCAM-1 and ICAM-1 expression in HUVECs. Treatment with LPS (100, 500, 1000 ng/mL) induced EPSTI1 expression in HUVECs at both mRNA and protein levels in a dose- and time-dependent manner. Knockdown of EPSTI1 significantly inhibited LPS-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. Moreover, we revealed that LPS induced EPSTI1 expression through p65 nuclear translocation. Thus, we conclude that EPSTI1 promotes THP-1 cell adhesion to endothelial cells by upregulating VCAM-1 and ICAM-1 expression, implying its potential role in the development of atherosclerosis.

Aim: Quercetin and isorhamnetin are common constituents of some herb extracts, such as extracts of gingko leaves and total flavones of Hippophae rhamnoides L. The intra-herb pharmacokinetics interactions between isorhamnetin and quercetin were investigated in the present study. Methods: Human MDR1 cDNA transfected MDCKII cells were used to validate whether isorhamnein interacted with P-gp. Caco-2 transport assays and a randomized, 3-way crossover pharmacokinetics study in rats were used to investigate the pharmacokinetics interactions. HPLC was used to determine cell transport samples. The total plasma concentrations of quercetinand isorhamnetin were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) by treatment with β-glucuronidase and sulfatase. Results: The permeability ratio (absorptive permeability/secretive permeability) of isorhamnetin across human MDR1 cDNA transfected MDCKII cells, Caco-2 cells and wild-type MDCKII cells are 0.25±0.02, 0.74±0.05, and 1.41±0.06, respectively. This result proved the role of P-gp in the cell efflux of isorhamnetin. While co-transporting with each other across Caco-2 cells monolayer, the permeability ratio of isorhamnetin and quercetin increased by 4.3 and 2.2 times. After coadministration with each other to rats, the Cmax, AUC0–72 h, and AUC0–∞ of both isorhamnetin and quercetin significantly increased compared with single administration. Conclusion: The above results proved intra-herb pharmacokinetics interaction between quercetin and isorhamentin. P-gp might play an important role, whereas other drug efflux pumps, such as multi-drug resistance associate protein 2 and breast cancer resistance protein, might be involved. Accordingly, besides the drug-herb interactions, intra-herb interaction might be brought into view with the wide use of herbal-based remedies.