Protective effect of fermented Red ginseng on a transient focal ischemic rats

Red ginseng and fermented red ginseng were prepared, and their composition of ginsenosides and antiischemic effect were investigated. When ginseng was steamed at 98-100 degrees C for 4 h and dried for 5 h at 60 degrees C, and extracted with alcohol, its main components were ginsenoside Rg3> ginsenoside Rb1 > ginsenoside Rb2. When the ginseng was suspended in water and fermented for 5 days by previously cultured Bifidobacterium H-1 and freeze-dried (fermented red ginseng), its main components were compound K > ginsenoside Rg3 > or = ginsenoside Rh2. Orally administered red ginseng extract did not protect ischemia-reperfusion brain injury. However, fermented red ginseng significantly protected ischemica-reperfusion brain injury. These results suggest that ginsenoside Rh2 and compound K, which was found to be at a higher content in fermented red ginseng than red ginseng, may improve ischemic brain injury.     

Evaluation of antipruritic effects of red ginseng and its ingredients in mice

The anti-pruritic effect of red ginseng (the steamed root of Panax ginseng C.A. Meyer, Araliaceae), a traditional medicine in Asian countries, was investigated in mouse scratching behavior models induced by either compound 48/80 or histamine. Red ginseng and its saponin fraction, but not its polysaccharide fraction, showed an anti-pruritic effect. Representative constituents in the saponin fraction, ginsenosides Rg3 and Rh2, inhibited scratching behavior and vascular permeability. These ginsenosides also inhibited the expression of TNF-alpha and IL-4 induced by IgE-antigen complex in RBL-2H3 cells, as well as acetic acid-induced writhing in mice. These results suggest that red ginseng and its ingredients, ginsenosides Rg3 and Rh2, may inhibit scratching behavior by inhibiting IL-4 and TNF-alpha expression, promoting membrane stability, and inhibiting Ca (++) influx.     

Inhibitory effects of Korean red ginseng and its genuine constituents ginsenosides Rg3, Rf, and Rh2 in mouse passive cutaneous anaphylaxis reaction and contact dermatitis models

The inhibitory effects of the Korean red ginseng (steamed root of Panax ginseng C.A. MEYER, family Araliaceae) saponin fraction (KRGS) and its constituents ginsenosides Rg3, Rf, and Rh2 in mouse passive cutaneous anaphylaxis (PCA) and contact dermatitis models were measured. Orally administered KRGS and its genuine ginsenosides potently inhibited the PCA reaction induced by IgE. However, when these ginsenosides were intraperitoneally administered, ginsenoside Rh2 showed the most potent inhibition. The ginsenoside Rh2 also the most potently inhibited the beta-hexosaminidase release from RBL-2H3 cells induced by IgE with antigen. KRGS administered topically at a dose of 0.1% suppressed ear swelling in an oxazolone-induced mouse contact dermatitis model by 38.8%. Its constituents ginsenosides Rg3, Rf, and Rh2 at a concentration of 0.05% also potently suppressed mouse ear swelling by 47.5%, 34.8%, and 49.9% at 16 d, respectively. These ginsenosides also significantly reduced mRNA expression levels of cyclooxygenase (COX)-2, interleukin (IL)-1beta, tumor necrosis factor-alpha and interferon-gamma induced by oxazolone applied to mouse ears. However, the ginsenosides, except for ginsenoside Rh2, almost did not notably reduce IL-4 levels. The ginsenoside Rh2 also potently inhibited COX-2 and inducible NO synthetase protein expression in liphopolysaccharide-stimulated RAW264.7 cells. Based on these findings, KRGS and its ginsenosides are suggested to improve atopic and contact dermatitis by regulating expression of cytokines.     

AMP-activated protein kinase: A potential target for ginsenosides?

Panax ginseng is a best-selling medicinal plant showing an antidiabetic activity via human, animal and in vitro studies. Among bioactive constituents found in ginseng, ginsenosides are known to be responsible for antidiabetic activity of ginseng. Ginsenoside Rb2, one of the major ginsenosides found in Asian ginseng, is shown to inhibit palmitate-induced gluconeogenesis in H4IIE rat hepatocytes via AMP-activated protein kinase (AMPK)-induced up-regulation of orphan nuclear receptor small heterodimer partner (SHP). Up to now, about thirteen articles were published to demonstrate that the pharmacological or physiological activities of ginsenosides are associated with AMPK, and only protopanaxatriol-type ginsenosides such as Re, Rg1 and Rg2, have been shown to suppress the hepatic glucose production. Therefore, Rb2 is the first protopanaxadiol-type ginsenoside shown to inhibit hepatic gluconeogenesis through AMPK activation. Further work will reveal whether activation of AMPK pathway by Rb2 would be beneficial to diabetic animals or type 2 diabetic patients.     

Transformation of ginseng saponins to ginsenoside rh<Subscript>2</Subscript> by acids and human intestinal bacteria and biological activities of their transformants

When ginseng water extract was incubated at 60 degrees C in acidic conditions, its protopanaxadiol ginsenosides were transformed to ginsenoside Rg3 and delta20-ginsenoside Rg3. However, protopanaxadiol glycoside ginsenosides Rb1, Rb2 and Rc isolated from ginseng were mostly not transformed to ginsenoside Rg3 by the incubation in neutral condition. The transformation of these ginsenosides to ginsenoside Rg3 and delta20-ginsenoside Rg3 was increased by increasing incubation temperature and time in acidic condition: the optimal incubation time and temperature for this transformation was 5 h and 60 degrees C resepectively. The transformed ginsenoside Rg3 and delta20-ginsenoside Rg3 were metabolized to ginsenoside Rh2 and delta20-ginsenoside Rh2, respectively, by human fecal microflora. Among the bacteria isolated from human fecal microflora, Bacteroides sp., Bifidobacterium sp. and Fusobacterium sp. potently transformed ginsenoside Rg3 to ginsenoside Rh2. Acid-treated ginseng (AG) extract, fermented AG extract, ginsenoside Rh2 and protopanaxadiol showed potent cytotoxicity against tumor cell lines. AG extract, fermented AG extract and protopanaxadiol potently inhibited the growth of Helicobacter pylori.     

American ginseng: Potential structure-function relationship in cancer chemoprevention

Ginseng has a prominent position on the list of best-selling herbal products in the world, and its main active constituents are thought to be ginsenosides. Compared with the long history of use and widespread research on Asian ginseng, studies of American ginseng are relatively limited, especially regarding cancer chemoprevention. In recent studies of American ginseng, steaming or heating altered the ginsenoside profile and thereby increased anticancer effects. Yet the ginsenoside structures and their activities have not been systematically elucidated. In this commentary, we introduce the different ginsenosides in American ginseng, both the naturally occurring compounds and those resulting from steaming or biotransformation. We briefly review American ginseng's reported anticancer effects and their mechanisms of action, and explore the possible structural-function relationship with a focus on sugar molecules, hydroxyl groups and stereoselectivity in ginsenosides. Understanding these relationships may produce insights into chemical and pharmacological approaches for enhancing the chemopreventive effects of ginsenoside and for developing novel anticancer agents.     

Comparison of qualitative and quantitative in vitro ginsenoside production in callus cultures of three Panax species

The qualitative and quantitative difference in the various ginsenoside constituents of the crude butanol-soluble saponin fractions of callus cultures of two Indian species of Panax namely P. sikkimensis and P. pseudoginseng have been compared with that of P. quinquefolium (American ginseng). The 45-50 days old calli of the two Indian species, though found to accumulate crude ginsenoside at levels (0.9% and 1.1%, respectively) comparable to that in P. quinquefolium (1.2%), P. pseudoginseng callus showed high productivity of ginsenosides Rf (40.57%) and Ro (19.60%). P. quinquefolium calli on the other hand accumulated more of Rb and Rg group of ginsenosides but while the former appeared to be a Rg (2) accumulator the callus of the later was rich in the Rg (1) fraction.     

Drying of steamed Asian ginseng (Panax ginseng) roots by microwave-hot air combination

Steamed Asian ginseng (Panax ginseng) roots were dried by a combined microwave-hot air method in a modified experimental microwave oven. Hot air drying was used as a reference method. The drying time to achieve the desired moisture level (10%) as well as the ginsenoside contents and the color of the final product were determined. The ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Ro were analyzed by HPLC. Compared with hot air drying, the combined microwave-hot air drying method resulted in a substantial decrease (approximately 30-40%) in drying time and had little influence on the ginsenoside contents and the color of the final product.     

Pharmacological study on Panax ginseng C. A. Meyer. XV. Effects of 70% methanolic extract from red and white ginseng on the antitumor activity of mitomycin C]

The influence of various fractions and ginsenosides from the 70% methanolic extract (RMe) of Red Ginseng (a steamed and dried root of Panax ginseng C. A. Meyer) on the cytocidal effect of mitomycin C (MMC) against Ehrlich ascites carcinoma was investigated in vitro. The AcOEt soluble portion (RMe-I) showed an increasing effect on the activities of lysosomal enzymes in the cultured tumor cells. RMe-I promoted the uptake of MMC into the tumor cells and enhanced the cytotoxicity of MMC against the cultured tumor cells. 20(S)-, 20(R)-ginsenoside Rg3 and ginsenoside Rh2 isolated from RMe-I promoted the uptake of MMC into the tumor cells but ginsenosides from the n-BuOH soluble portion (RME-II) had no effect. Furthermore, the influence of RMe and the 70% methanolic extract (WMe) from White Ginseng (a dried root of Panax ginseng C. A. Meyer) on the cytocidal effect of MMC was investigated in vivo. MMC combined with RMe showed stronger antitumor effects against the ascites form of mouse Ehrlich ascites carcinoma and rat ascites hepatoma AH 130 than MMC combined with WMe. The activities of lysosomal enzymes in tumor cells were also more increased in comparison with that combined MMC and WMe.     

Ginsenoside Rg3 mediates endothelium-dependent relaxation in response to ginsenosides in rat aorta: role of K+ channels

The aim of the present study was to characterize the endothelium-dependent relaxation elicited by ginsenosides, a mixture of saponin extracted from Panax ginseng, in isolated rat aorta. Relaxations elicited by ginsenosides were mimicked by ginsenoside Rg1 and ginsenoside Rg1, two major ginsenosides of the protopanaxatriol group. Ginsenoside Rg3 was about 100-fold more potent than ginsenoside Rg1. The endothelium-dependent relaxation in response to ginsenoside Rg3 was associated with the formation of cycle GMP. These effects were abolished by N(G)-nitro-L-arginine and methylene blue. Relaxations in response to ginsenoside Rg3 were unaffected by atropine, diphenhydramine, [D-Pro2, D-Trp7,9]substance P, propranolol, nifedipine, verapamil and glibenclamide but were markedly reduced by tetraethylammonium. Tetraethylammonium modestly reduced the relaxation induced by sodium nitroprusside. These findings indicate that ginsenoside Rg3 is a major mediator of the endothelium-dependent nitric oxide-mediated relaxation in response to ginsenosides in isolated rat aorta, possibly via activation of tetraethylammonium-sensitive K+ channels.     

主要人参皂甙的分布和比例及人参产品的质量控制

采用反相高效液相色谱法，对１５０多种西洋参、人参及三七的根、叶及其产品进行了分析。以８种主要的人参皂甙Ｒｇ，Ｒｅ，Ｒｆ，Ｒｂ１，Ｒｃ，Ｒｂ２，Ｒｇ２和Ｒｄ作为对照品，来评价人参及其产品的质量，这８种人参皂甙的分布及其比例在对人参及其商品的定性、定量分析方面具有显著的意义。本文首次提出了单体皂甙的含量比率这一有价值的数据在人参品种及不同用药部位鉴定方面的有效性。     

The physiological effects of Aralia, Panax and Eleutherococcus on exercised rats

Relative and total amount of saponins in Panax ginseng, Panax quinquefolius, Aralia mandshurica and Eleutherococcus senticosus were determined by thin-layer chromatography and by a spectrophotometric method. The ginsenoside Rg1 was present in American ginseng. Aralia and Eleutherococcus did not contain diol- and triol-type ginsenosides. Low concentrations of ginsenosides were found in Oriental red ginsengs (1.4-2.7%). Orally administered Araliaceae saponin extracts did not affect plasma lactic acid, glucagon, insulin or liver glycogen levels in exercised rats and did not prolong their swimming time. Plasma glucose levels in resting rats were decreased by saponin extracts of Canadian white, American red, Sanchi, Aralia, Eleutherococcus, Korean red and Shiu-Chi ginsengs.     

Simultaneous quantification of 14 ginsenosides in Panax ginseng C.A. Meyer (Korean red ginseng) by HPLC-ELSD and its application to quality control

A new method of high-performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) was developed for the simultaneous quantification of 14 major ginsenosides, which are the marker compounds of Panax ginseng C.A. Meyer (Korean red ginseng). Various types of ginseng samples were extracted, and the amounts of the 14 ginsenosides (Rg1, Re, Rf, Rh1, Rg2, Rb1, Rc, Rb2, Rb3, Rd, Rg3, Rk1, Rg5, and Rh2) were determined by reverse-phase HPLC-ELSD using digoxin as an internal standard. The mobile phase consisted of a programmed gradient of aqueous acetonitrile. Calibration curves for each ginsenoside were determined for the quantification. The method was validated for linearity, precision, accuracy, limit of detection, and limit of quantification. This quantification method was applied to several finished ginseng products including white ginseng, red ginseng powder, and red ginseng concentrate. The amounts of the 14 ginsenosides in the various ginseng samples could be analyzed simultaneously. This validated HPLC method is expected to provide a new basis for the quality assessment of ginseng products.     

Medicinal history and ginsenosides composition of Panax ginseng rhizome, "Rozu"

Ginseng is prepared from Panax ginseng C.A. Meyer root. The root of wild P. ginseng has long tortuous rhizome called traditionally "Rozu" in Japanese. In the present historical studies on ginseng, it has been proven that ginseng has sometimes been used after removing "Rozu" due to its emetic effects. However, ginseng with "Rozu" is prescribed in almost all the present Kampo formulations used clinically in China and Japan. Possible reasons for this are (1) some formulations including "Rozu" have been used for vomiting resulting from the retention of fluid in the intestine and stomach, "tan-in" in Japanese, and (2) the present cultivated ginseng has shorter "Rozu" than wild ginseng. Furthermore, it is proved that "Rozu", rich in ginsenoside Ro with oleanane-type aglycone, is distinguished from ginseng roots rich in ginsenosides Rb1 and Rg1 with dammarane-type aglycone. This is the first report to declare the distribution of ginsenosides in underground parts of wild P. ginseng. Ginsenoside Ro is a minor ginsenoside in ginseng whereas it is the major ginsenoside in P. japonicus rhizome (chikusetsu-ninjin in Japanese). Ginsenoside Ro is characterized by antiinflammatory effects which differ from ginsenosides Rb1 and Rg1 responsible for adaptogenic effects of ginseng. These results suggest that "Rozu" containing both oleanane- and dammarane-type ginsenosides might be a promising raw material distinct from ginseng root or P. japonicus rhizome.     

Effects of ginsenosides,active components of ginseng,on nicotinic acetylcholine receptors expressed in Xenopus oocytes

We investigated the effects of ginsenosides, the active ingredient of ginseng, on neuronal or muscle-type nicotinic acetylcholine receptor channel activity expressed in Xenopus oocytes after injection of cRNA encoding bovine neuronal alpha3beta4, alpha7 or human muscle alphabetadeltavarepsilon subunits. Treatment with acetylcholine elicited an inward peak current (I(ACh)) in oocytes expressing nicotinic acetylcholine receptor subtypes. Cotreatment with ginsenoside Rg2 and acetylcholine inhibited I(ACh) in oocytes expressing with alpha3beta4 or alphabetadeltavarepsilon but not in oocytes expressing alpha7 nicotinic acetylcholine receptors. The inhibition of I(ACh) by ginsenoside Rg2 was reversible and dose-dependent. The half-inhibitory concentrations (IC50) of ginsenoside Rg2 were 60.2+/-14.1 and 15.7+/-3.5 microM in oocytes expressing alpha3beta4 and alphabetadeltavarepsilon nicotinic acetylcholine receptors, respectively. The inhibition of I(ACh) by ginsenoside Rg2 was voltage-independent and noncompetitive. Other ginsenosides besides ginsenoside Rg2 also inhibited I(ACh) in oocytes expressing alpha3beta4 or alphabetadeltavarepsilon nicotinic acetylcholine receptors. The order of potency for the inhibition of I(ACh) was ginsenoside Rg2>Rf>Re>Rg1>Rc>Rb2>Rb1 in oocytes expressing alpha3beta4 nicotinic acetylcholine receptors and was ginsenoside Rg2>Rf>Rg1>Re>Rb1>Rc>Rb2 in oocytes expressing alphabetadeltavarepsilon nicotinic acetylcholine receptors. These results indicate that ginsenosides might regulate nicotinic acetylcholine receptors in a differential manner and this regulation might be one of the pharmacological actions of Panax ginseng.     

人参的化学成分及药理活性的研究进展与展望

对人参化学成分、人参与西洋参的鉴别方法、人参皂苷的代谢及人参的药理研究的新进展给予综述并对人参的研究作一简要展望     

Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium

Medical application of Panax ginseng was first found in "Shen-Nong Herbal Classic"around 200 AD Panax quinquefolium was first introduced in "Essential of Materia Medica" in 1694 in China. The most important bioactive components contained in P ginseng and P quinquefolium are ginseng saponins (GS). The contents of ginsenoside Rb1, Re, and Rd in P quinquefolium are higher than they are in P ginseng. In P ginseng, the contents of Rg1,Rb2, and Rc are higher than they are in P quinquefolium. P ginseng had a higher ratio of Rg1: Rb1, and which was lower in P quinquefolium. After steaming for several hours, the total GS will decrease. However, some ginsenosides (Rg2, 20R-Rg2, Rg3, Rh1 and Rh2) increase, while others (Rb1, Rb2, Rb3, Rc, Rd, Re, and Rg1) decrease. However, variation, especially in P quinquefolium, is high. P ginseng and P quinquefolium are general tonics and adaptogens. Rg1 and Rb1 enhance central nervous system (CNS) activities, but the effect of the latter is weaker. Thus, for the higher contents of Rg1, P ginseng is a stimulant, whereas the Rb1 contents of P quinquefolium are mainly calming to the CNS. Re, Rg1, panaxan A and B from P ginseng are good for diabetes. Re and Rg1 enhance angiogenesis, whereas Rb1, Rg3 and Rh2 inhibit it. Rh2, an antitumor agent, can be obtained from Rb1 by steaming. The content of Re in P quinquefolium are higher than in P ginseng by 3-4 times. The vasorelax, antioxidant, antihyperlipidemic, and angiogenic effects of Re are reported. Thus, for the CNS "hot," wound healing and hypoglycemic effects, P ginseng is better than P quinquefolium. For anticancer effects, P quinquefolium is better.     

Asian ginseng enhances the anti-proliferative effect of 5-fluorouracil on human colorectal cancer: Comparison between white and red ginseng

Previous studies showed that Asian ginseng, Panax ginseng C.A. Meyer, may have anti-cancer properties. However, there is limited data exploring the use of Asian ginseng as an adjuvant to chemotherapy, and minimal mechanistic studies related to their possible synergistic activities. In this study, the content of 8 ginsenosides, Rb1, Rb2, Rb3, Rc, Rd, Re, Rg1 and Rg3, in the extracts of white ginseng (WG) and red ginseng (RG) were determined by HPLC. Using HCT-116 human colorectal cancer cells, we compared the efficacy of WG and RG. We evaluated the synergy between ginseng and 5-fluorouracil (5-FU), and explored the mechanism of their anti-proliferative effects. As single extract, WG or RG used at concentrations of 0.1, 0.2 and 0.3 mg/mL, inhibited HCT-116 cell proliferation in a concentration-related manner. WG at 0.2 mg/mL did not show obvious synergy with 5-FU co-treatment, while RG at 0.2 and 0.3 mg/mL significantly enhanced the anti-proliferative effects of 5-FU at concentrations of 10, 50 and 100 μM (P < 0.05). Using flow cytometric assay, RG 0.3 mg/mL did not affect cancer cell apoptotic induction activity. However, the RG induced cell cycle arrest in the G1 phase, while 5-FU arrested the cell in the S phase. Different ginsenoside profiles are responsible for the observed differences in pharmacological effects. The effects of 8 ginsenosides on HCT-116 cells were assayed. Rd and Rg3 showed positive anti-proliferative effect. Our data suggested a potential for RG as an adjuvant therapy in the treatment of colorectal cancer, via a synergistic action.     

Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer

Three new dammarane-type triterpene ginsenosides, together with six known ginsenosides, were isolated from the leaves of Panax ginseng C.A. Meyer. The new saponins were named as ginsenoside Rh??, ginsenoside Rh??, and ginsenoside Rh??. Their structures were elucidated as (20S)-3β,6α,12β,20-tetrahydroxydammara-25-ene-24-one 20-O-β-d-glucopyranoside (1), (20S)-3β,12β,20,24,25-pentahydroxydammarane 20-O-β-d-glucopyranoside (2), and (20S,23E)-3β,12β,20,25-tetrahydroxydammara-23-ene 20-O-β-d-glucopyranoside (3) on the basis of 1D and 2D NMR experiments and mass spectra. The known ginsenosides were identified as ginsenoside M(?cd), ginsenoside Rg?, ginsenoside Rb?, gypenoside XVII, gypenoside IX, and 20-(E)-ginsenoside F?.     

Ginsenoside Rh2 reduces ischemic brain injury in rats

Ginseng was incubated under mildly acidic conditions and its inhibitory effect on a rat ischemia-reperfusion model was investigated. When ginseng was treated with 0.1% hydrochloric acid at 60 degrees C, its protopanaxadiol saponins were transformed to diasteromeric ginsenoside Rg3 and Delta20-ginsenoside Rg3. When the transformed ginseng extract, of which the main component was ginsenosides Rg3, was treated with human intestinal microflora, the main metabolite was ginsenoside Rh2. Orally administered acid-treated ginseng (AG) extract and ginsenoside Rh2 potently protect ischemia-reperfusion brain injury. The ginsenoside Rh2 also inhibited prostaglandin-E2 synthesis in lipopolysaccharide-stimulated RAW264.7 cells, but showed no in vitro antioxidant activity. These results suggest that AG and ginsenoside Rh2 can improve ischemic brain injury.