By contrast, if no sugar moieties were attached to the 20th carbon of the ginsenosides such as Rg3, Rh2, and Rg2, the ginsenosides acted as a prooxidant. In ginsenosides such as Rh1, glucose is attached to the sixth carbon instead of the 20th, and in this case, the ginsenoside acts as an antioxidant only [29]. All these aggregated reports revealed that the prevention of ROS generation

by ginseng may be an important milestone in the prevention of oxidative damage. Ginsenoside Rb1 has protective effects on human umbilical vein endothelial cells in vitro [30]. Water extract of Korean red ginseng stimulates angiogenesis by activating the phosphoinositol-3-kinase GSK126 (PI3K)/Akt-dependent extracellular signal-regulated kinase 1/2 and endothelial nitric oxide synthase (eNOS) pathways in human umbilical vein endothelial cells [31]. Angiomodulatory and neurological effects are also shown by ginsenosides [32]. One study shows that potassium channels of vascular smooth muscle PD-1/PD-L1 mutation cells have

been activated by ginsensoside Re through the PI3K/Akt and NO pathways [33]. Another study shows that ginsenoside Re has nongenomic effects in endothelial cells through the glucocorticoid receptor (GR) [34]. Capillary morphogenesis was attenuated by ginsenoside Rb1 [35]. Another in vitro study revealed the enhancement of vascular endothelial cell proliferation and migration by extracts of P. ginseng and P. notoginseng [36]. Saponin from P. notoginseng shows angiogenic effects on both human umbilical vein endothelial cells and in zebrafish models [37]. It is also reported that atherosclerotic lesions in apolipoprotein E (ApoE)-deficient

mice and tumor necrosis factor-alpha-induced endothelial adhesion molecule expression have been reduced by P. notoginseng [38]. Production of NO was increased Pyruvate dehydrogenase lipoamide kinase isozyme 1 by ginsenoside Rg3 by increasing phosphorylation and expression of eNOS [39]. In human umbilical vein endothelial cells, fibroblast growth factor-induced angiogenesis was inhibited by compound K through the modulation of p38 mitogen-activated protein kinase (PK) and Akt [40]. The aforementioned reports propose that the saponin extracted from ginseng protects vascular endothelial cells through the NO-, Akt-, and GR-mediated signaling pathways. Effects of ginseng and ginsenosides have been sufficiently studied on the cardiovascular system. Through the production and release of NO, endothelium regulates blood vessel tone [41], [42] and [43]. Production of NO has been stimulated by ginsenosides by a number of ways. It is reported that NO production in human aortic endothelial cells was induced by purified ginsenoside Rb1 [44]. Ginsenoside stimulates NO release in human umbilical vein endothelial cells by phosphorylation of GR, PI3K, Akt/PKB, and eNOS [45]. In isolated canine corpus cavernosum model, ginsenoside Rg3 induced vasodilation [46], which shows that arterial stiffness has been improved by Korean red ginseng and ginsenosides [47].