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Modulating angiogenesis: The yin and the yang in ginseng

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Author: Sengupta, S. · Toh, S.A. · Sellers, L.A. · Skepper, J.N. · Koolwijk, P. · Leung, H.W. · Yeung, H.W. · Wong, R.N.S. · Sasisekharan, R. · Fan, T.P.D.
Type:article
Date:2004
Source:Circulation, 10, 110, 1219-1225
Identifier: 237994
doi: doi10.1161/01.CIR.0000140676.88412.CF
Keywords: Biology · Biomedical Research · Angiogenesis · Nitric oxide · ginseng extract · ginseng polysaccharide · herbaceous agent · nitric oxide synthase · Panax notoginseng extract · panax quinquefolium extract · phosphatidylinositol 3 kinase · polymer · protein kinase B · sterol derivative · animal experiment · animal model · antiangiogenic activity · cell invasion · cell proliferation · chemical analysis · chemical composition · controlled study · drug effect · drug identification · drug isolation · drug mechanism · drug screening · drug structure · endothelium cell · herbal medicine · human cell · human tissue · in vitro study · in vivo study · law · mass spectrometry · neovascularization (pathology) · nonhuman · phenotype · protein expression · regulatory mechanism · species differentiation · standardization · wound healing · 1-Phosphatidylinositol 3-Kinase · Americas · Angiogenesis Inducing Agents · Angiogenesis Inhibitors · Animals · Cells, Cultured · China · Drug Implants · Endothelial Cells · Endothelium, Vascular · Enzyme Inhibitors · Ginsenosides · Humans · Korea · Male · Mice · Mice, Inbred C57BL · Molecular Structure · Neovascularization, Pathologic · NG-Nitroarginine Methyl Ester · Panax · Phytotherapy · Signal Transduction · Species Specificity · Spectrometry, Mass, Electrospray Ionization · Surgical Sponges · Umbilical Veins

Abstract

Background-Ginseng is a commonly used nutraceutical. Intriguingly, existing literature reports both wound-healing and antitumor effects of ginseng extract through opposing activities on the vascular system. To elucidate this perplexity, we merged a chemical fingerprinting approach with a deconstructional study of the effects of pure molecules from ginseng extract on angiogenesis. Methods and Results-A mass spectrometric compositional analysis of American, Chinese and Korean, and Sanqi ginseng revealed distinct "sterol ginsenoside" fingerprints, especially in the ratio between a triol, Rg1, and a diol, Rb1, the 2 most prevalent constituents. Using a Matrigel implant model and reconstituting the extracts using distinct ratios of the 2 ginsenosides, we demonstrate that the dominance of Rg1 leads to angiogenesis, whereas Rb1 exerts an opposing effect. Rg1 also promoted functional neovascularization into a polymer scaffold in vivo and the proliferation of, chemoinvasion of, and tubulogenesis by endothelial cells in vitro, an effect mediated through the expression of nitric oxide synthase and the phosphatidylinositol-3 kinase→Akt pathway. In contrast, Rb1 inhibited the earliest step in angiogenesis, the chemoinvasion of endothelial cells. Conclusions-The present study explains, for the first time, the ambiguity about the effects of ginseng in vascular pathophysiology based on the existence of opposing active principles in the extract. We also unraveled a speciogeographic variation impinging on the compositional fingerprint that may modulate the final phenotype. This emphasizes the need for regulations standardizing herbal therapy, currently under the Dietary Supplement and Health Education Act. Furthermore, we propose that Rg1 could be a prototype for a novel group of nonpeptide molecules that can induce therapeutic angiogenesis, such as in wound healing. Chemicals / CAS: nitric oxide synthase, 125978-95-2; phosphatidylinositol 3 kinase, 115926-52-8; protein kinase B, 148640-14-6; 1-Phosphatidylinositol 3-Kinase, EC 2.7.1.137; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Drug Implants; Enzyme Inhibitors; ginsenoside Rb1; ginsenoside Rg1, 22427-39-0; Ginsenosides; NG-Nitroarginine Methyl Ester, 50903-99-6