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The purported effects of "circulation-improving" herbs used in traditional Chinese medicine (TCM) show striking similarities with the vascular actions of nitric oxide (NO) produced by the endothelial NO synthase (eNOS). We have previously reported that Salviae miltiorrhizae radix and Zizyphi spinosae semen upregulate eNOS expression. In the present study, we studied the effect on eNOS gene expression of 15 Chinese herbs with potential effects on the vasculature, and identified Prunella vulgaris L. (PVL) (flowering spike) as a potent eNOS-upregulating agent. In EA.hy 926 cells, a cell line derived from human umbilical vein endothelial cells (HUVEC), an aqueous extract of PVL increased eNOS promoter activity, eNOS mRNA and protein expressions, as well as NO production in concentration- and time-dependent manners. We have previously shown that ursolic acid (a constituent of Salviae miltiorrhizae radix), betulinic acid (a compound present in Zizyphi spinosae semen), luteolin and cynaroside (ingredients of artichoke, Cynara scolymus L.) are capable of enhancing eNOS gene expression. These compounds are also present in significant quantities in PVL. Thus, PVL contains active principles that stimulate human eNOS gene expression, and such compounds may have therapeutic potential against cardiovascular diseases.

Rhodiola crenulata root extract (RCE), a traditional Chinese medicine, has been shown to regulate glucose and lipid metabolism via the AMPK pathway in high glucose (HG) conditions. However, the effect of RCE on HG-induced endothelial dysfunction remains unclear. The present study was designed to examine the effects and mechanisms of RCE against hyperglycemic insult in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without RCE and then exposed to 33mM HG medium. The cell viability, nitrite production, oxidative stress markers, and vasoactive factors, as well as the mechanisms underlying RCE action, were then investigated. We found that RCE significantly improved cell death, nitric oxide (NO) defects, and oxidative stress in HG conditions. In addition, RCE significantly decreased the HG-induced vasoactive markers, including endothelin-1 (ET-1), fibronectin, and vascular endothelial growth factor (VEGF). However, the RCE-restored AMPK-Akt-eNOS-NO axis and cell viability were abolished by the presence of an AMPK inhibitor. These findings suggested that the protective effects of RCE were associated with the AMPK-Akt-eNOS-NO signaling pathway. In conclusion, we showed that RCE protected endothelial cells from hyperglycemic insult and demonstrated its potential for use as a treatment for endothelial dysfunction in diabetes mellitus.

Ginseng has been reported to have diverse pharmacological effects. One of the therapeutic claims for ginseng is to enhance sexual function. Ginsenosides are considered as the major active constituents. A steaming process can alter the ginsenoside profile of ginseng products. The structure–function relationship of ginsenosides in the treatment of erectile dysfunction (ED) has not been investigated yet. In this work, 15 different processed ginsengs are produced by steaming, and 13 major ginsensosides are quantified by liquid chromatography with UV detection, including Rg1, Re, Rf, Rb1, Rc, Rb2, Rf, Rk3, Rh4, 20S-Rg3, 20R-Rg3, Rk1, and Rg5. Their anti-ED activities are screened using hydrocortisone-induced mice model (Kidney Yang Deficiency Syndrome in Chinese Medicine) and primary corpus cavernosum smooth muscle cells (CCSMCs). A processed ginseng with steaming treatment at 120${}^{\circ }$C for 4h and five times possesses abundant ginsenosides Rk1, Rk3, Rh4 and Rg5 transformed via deglycosylation and dehydroxylation, and produces optimal activity against ED. The number of sugar molecules, structure of hydroxyl groups and stereoselectivity in ginsenosides affect their anti-ED activity. Among the 13 ginsenosides, Rk1, Rk3, Rh4 and Rg5 are the most efficient in decreasing intracellular calcium levels by inhibiting phosphodiesterase 5A (PDE5A) to reduce the degradation of cyclic guanosine monophosphate (cGMP) in CCSMCs. Rg5 also restrain hypoxia inducible factor-1$\alpha$ (HIF-1$\alpha )$ expression in hypoxia state, and increase endothelial nitric oxide synthase (eNOS) expression in isolated rat cavernous tissue. These observations suggest a role for steamed ginseng containing two pairs of geometric isomers (i.e., Rk1/Rg5 and Rk3/Rh4) in the treatment of ED.

Angiogenesis plays a crucial role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration are critical steps in tumor angiogenesis. Here, we investigated the anti-angiogenic activity of xanthorrhizol, a sesquiterpenoid isolated from the Indonesian medicinal plant Curcuma xanthorrhiza. Xanthorrhizol at noncytotoxic concentrations inhibited the proliferation, migration, and formation of capillary-like tubes in VEGF-treated human umbilical vein endothelial cells (HUVECs). Xanthorrhizol inhibited the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin in VEGF-treated HUVECs. The expression and transcriptional activity of NF-$\kappa$B were downregulated by xanthorrhizol in VEGF-treated HUVECs. Furthermore, xanthorrhizol significantly inhibited VEGF-induced angiogenesis in the chorioallantoic membrane of fertilized eggs and Matrigel plugs subcutaneously injected into mice. Xanthorrhizol inhibited tumor volume and tumor-derived angiogenesis in mice inoculated with breast cancer cells. The in vitro and in vivo anti-angiogenic activities of xanthorrhizol were as potent as those of curcumin, a well-known anticancer agent derived from C. longa. Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-$\kappa$B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.