The Chinese Herb Academy Collected Abstracts Ren Shen Radix Ginseng

Kim SH, Jeong KS, Ryu SY, Kim TH. Panax ginseng prevents apoptosis in hair follicles and accelerates recovery of hair medullary cells in irradiated mice. In Vivo 1998 Mar-Apr;12(2):219-222

Abstract: We studied the effect of the water fraction of Panax ginseng, one of traditional oriental medicine herbs on apoptosis and the formation of medullary cell in the hair follicles of irradiated mice. The hair follicle or its differentiated product, the hair, which represents a linear historical record of follicular proliferative activity, could provide a biological indicator of the effect of radioprotective drugs. Adult N:GP(s) mice with hair follicles synchronously in the middle of the hair growth cycle received whole-body doses of gamma-radiation. The hair follicles were analysed either 12 hours after irradiation with 2 Gy in the experiment on the apoptosis, or 3 days after irradiation with 3 Gy in the experiment on the forming medulla. The number of medullary cells per unit length (100 microns) were measured by H and E staining. Apoptosis was detected by a nonisotopic in situ DNA end-labeling (ISEL) technique and H and E stain applied to the serial histologic sections. Ginseng administration before irradiation resulted in a suppression of apoptosis, as shown by a reduced number of cells stained with ISEL for fragmented DNA, both i.p. (0.3 mg/head, p < 0.05) and p.o. (2 mg/ml of drinking water, p < 0.05) treatment. In addition, ginseng treatment was associated with an increase in the number of medullary cell per unit length as compared with the vehicle treated mice (p < 0.001, i.p.; p < 0.05, p.o.). These results indicate that the water fraction of ginseng can exert a potent effect on the recovery of the hair follicles by its combined effects on proliferation and apoptosis of the cells in the hair follicle.

Kumar R, Grover SK, Divekar HM, Gupta AK, Shyam R, Srivastava KK. Enhanced thermogenesis in rats by Panax ginseng, multivitamins and minerals. Int J Biometeorol 1996 Nov;39(4):187-191

Abstract: Substances which enhance endurance for physical and mental work and increase non-specific resistance to stress during a prolonged stay in physiologically adverse habitats are called 'adaptogens'. Panax ginseng is well known for its anti-stress and adaptogenic properties. In the present study, adaptogenic activity by the intake of a herbo-vitamin-mineral preparation (HVMP) containing P. ginseng and multivitamin-mineral preparation (MVMP) was evaluated using the cold-hypoxia-restrained (C-H-R) animal model. The aim was to determine whether the cold tolerance and recovery from acute hypothermia mediated by P. ginseng was modified by simultaneous intake of additional vitamins and minerals. Results suggest that the adaptogenic effect of HVMP was more or less the sum total of its two components P. ginseng and MVMP. In HVMP, P. ginseng was found to be effective for developing resistance to cooling and MVMP helped in stimulating faster recovery from acute hypothermia.

Metori K, Furutsu M, Takahashi S. The preventive effect of ginseng with du-zhong leaf on protein metabolism in aging. Biol Pharm Bull 1997 Mar;20(3):237-242

Abstract: Stimulation of collagen synthesis prevents the aging process. We found such a synergistic effect by using the leaves of Eucommia ulmoides Oliver, Eucomiaceae (Du-Zhong leaf) and the roots of Panax ginseng C. A. MEYER (Ginseng). The formula consists of amounts which exert no effect when used individually. We tested several formula ratios of Ginseng and Du-Zhong leaf, 1:1, 1:2, 1:3 and 1:4, and concluded that the last two formulas were effective. However, we did not observe a significant difference between 1:3 and 1:4. Thus, it was demonstrated that the formula ratio of Ginseng to Du-Zhong leaf of 1:3 was the most effective for the stimulation of collagen synthesis and the prevention of decreased protein metabolism in aging.

Takei Y, Yamamoto T, Higashira H, Hayashi K. Identification of basic fibroblast growth factor-like immunoreactivity in panax ginseng extract: investigation of its molecular properties. Biosci Biotechnol Biochem 1996 Apr;60(4):584-588

Abstract: Basic fibroblast growth factor (bFGF)-like immunoreactivity was detected in extracts of Panax ginseng root by using a sensitive two-site enzyme immunoassay specific for human bFGF (hbFGF). In an investigation of the molecular properties of this bFGF-like molecule (bFGF-LI), the bFGF-LI and hbFGF were found to be equivalent with respect to antigenicity, molecular weight, isoelectric point, affinity for binding to heparin, and mitogenic activity toward BALB/c3T3 fibroblasts. The identification of this bFGF-LI molecule in Panax ginseng root helps to explain various activities of the traditional Chinese medicine ginseng.

Chen ZK, Fan CX, Ye YH, Yang L, Jiang Q, Xing QY. Isolation and characterization of a group of oligopeptides related to oxidized glutathione from the root of Panax ginseng.
J Pept Res 1998 Aug;52(2):137-142
Abstract: Six gamma-glutamyl oligopeptides were isolated for the first time from aqueous methanol extracts of Panax ginseng root by using column chromatography on ion-exchange resin, gel filtration and reverse-phase high-performance liquid chromatography. Their structures had been established with the methods of amino acid analysis, N-terminal, C-terminal determination and double-coupling sequence analysis. They were: P-I (N-gamma-glutamylcystinyl-bis-glycine), P-ll (gamma-glutamylcysteinylglycine disulfide, oxidized glutathione), P-III (N,N'-bis-gamma-glutamylcystinylglycine), P-IV (gamma-glutamylcysteinylglycinamide disulfide), P-V (N-gamma-glutamylglycylcysteine disulfide), P-VI(gammaglutamylarginine); five of them are related to oxidized glutathione. The structures were further confirmed by the chemical synthesis. As far as we know, P-V (N-gamma-glutamylglycylcysteine disulfide) is a new biologically active peptide which exhibits somnogenic effect and is more potent than that of P-II.

Huong NT, Matsumoto K, Kasai R, Yamasaki K, Watanabe H. In vitro antioxidant activity of Vietnamese ginseng saponin and its components. Biol Pharm Bull 1998 Sep;21(9):978-981 Abstract: To elucidate the antioxidant action of Vietnamese ginseng saponin against free radial-mediated cellular damage, we examined the effect of Vietnamese ginseng saponin on lipid peroxidation in the mouse brain, liver, and liver microsomes by using two in vitro free radical generating systems (iron ferrous+ascorbic acid and iron ferrous+hydrogen peroxide). Free radical-mediated lipid peroxidation was determined by measuring the endogenous and stimulated accumulation of thiobarbituric acid reactive substance (TBA-RS). Vietnamese ginseng saponin (0.05-0.5 mg/ml), as well as vitamin E, significantly inhibited the formation of TBA-RS in tissue homogenates. Panax ginseng saponin, at the same concentration range as Vietnamese ginseng saponin, also had inhibitory action on free radical-mediated lipid peroxidation. However, majonoside-R2, ginsenoside-Rg1 and ginsenoside-Rb1, the main saponin components of Vietnamese ginseng saponin fraction, had no effect on lipid peroxidation. These results suggest that Vietnamese ginseng exerts a protective action against free radical-induced tissue injury and that this effect is attributable to minor components rather than the main saponin components tested.

Rimar S, Lee-Mengel M, Gillis CN. Pulmonary protective and vasodilator effects of a standardized Panax ginseng preparation following artificial gastric digestion. Pulm Pharmacol 1996 Aug;9(4):205-209
Abstract: We have previously demonstrated that purified ginsenosides produce pulmonary vasodilation and prevent effects of free radical injury on the lung. We examined the effect of artificially digested standardized ginseng preparation G115 in perfused rabbit lungs. G115 was incubated in artificial gastric juice (0.03 M NaCl + 0.08 M HCl) 37 degrees C for 1 h, and artificial intestinal juice (0.05 M KH2PO4 + 0.02 M NaOH) 37 degrees C for 5 h, neutralized with NaOH and lyophilized. Pulmonary vasoconstriction was induced with U46619, and cumulative additions of G115 in undigested, gastric digested and gastric and intestinal digested forms were made to the perfusate. In separate experiments, oxygen free radical injury by electrolysis was produced in the presence of G115 in the perfusate and ACh-induced vasodilation assessed before and after injury. Undigested, gastric digested and combined gastric and intestinal digested G115 significantly dilated lungs (44%, undigested; 26%, gastric digested; 45%, gastric and intestinal digested). In addition, both undigested (-27 +/- 5% vs. -24 +/- 5%) as well as gastric and intestinal digested G115 (-23 +/- 3% vs. -16 +/- 2%) preserved ACh-induced vasodilation following injury. Artificially digested G115 is a pulmonary vasodilator which protects against free radical injury, suggesting that oral G115 has the same effects.

Voces J, Alvarez AI, Vila L, Ferrando A, Cabral de Oliveira C, Prieto JG. Effects of administration of the standardized Panax ginseng extract G115 on hepatic antioxidant function after exhaustive exercise. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1999 Jun;123(2):175-184
Abstract: The effect of prolonged treatment with the standardized Panax ginseng extract G115 on the antioxidant capacity of the liver was investigated. For this purpose, rats that had received G115 orally at different doses for 3 months and untreated control rats were subjected to exhaustive exercise on a treadmill. A bell-shaped dose response on running time was obtained. The results showed that the administration of G115 significantly increases the hepatic glutathione peroxidase activity (GPX) and the reduced glutathione (GSH) levels in the liver, with a dose-dependent reduction of the thiobarbituric acid reactant substances (TBARS). After the exercise, there is reduced hepatic lipid peroxidation, as evidenced by the TBARS levels in both the controls and the treated animals. The GPX (glutathione peroxidase) and SOD (superoxide dismutase) activity are also significantly increased in the groups receiving G115, compared with the controls. The hepatic transaminase levels, ALT (Alanine-amino-transferase) and AST (Aspartate-amino-transferase), in the recuperation phase 48 h after the exercise, indicate a clear hepatoprotective effect related to the administration of the standardized Panax ginseng extract G115. At hepatic level, G115 increases the antioxidant capacity, with a marked reduction of the effects of the oxidative stress induced by the exhaustive exercise.

Cui X, Sakaguchi T, Ishizuka D, Tsukada K, Hatakeyama K. Orally administered ginseng extract reduces serum total cholesterol and triglycerides that induce fatty liver in 66% hepatectomized rats. J Int Med Res 1998 Aug-Sep;26(4):181-187
Abstract: The effects of ginseng extract (from the root of Panax ginseng) on factors inducing fatty liver were examined in 66% hepatectomized rats. Oral administration of ginseng extract at 125 or 250 mg/kg/day produced statistically significant reductions in total cholesterol and triglyceride concentrations in the blood 3 days after hepatectomy (P<0.05); the total cholesterol response appeared to be dose-related. Administration of ginseng extract at both doses also reduced total cholesterol and triglyceride concentrations in the liver 3 days after hepatectomy. Food intake and serum chemistry parameters indicating liver and kidney function were unchanged after ginseng administration except for the lipid metabolic parameters. These observations suggest that orally administered ginseng extract can suppress the formation of fatty liver after hepatic resection.

Chen X. Cardiovascular protection by ginsenosides and their nitric oxide releasing action. Clin Exp Pharmacol Physiol 1996 Aug;23(8):728-732
Abstract: 1. In an animal model in vivo, ginsenosides (GS), saponins from Panax ginseng, were shown to protect against myocardial ischaemia/reperfusion damage with concomitant increased 6-keto-PGF1 alpha and decreased lipid peroxidation. 2. In perfused rabbit lung in situ and isolated rabbit aortic rings, GS protected the pulmonary and aortic endothelium against electrolysis-induced free radical injury. Purified components of GS, Rb1 and especially Rg1, relaxed pulmonary vessels and this effect was eliminated by nitro-L-arginine, an inhibitor of nitric oxide (NO) synthase. 3. In cultured bovine aortic endothelial cells, GS enhanced the conversion of [14C]-L-arginine to [14C]-L-citrulline, indicating an increased release of NO. 4. As the neurotransmitter inducing penile erection, NO release was shown to be enhanced by GS in rabbit corpus cavernosum (CC) in vitro. Ginsenosides enhanced both acetylcholine-induced and transmural nerve stimulation-activated relaxation associated with increased tissue cGMP. The latter effect was eliminated by tetrodotoxin and was associated with decreased tissue cGMP. Ginsenoside-enhanced CC relaxation was attenuated by nitro-L-arginine and oxyhaemoglobin, and enhanced by superoxide dismutase. 5. It is postulated that cardiovascular protection by GS may be partly mediated by the release of NO, a potent antioxidant, and that the GS-enhanced release of NO from endothelial cells, especially from perivascular nitric oxidergic nerves in the CC, may partly account for the aphrodisiac effect of Panax ginseng used in traditional Chinese medicine.

Cui X, Sakaguchi T, Shirai Y, Hatakeyama K. Orally administered Panax ginseng extract decreases platelet adhesiveness in 66% hepatectomized rats. Am J Chin Med 1999;27(2):251-256
The effect of oral administration of Panax ginseng extract (GE) on platelet adhesiveness was examined in 66% hepatectomized rats. A significant decrease in platelet adhesiveness was obtained when 125 mg/kg/day GE was administered for 6 days before and after hepatectomy. The total cholesterol concentration in the serum was also decreased by GE administration. Food intake was unaffected by GE administration. Serum parameters indicating liver and kidney function were unchanged after GE administration except for lipid metabolic parameters. Because enhanced platelet adhesiveness and hyperlipidemia induces atherosclerosis, these results suggest that orally administered GE is capable of improving the atherosclerotic condition associated with hepatectomy.

Kim ND, Kang SY, Park JH, Schini-Kerth VB. Ginsenoside Rg3 mediates endothelium-dependent relaxation in response to ginsenosides in rat aorta: role of K+ channels. Eur J Pharmacol 1999 Feb 12;367(1):41-49
Abstract: 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.

Park HJ, Lee JH, Song YB, Park KH. Effects of dietary supplementation of lipophilic fraction from Panax ginseng on cGMP and cAMP in rat platelets and on blood coagulation. Biol Pharm Bull 1996 Nov;19(11):1434-1439
Abstract: We have studied the effect of dietary supplementation with 25 mg (0.0025% of the total diet) of a lipophilic fraction (LF) from Panax ginseng on rat platelet aggregation induced by collagen or thrombin, and on blood coagulation. When platelets prepared from 15% corn oil plus LF-administered rats (COLF) were stimulated by thrombin (0.1 units/ml) and collagen (100 micrograms/ml), the cGMP level was significantly increased as compared with those from 15% corn oil only-administered rats (CO). The levels of cAMP in COLF were decreased by thrombin, but was increased by collagen. Furthermore, the levels of both cGMP and cAMP were also increased by the exogenous addition of LF to thrombin- and collagen-stimulated platelets. These results mean that LF increases cGMP directly and cAMP indirectly, and thus inhibits thrombin- or collagen-induced rat platelet aggregation. Both the thrombin time (TT) and activated partial thromboplastin time (APTT) were prolonged more in citrated platelet-poor plasma from COLF than in that from CO. The level of lipids such as triglyceride, total cholesterol, high density lipoprotein-cholesterol and low density lipoprotein-cholesterol was decreased in serum from COLF more than in that of CO. Thus, these results suggest that dietary LF regulates the levels of cGMP and cAMP, and prolongs the time interval (TT, APTT) between the conversion of fibrinogen to fibrin. Accordingly, our data demonstrate that dietary LF has an antithrombotic effect in vivo.

Park HJ, Rhee MH, Park KM, Nam KY, Park KH.
Effect of non-saponin fraction from Panax ginseng on cGMP and thromboxane A2 in human platelet aggregation.
J Ethnopharmacol 1995 Dec 15;49(3):157-162
Abstract: The non-saponin fraction (NSF; lipophilic fraction) from the roots of Panax ginseng inhibited the aggregation of human platelets induced by thrombin (0.1 units/ml) in a dose-dependent manner. NSF induced the elevation of cGMP concentration in human platelets in a similar manner to molsidomine, a known vasodilator. NSF also inhibited Ca(2+)-influx into platelets. While verapamil, a Ca(2+)-antagonist, increased the cAMP level in platelets stimulated by thrombin, NSF had little effect on cAMP formation. Instead, NSF potently inhibited the thromboxane A2 (TXA2) production. The results suggest that NSF may regulate the levels of cGMP and TXA2 to inhibit platelet aggregation induced by thrombin.

Peng CF, Li YJ, Li YJ, Deng HW. Effects of ginsenosides on vasodilator nerve actions in the rat perfused mesentery are mediated by nitric oxide. J Pharm Pharmacol 1995 Jul;47(7):614-617
Abstract: This study was designed to explore the effect of ginsenosides, saponins from Panax ginseng, on the vasodilator nerve actions in the rat perfused mesentery and the mechanism of this effect. In the rat perfusion mesentery, when adrenergic nerves were blocked by guanethidine (5 x 10(-6) M) and vascular muscle tone was increased with methoxamine (5 x 10(-6)-10(-5) M), transmural field stimulation produced a frequency-dependent vasodilator response, which is due to the release of calcitonin gene-related peptide; ginsenosides significantly suppressed this vasodilator response in a concentration-dependent manner (3-30 micrograms mL-1). After pretreatment with saponin (50 micrograms mL-1, 3 min) to damage endothelial cells, this suppressing effect of ginsenosides was unaltered. However, the effect was abolished by N omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide synthesis and addition of L-arginine (3 x 10(-4) M) restored this suppressing effect. Methylene blue (10(-5) M), an inhibitor of guanylate cyclase, also abolished the suppressing effect of ginsenosides. However, ginsenosides did not alter the relaxation responses caused by exogenous calcitonin gene-related peptide administration. We conclude that ginsenosides can produce an inhibitory effect on the vasodilator response prejunctionally in the rat perfused mesentery and that this effect of ginsenosides may be mediated by nitric oxide released from non-adrenergic, non-cholinergic nerves.

Zhang YG, Liu TP. Influences of ginsenosides Rb1 and Rg1 on reversible focal brain ischemia in rats. Chung Kuo Yao Li Hsueh Pao 1996 Jan;17(1):44-8
Abstract: AIM: To study the influences of ginsenosides Rb1 and Rg1 (active components of the total saponins of Panax ginseng) on the brains against ischemia-reperfusion injury. METHODS: Rat focal cerebral ischemia was induced by reversible middle cerebral artery occlusion (MCAO) without craniectomy. The influences of ginsenoside Rb1 and Rg1 on infarct size (IS), neurologic deficit (ND) and the contents of calcium and potassium in the infarct were observed. RESULTS: In a 2-h ischemia, Rb1 10-40 mg.kg-1 i.v. 30 min before MCAO decreased IS by 20%-49% and ND score from 5.1 to 4.1-2.3, and inhibited Ca accumulation and K loss by 22%-50% and 18-37%, respectively; Rb1 10-40 mg.kg-1 i.v. immediately after MCA was recanalized decreased IS by 12%-35% and ND score from 5.2 to 4.3-3.3, and inhibited Ca accumulation and K loss by 10%-40% and 17%-30%, respectively. In permanent ischemia, Rb1 40 mg.kg-1 i.v. reduced IS, ND, Ca accumulation and K loss. However, Rg1 40 mg.kg-1 i.v. did not show effect on both permanent and 2-h MCAO. CONCLUSIONS: Rb1 protected brain from ischemic and reperfusion injuries.

Drug Interactions

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med, 89(2):2200-11 1998 Nov 9
Abstract: Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for. If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole. However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids. Nonsteroidal anti-inflammatory drugs may negate the usefulness of feverfew in the treatment of migraine headaches. Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium. Additionally, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate. Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects. Since the mechanism of action of St John wort is uncertain, concomitant use with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors is ill advised. Valerian should not be used concomitantly with barbiturates because excessive sedation may occur. Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring. Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease phenytoin levels as well as diminish drug efficacy. Kava when used with alprazolam has resulted in coma. Immunostimulants (eg, Echinacea and zinc) should not be given with immunosuppressants (eg, corticosteroids and cyclosporine). Tannic acids present in some herbs (eg, St John wort and saw palmetto) may inhibit the absorption of iron. Kelp as a source of iodine may interfere with thyroid replacement therapies. Licorice can offset the pharmacological effect of spironolactone. Numerous herbs (eg, karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus.

Zhu M; Chan KW; Ng LS; Chang Q; Chang S; Li RC . Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol, 51(2):175-80 1999 Feb
Abstract : We evaluated the significance of a reported clinical case of drug-drug interaction between ginseng and warfarin using a robust pharmacokinetic/pharmacodynamic approach in a rat model. The influence of ginseng on the pharmacokinetics and pharmacodynamics of oral warfarin after a single dose (2 mg kg(-1)) and at steady state (0.2 mg kg(-1) daily x 6 days) was studied in male Sprague-Dawley rats. Prothrombin time was employed as a pharmacodynamic index. Warfarin plasma concentration and vitamin K content in the ginseng extract were assessed by validated HPLC assays. The pharmacokinetics of warfarin after a single dose were not altered in the presence of ginseng; peak plasma concentration (control 7.8+/-0.5; ginseng 7.3+/-2.5 microg mL(-1)), time to peak (control 2.6+/-1.0; ginseng 3.1+/-1.1 h), elimination half-life (control 14.3+/-5.8; ginseng 10.6+/-3.1 h), and oral clearance (control 17.5+/-3.3; ginseng 20.2+/-5.5 mL h(-1)) were not significantly different (P>0.05). Similarly, alterations in the pharmacokinetics of warfarin were not detected under the multiple dosing paradigm. Under both dosing conditions, ginseng also showed no significant impact on the pharmacodynamics of warfarin as assessed by the area under the prothrombin time vs time curve (multiple dosing; control 3776+/-619, ginseng 3830+/-362 sh) and maximum prothrombin time (control 57.2+/-11.8, ginseng 63.3+/-9.1 s). Furthermore, the content of vitamin K was undetectable in the ginseng decoction. In conclusion, current data obtained in the rat showed no significant impact of ginseng on the pharmacokinetics/pharmacodynamics of warfarin when they are concomitantly administered.

Chung E, Lee KY, Lee YJ, Lee YH, Lee SK. Ginsenoside Rg1 down-regulates glucocorticoid receptor and displays synergistic effects with cAMP. Steroids 1998 Jul-Aug;63(7-8):421-424
abstract: Ginsenoside-Rg1 (G-Rg1) from the roots of Panax ginseng C. A. Meyer has been shown to bind to the glucocorticoid receptor (GR). To further explore the effect of G-Rg1 binding to GR, a luciferase reporter gene containing two copies of a glucocorticoid response element was constructed and transiently transfected into FTO2B rat hepatoma cells. A dose-dependent induction of the reporter gene was observed in response to G-Rg1, and the inductive effect was blocked by treatment with the antiglucocorticoid RU486. In addition, both G-Rg1- and dexamethasone (Dex)-induced transcription was synergistically enhanced by the treatment of dibutyryl cAMP (Bt2-cAMP). G-Rg1 treatment also led to the down-regulation of intracellular GR content, which was similar to the effect of Dex. By showing that G-Rg1 down-regulates GR and induces GR-mediated transcription synergistically with cAMP, we conclude that G-Rg1 is a functional GR ligand in FTO2B cells.

Kim W, Hwang S, Lee H, Song H, Kim S. Panax ginseng protects the testis against 2,3,7, 8-tetrachlorodibenzo-p-dioxin induced testicular damage in guinea pigs. BJU Int 1999 May;83(7):842-849
Abstract: OBJECTIVES: To investigate histopathologically the beneficial effects of Panax ginseng extract on guinea pig testes damaged by 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD). MATERIALS AND METHODS: Ninety guinea pigs were divided into six equal groups. The normal controls (group 1) received vehicle and saline; group 2 received TCDD (1 microgram/kg) intraperitoneally; group 3 and 4 received 100 or 200 mg/kg per day of Panax ginseng water extract (PG-WE) intraperitoneally for 28 days from 1 week before TCDD injection; groups 5 and 6 received PG-WE for 14 days from 1 week after TCDD treatment. RESULTS: The gain in body weight was less in groups treated with TCDD than in controls. Moreover, the body weight of group 2 decreased from 14 days after TCDD exposure, while that of groups 3 and 4 increased; there was no decrease in body weight in groups 3-6. The decrease in testicular weight caused by TCDD was prevented by PG-WE. Light microscopy showed smaller tubules and late maturation arrest in group 2; electron microscopy showed a dissolution of the germinal epithelium, disrupted tight junctions between adjacent Sertoli cells, and altered germ cells at all developmental stages. The maturation arrest in germ cells caused by TCDD was ameliorated in groups 3-6. The testes almost completely recovered in groups 3 and 4 and there was some therapeutic effect of PG-WE in groups 5 and 6. CONCLUSIONS: These results confirm the protective and therapeutic effects of Panax ginseng on atrophy and testicular damage induced by TCDD, providing evidence that ginseng might be a useful agent in preventing and treating testicular damage induced by environmental pollutants.

Lee YJ, Chung E, Lee KY, Lee YH, Huh B, Lee SK. Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor. Mol Cell Endocrinol 1997 Oct 20;133(2):135-140
Abstract: We have examined the possibility that a component of Panax ginseng, ginsenoside-Rg1 (G-Rg1), acts by binding to the glucocorticoid receptor (GR). G-Rg1 competed for [3H]dexamethasone (Dex) binding to GR with a specific affinity of 1-10 microM and activated a glucocorticoid responsive element-containing luciferase reporter gene. The dose-dependence patterns of G-Rg1 and Dex for these two effects were nearly identical, although two to three orders of magnitude higher concentration of G-Rg1 than that of Dex was required for the same magnitude of response. At the cellular level, the growth of FT02B cells was suppressed by G-Rg1 as well as by Dex, each of whose effects were abolished by RU486. These results demonstrate that G-Rg1 is a functional ligand of GR.

Allen JD, McLung J, Nelson AG, Welsch M. Ginseng supplementation does not enhance healthy young adults' peak aerobic exercise performance.J Am Coll Nutr 1998 Oct;17(5):462-466
Abstract: OBJECTIVE: To determine the short term effects (21 days) of 200 mg (7% standardized) Panax ginseng supplementation vs. placebo on peak aerobic exercise performance in healthy young adults, with unrestricted diets. METHODS: Twenty men and eight women (age = 23.2 +/- 3.2 years, height = 175.8 +/- 8.6 cm; weight = 75.2 +/- 15.3 kg) were randomly assigned to either a Panax ginseng or placebo group for a period of 3 weeks in a double blind design. Prior to and following treatment the subjects performed a symptom limited graded exercise test on a Schwinn Airdyne ergometer. The data were analyzed using an analysis of variance. RESULTS: No significant treatment effect was observed for the dependent variables of VO2, exercise time, workload, plasma lactate and hematocrit at peak levels, or for heart rate and rate of perceived exertion at 150 watts, 200 watts and peak. CONCLUSIONS: The results of this study do not support an ergogenic effect on peak aerobic exercise performance following a 3-week supplementation period of 200 mg 7% Panax ginseng in healthy young adults with moderate exercise capacities and unrestricted diets.

Salvati G, Genovesi G, Marcellini L, Paolini P, De Nuccio I, Pepe M, Re M. Effects of Panax Ginseng C.A. Meyer saponins on male fertility. Panminerva Med 1996 Dec;38(4):249-254
Abstract: Sixty-six patients have been treated with Panax Ginseng C.A. Meyer extract, of whom 30 oligoastenospermic sine causa (group A), 16 oligoastenospermic with idiopathic varicocele (group B). Twenty age-matched volunteers were used as controls (group C). Use of Panax Ginseng extract showed an increase in spermatozoa number/ml and progressive oscillating motility, an increase in plasma total and free testosterone, DHT, FSH and LH levels, but a decrease in mean PRL. It is suggested that ginsenosides may have an effect at different levels of the hypothalamus-pituitary-testis axis.

Immunomodulation

Kim YR, Lee SY, Shin BA, Kim KM. Panax ginseng blocks morphine-induced thymic apoptosis by lowering plasma corticosterone level. Gen Pharmacol 1999 Jun;32(6):647-652
Abstract: The effects of Panax ginseng on morphine-induced immune suppression were studied. Morphine (20 mg/kg, SC, 4 days) decreased body weight increment rate and caused atrophy of thymus and spleen. These changes were partly reversed by concomitant administration of ginseng total saponin (GTS, 100 mg/kg, oral, 9 days). Morphine elevated the serum corticosterone level and caused the DNA fragmentation of thymocytes. These sequential events were completely blocked by a concomitant administration of GTS. Flow cytometry analysis showed that GTS specifically blocked morphine-induced apoptosis of thymocytes.

Lee YS, Chung IS, Lee IR, Kim KH, Hong WS, Yun YS. Activation of multiple effector pathways of immune system by the antineoplastic immunostimulator acidic polysaccharide ginsan isolated from Panaxginseng. Anticancer Res 1997 Jan-Feb;17(1A):323-331
Abstract: In the present study an acidic polysaccharide ginsan, with a molecular weight of 150,000, devoid of lectin properties, was purified from Panax ginseng C.A. Meyer (Araliaceae). Ginsan induced the proliferation of T cells and B cells. Spleen cells became cytotoxic to a wide range of tumor cells without major histocompatibility complex-restriction after 4 or 5 days culture in vitro with ginsan. For the generation of these ginsan-activated killer (AK) cells adherent macrophages and CD4+ cells were needed as accessory cells. The generation of ginsan-AK cells was blocked in the presence of anti-IL-2, anti-IFN gamma, anti-IL-1 or anti-TNF alpha antibodies, showing the importance of these cytokines in the process. The surface phenotypes of the 4 day-cultured ginsan-AK cells was Thy1+, AsGM1+, CD8+, which is distinct from rIL-2 induced lymphokine activated killer (LAK) cells that were CD8. The ginsan also activated macrophages to produce reactive nitrogen intermediates and become tumoricidal. It also exhibited significant in vivo antitumor activity against B16 melanoma cells lines, and in the benzo(a)pyrene-induced autochthonous lung tumor model, at much lower doses than the maximum tolerate doses. Indeed, no mice died, which injected with ginsan at 1g/kg body weight intraperitoneally. In conclusion, 'ginsan' could potentially be an ideal nontoxic antineoplastic immunostimulator by activating multiple effector arms of the immune system.

Liu J, Wang S, Liu H, Yang L, Nan G.
Stimulatory effect of saponin from Panax ginseng on immune function of lymphocytes in the elderly. Mech Ageing Dev 1995 Aug 31;83(1):43-53
Abstract: We used the saponin Rg1 extracted from Panax ginseng to study its effects on lymphocytes of 10 young and 19 elderly persons. The proliferative response of lymphocytes cocultured for 72 h with PHA and saponin was measured by using MTT method and the 3H-TdR incorporation procedure. PHA and Rg1 had stimulative effects on the phenotype of lymphocytes (P < 0.001). Rg1 also increased the fluidity of lymphocyte membrane of the aged (P < 0.001). The CD25 and CD45RA positive cells of lymphocytes in the elderly were lower than those of the young people, 8.6% +/- 2.7% vs 10.43% +/- 3.5%; 20.95% +/- 15.5% vs. 50.86% +/- 4.2%, respectively. More CD45RO positive cells (41.5% +/- 13.9%) than CD45RA positive cell lymphocyte populations were seen in the aged. The CD45RO positive cells of the young people were 39.63% +/- 3.2%. We discussed the cause of declined immune function of lymphocytes of aged person and the mechanism of the effect of P. ginseng on lymphocytes.

Sonoda Y, Kasahara T, Mukaida N, Shimizu N, Tomoda M, Takeda T. Stimulation of interleukin-8 production by acidic polysaccharides from the root of Panax ginseng. Immunopharmacology 1998 Jan;38(3):287-294
Abstract: The root of Panax ginseng C.A. Meyer, is a well-known important Chinese traditional medicine used as a stomachic, tonic, sedative and as an elixir called Ginseng in China and Japan. The precise mechanism of the biological actions of this plant is not fully understood. In order to elucidate the immunomodulating activities of this plant, we examined the direct effects of four of its components, acidic polysaccharides isolated in previous studies, on cytokine (interleukin-8; IL-8) production by a human monocytic cell line, THP-1, and human blood monocytes in vitro, as IL-8 is a potent inflammatory cytokine involved in neutrophil chemotaxis and activation. We found that one component, ginsenan S-IIA, is a potent inducer of IL-8 production by human monocytes and THP-1 cells, and this induction is accompanied by increased IL-8 mRNA expression.

Chen X, Lee TJ. Ginsenosides-induced nitric oxide-mediated relaxation of the rabbit corpus cavernosum.
Br J Pharmacol 1995 May;115(1):15-18
Abstract: 1. Ginsenosides, the active ingredients extracted from Panax ginseng, have been shown to promote nitric oxide (NO) release in bovine aortic endothelial cells. Since the endothelial cells and the perivascular nerves in penile corpus cavernosum contain NO synthase and an NO-like substance has been shown to be released from these cells which relaxes corpus cavernosum, the possibility that ginsenosides may relax corpus cavernosum by releasing endogenous NO was examined. 2. With an in vitro tissue superfusion technique, ginsenosides (250, 500 and 750 micrograms ml-1) relaxed corpus cavernosum, concentration-dependently. 3. Using an in vitro tissue bath technique, acetylcholine (ACh)-induced relaxations were increased in the presence of ginsenosides (250 micrograms ml-1). 4. Ginsenosides at 100 micrograms ml-1 significantly enhanced the tetrodotoxin (TTX)-sensitive relaxation of corpus cavernosum elicited by transmural nerve stimulation. 5. The ginsenosides-induced, ACh-induced and ginsenosides-enhanced transmural nerve stimulation-elicited relaxations were significantly attenuated by NG-nitro-L-arginine (100 microM) and oxyhaemoglobin (oxyHb; 5-10 microM), and were enhanced by superoxide dismutase (SOD; 50 u ml-1). 6. The relaxations and their attenuation by NG-nitro-L-arginine and TTX were associated with increase and decrease in tissue cyclic GMP levels, respectively. 7. It is concluded that ginsenosides may release NO from endothelial cells, and enhance NO release from endothelial cells elicited by other vasoactive substances and from perivascular nitrergic nerves in the corpus cavernosum. These endothelial and neurogenic effects of ginsenosides in inducing relaxation of the corpus cavernosum may account for the aphrodisiac effect of Panax ginseng.

Kang M, Yoshimatsu H, Oohara A, Kurokawa M, Ogawa R, Sakata T. Ginsenoside Rg1 modulates ingestive behavior and thermal response induced by interleukin-1 beta in rats. Physiol Behav 1995 Feb;57(2):393-396
Abstract: Effects of ginsenoside Rg1 (Rg1), a major component of panax ginseng, on changes in ingestive behavior and rectal temperature induced by interleukin-1 beta (IL-1 beta) were investigated in rats. Intraperitoneal (ip) injection of IL-1 beta suppressed food and water intake and elevated rectal temperature. The suppressive effect of IL-1 beta on water intake was converted to an increase when 4.0 mM Rg1 was continuously infused into the third cerebroventricle (ICV) at a rate of 0.966 microliters/h. The elevation of rectal temperature induced by IL-1 beta was attenuated by ICV infusion of Rg1. The feeding suppression caused by IL-1 beta was unaffected by ICV infusion of Rg1. These results suggest that sustained ICV infusion of Rg1 may modulate the effects of IL-1 beta on ingestive behaviors, i.e., increase in water intake and sustained decrease in food intake, resulting in a lowering of body temperature.

Mitra SK, Chakraborti A, Bhattacharya SK. Neuropharmacological studies on Panax ginseng. Indian J Exp Biol 1996 Jan;34(1):41-47
Abstract: Panax ginseng root powder is extensively used in the Far East for a wide variety of clinical ailments and to improve general physical and mental wellbeing. It is now also being used in the Occident because of the adaptogenic activity of the plant. The present investigation was conducted to evaluate the neurophamacological profile of activity of P. ginseng (ginseng), since the available data were meagre and often controversial. Ginseng had a complex profile of activity, sometimes difficult to reconcile on the available neurochemical reports on the plant. Thus, it did not appear to affect pentobarbitone sleep induction or spontaneous motor activity but potentiated amphetamine-induced increase in motility. However, ginseng attenuated the other effects of amphetamine, namely, stereotypy and lethality in aggregated mice. The drug exhibited antinociceptive activity and potentiated the antinociceptive effects of both pentazocine and aspirin. Haloperidol catalepsy was potentiated while the behavioural responses of 5-hydroxytryptophan (5-HTP) and L-DOPA were both attenuated. Ginseng had no anticonvulsant action, nor did it potentiate the anticonvulsant effects of phenobarbitone and diazepam. The drug had per se hyperthermic effect and attenuated the hypothermic response of reserpine and 5-HTP induced hyperthermia. Ginseng exhibited significant aggression-inhibiting effect in doses which had no significant effect on spontaneous motility. The results have been discussed on the neurotransmitter function basis of the experimental paradigms and the likely effect of ginseng on these actions.

Nitta H, Matsumoto K, Shimizu M, Ni XH, Watanabe H. Panax ginseng extract improves the performance of aged Fischer 344 rats in radial maze task but not in operant brightness discrimination task. Biol Pharm Bull 1995 Sep;18(9):1286-1288
Abstract: The effect of Panax ginseng extract on the learning performance of aged Fischer 344 rats using the 8-arm radial maze task and the operant discrimination task was examined. Aged rats showed significantly impaired learning performance in both tasks. Daily administration of ginseng extract (8 g/kg/d, p.o. for 12-33 d) ameliorated the impairment of learning performance in the radial maze task but not in the operant discrimination task. These results suggest that subchronic treatment with ginseng extract improves spatial cognitive impairment in aged rats.

Nitta H, Matsumoto K, Shimizu M, Ni XH, Watanabe H. Panax ginseng extract improves the scopolamine-induced disruption of 8-arm radial maze performance in rats.Biol Pharm Bull 1995 Oct;18(10):1439-1442
Abstract: The effects of Panax ginseng ethanol extract and its water (WSF)- and lipid-soluble (LSF) fractions on the scopolamine-induced disruption of radial maze performance in rats were examined. Ginseng root was refluxed with ethanol, and WSF and LSF were prepared from this ethanol extract. Scopolamine (0.075-0.3 mg/kg, i.p.) dose-dependently impaired the maze performance. However, the oral administration of Panax ginseng ethanol extract and WSF (2-8 g dried root/kg) 90 min before testing improved the maze performance disrupted by scopolamine (0.3 mg/kg) in a dose-dependent manner, but LSF failed to attenuate the disruption. These data suggest that ginseng extract possesses a beneficial effect regarding spatial cognitive impairment and that the water-soluble fraction of ginseng extract mainly contributes to the effect of the ethanol extract.

Han SW, Kim H. Ginsenosides stimulate endogenous production of nitric oxide in rat kidney. Int J Biochem Cell Biol 1996 May;28(5):573-580
Abstract: Ginsenosides (GS), saponins purified from Panax ginseng, increase renal blood flow in rats. Nitric oxide (NO) is thought to be the substance endogenously released by GS in preconstricted lungs and cultured endothelial cells. The present study aims to determine whether GS could stimulate endogenous release of NO in rat kidney and whether GS affected the activity of NO synthase in kidney tissues. The serum and urine levels of the stable NO metabolites, nitrite (NO2) and nitrate (NO3) and urinary cGMP levels were measured 8 hr after a single intraperitoneal injection of GS (200 mg/kg) into rats. The effects of the NO synthesis inhibitor, N omega-nitro-L-arginine methyl ester and the NO precursor, L-arginine, on the GS-induced changes were also determined. The activity of NO synthase, as determined by conversion of [14C]-L-arginine to [14C]-L-citrulline, in whole kidney, glomeruli and cortical tubules was also investigated. A single injection of GS resulted in endogenous production of NO as reflected by increase in serum and urine levels of NO2/NO3 and urinary cGMP levels, which were inhibited by the addition of N omega-nitro-L-arginine methyl ester and restored by L-arginine. GS also stimulated the activity of NO synthase in whole kidney as well as glomeruli and cortical tubules, and this increase was significantly prevented by N omega-nitro-L-arginine methyl ester. It was concluded that stimulation in endogenous production of NO by GS may contribute to its antinephritic action and may play a protective role in the kidney.

Aphale AA, Chhibba AD, Kumbhakarna NR, Mateenuddin M, Dahat SH. Subacute toxicity study of the combination of ginseng (Panax ginseng) and ashwagandha (Withania somnifera) in rats: a safety assessment. Indian J Physiol Pharmacol 1998 Apr;42(2):299-302
Abstract: Ginseng (Panax ginseng) and Ashwagandha (Withania somnifera) are widely used as geriatric tonics. Both individually have not shown any toxicity on long term administration. Study was planned to assess the safety of the combination by doing subacute toxicity study in rats with 90 days oral administration using three doses. Food consumption, body weight, haematological, biochemical and histopathological parameters were studied. There was significant increase in body weight, food consumption and liver weight, and improved hematopoiesis was observed. Brain, heart, lung, liver, spleen, kidneys, stomach, testis and ovaries were normal on gross examination and histopathologically. Subacute toxicity studies in rats did not reveal any toxicity.
Bensky, Dan, Chinese Herbal Medicine: Materia Medica, Seattle, WA: Eastland Press 1986

Abdrasilov BS, Kim YuA, Nurieva RI, Dedkova EN, Leonteva GA, Park HJ, Zinchenko VP. The effect of total saponins from Panax Ginseng C.A. Meyer on the intracellular signalling system in Ehrlich ascites tumor cells. Biochem Mol Biol Int 1996 Mar;38(3):519-526
Abstract: The mechanisms of action of total saponins from Panax Ginseng C.A.Meyer on the elements of intracellular signalling system in Ehrlich ascites tumor cells were studied. The action of total saponins was compared with the effect of ATP, a classical activator of these cells. Saponins at concentrations of 10(-6)-10(-3)% increased [Ca2+]i, mobilized Ca2+ ions from the endoplasmic reticulum (ER) and activated the influx of Ca2+ to cells. Like ATP, saponins activated the Na+/H+ exchange and Ca(2+)-dependent K+ channels. Of all the parameters, only the activation of Ca2+ influx in cell is directly affected by saponins. The changes in other parameters are connected with nonspecific activation of purinoreceptors. The analysis of the kinetic data suggests that, as distinct from ATP-dependent activation of purinoreceptor, saponins first activate the Ca2+ influx to cells and only then induce the mobilization of Ca2+ from ER.

Kim YS, Kim DS, Kim SI. Ginsenoside Rh2 and Rh3 induce differentiation of HL-60 cells into granulocytes: modulation of protein kinase C isoforms during differentiation by ginsenoside Rh2. Int J Biochem Cell Biol 1998 Mar;30(3):327-338
Abstract: Ginsenoside Rh1 or Rh2 differentiated B16 melanoma or F9 teratocarnoma to phenotypic normal melanocyte-like cells or parietal endoderm-like cells. Ginsenoside Rh3 and Rh4 were recently isolated from Panax ginseng, but their biochemical and pharmacological effects remain unidentified. The present study investigated whether the ginsenoside Rh group (G-Rh1, -Rh2, -Rh3 and -Rh4) having similar structures induce differentiation of HL-60 cells and whether protein kinase C (PKC) is involved in differentiation by ginsenoside. Differentiation was assessed by Wright-Giemsa stain and nitroblue tetrazolium reduction. G-Rh2 and G-Rh3 induced differentiation of HL-60 cells into morphologically and functionally granulocytes but G-Rh1 and G-Rh4 did not. G-Rh2 and G-Rh3 arrested the cell cycle at the G1/S phase, consistent with the ability to induce differentiation in a decreasing order of retinoic acid > G-Rh2 > G-Rh3. During differentiation by G-Rh2, Ca2+/phospholipid-dependent PKC activity was increased in both the cytosol and total cell extract and Ca2+/phospholipid-dependent phosphorylation of 38 and 200 kDa endogenous proteins increased, while phosphorylation of 60, 64, 66 and 97 kDa proteins was Ca2+/phospholipid-independent. When cytosolic PKC isoforms were analyzed by immunoblotting, no significant change was observed in the alpha level, however, the immunoreactive 60 kDa band of a similar mass to the PKC catalytic fragment appeared following treatment with G-Rh2. The beta isoform was gradually increased with prolonged treatment. The gamma isoform was not detected in the cytosol of untreated cells, whereas a small amount was detected 5 days after treatment. It is concluded that G-Rh2 and G-Rh3 can induce differentiation of HL-60 cells into granulocytes and modulation of PKC isoform levels may contribute to differentiation of HL-60 cells by G-Rh2.

Kim SE, Lee YH, Park JH, Lee SK. Ginsenoside-Rs4, a new type of ginseng saponin concurrently induces apoptosis and selectively elevates protein levels of p53 and p21WAF1 in human hepatoma SK-HEP-1 cells.Eur J Cancer 1999 Mar;35(3):507-11
Abstract: In this paper, we present evidence that ginsenoside-Rs4 (G-Rs4; an acetylated analogue of ginsenoside-Rg5), a new ginseng saponin isolated from Panax ginseng C. A. Meyer, elevates protein levels of p53 and p21WAF1, which are associated with the induction of apoptosis in SK-HEP-1 cells. Flow cytometric analyses showed that G-Rs4 initially arrested the cell cycle at the G1/S boundary, but consequently induced apoptosis as evidenced by generating an apoptotic peak. The induction of apoptosis was confirmed by the results of DNA fragmentation assays and alterations in cell morphology after treatment of the cells with G-Rs4. Immunoblot assays showed that G-Rs4 significantly elevated protein levels of p53 and p21WAF1, concurrently with the downregulation of both cyclins E- and A-dependent kinase activities and induction of apoptosis. We suggest that G-Rs4 induces apoptosis, the effect of which is closely related to the downregulation of both cyclins E- and A-dependent kinase activity as a consequence of selectively elevating protein levels of p53 and p21WAF1 in SK-HEP-1 cells.

Kim SE, Lee YH, Park JH, Lee SK.
Ginsenoside-Rs3, a new diol-type ginseng saponin, selectively elevates protein levels of p53 and p21WAF1 leading to induction of apoptosis in SK-HEP-1 cells.Anticancer Res 1999 Jan-Feb;19(1A):487-491
Abstract: In this paper, we present evidence that Ginsenoside-Rs3 (G-Rs3), a new diol-type ginseng saponin isolated from the roots of Panax ginseng C.A. Meyer, efficiently arrests the cell cycle at the G1/S boundary at lower doses, 0.1-5 microM, but induces apoptosis at higher doses, 10-25 microM, the effects of which were associated with selectively elevating protein levels of p53 and p21WAF1 in SK-HEP-1 cells. The cell growth suppressive and apoptosis inducing effects were confirmed by MTT assays together with flow cytometric analyses, morphological changes and DNA fragmentation. Immunoblotting showed that G-Rs3 significantly elevated protein levels of p53 and p21WAF1 prior to inducing apoptosis, while it did not elevate those of cyclin E, cyclin A, p27Kip1, and PCNA. Immune complex kinase assays showed that G-Rs3 downregulated the activities of both cyclins E- and A-associated kinases. Collectively, we suggest that G-Rs3 selectively elevates protein levels of p53 and p21WAF1 and hence downregulates the activities of the cyclin-dependent kinases, resulting in cell cycle arrest at the G1/S boundary. We also propose that apoptosis induced by G-Rs3 is related to the elevations of p53 and p21WAF1 in the cells.

Lee YN, Lee HY, Chung HY, Kim SI, Lee SK, Park BC, Kim KW. In vitro induction of differentiation by ginsenoides in F9 teratocarcinoma cells. Eur J Cancer 1996 Jul;32A(8):1420-1428
Abstract: The aim of this study was to determine the ability of the ginsenosides, extracts of Panax ginseng C.A. Meyer, to cause differentiation of F9 teratocarcinoma stem cells as a model system. F9 stem cells cultured in the presence of the ginsenosides together with dibutyryl cyclic AMP (dbcAMP) became parietal endoderm-like cells. Moreover, the expression of differentiation marker genes, such as laminin B1 and type IV collagen, was increased after treatment with the ginsenosides. Among the various purified ginsenosides, Rh1 and Rh2 were the most effective at causing differentiation of F9 cells. Since ginsenosides and glucocorticoid hormone have similar chemical structures, we examined the possibility of the involvement of a glucocorticoid receptor (GR) in the differentiation process induced by the ginsenosides. According to Southwestern blot analysis, a 94 kDa protein regarded as a GR was detected in F9 cells cultured in the medium containing the ginsenosides Rh1 or Rh2. In addition, F9 stem cells treated with the ginsenosides Rh1 or Rh2 and with RU486, a glucocorticoid antagonist with a high affinity for the GR, did not differentiate into endoderm cells morphologically, and the expression of laminin B1 gene was not induced in these cells. In a gel mobility shift assay, protein factors capable of binding to the glucocorticoid responsive element (GRE) specifically were detected in nuclear extracts of the ginsenoside-treated F9 cells. Moreover, overexpression of GR by cotransfection of GR expression vector and GRE-luciferase vector enhanced the transactivation activity of GRE promoter in the presence of ginsenosides Rh1 or Rh2 and was further augmented by dbcAMP. In addition, ginsenosides Rh1 and Rh2 bound to a GR assessed by whole-cell binding assay, even though the specific binding affinity was weaker compared to dexamethasone. Based on these data, we suggest that the ginsenosides Rh1 and Rh2 cause the differentiation of F9 cells and the effects of ginsenosides might be exerted via binding with a GR or its analogous nuclear receptor.

Nakata H, Kikuchi Y, Tode T, Hirata J, Kita T, Ishii K, Kudoh K, Nagata I, Shinomiya N. Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells. Jpn J Cancer Res 1998 Jul;89(7):733-740
Abstract: Ginsenoside Rh2 (Rh2), isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, inhibits the growth of B16 melanoma cells. This study was designed to evaluate the ability of Rh2 to inhibit growth of human ovarian cancer cells (HRA) in vitro and in nude mouse. Rh2 inhibited proliferations of various established human ovarian cancer cell lines in a dose-dependent manner between 10 and 60 microM in vitro and induced apoptosis at around the IC50 dose. When HRA cells were inoculated s.c. into the right flank of nude mice, all mice formed a palpable tumor within 14 days. Although i.p. administration of Rh2 alone hardly inhibited the tumor growth, when Rh2 was combined with cis-diamminedichloroplatinum(II) (CDDP) the tumor growth was significantly inhibited, compared to treatment with CDDP alone. When mice were treated p.o. with Rh2 daily (but not weekly), the tumor growth was significantly (P<0.01) inhibited, compared to CDDP treatment alone. When Rh2 was combined with CDDP, the degree of tumor growth retardation was not potentiated. The survival time was significantly (P<0.05) longer than that of medium alone-treated controls or the group treated with CDDP alone. Then, we examined whether p.o. administration of Rh2 has a dose-dependent inhibitory effect on the tumor growth. I.p. and weekly administration of CDDP had more potent antitumor activity in the order of 1 mg/kg, 2 mg/kg and 4 mg/kg, whereas p.o. and daily administration of Rh, (0.4 to 1.6 mg/kg) not only had antitumor activity comparable to that of 4 mg/kg CDDP, but also resulted in a significant increase of the survival. Doses of Rh2 used in this study did not result in any adverse side-effects as confirmed by monitoring hematocrit values and body weight, unlike 4 mg/kg CDDP, which had severe side-effects. It is noteworthy that p.o. but not i.p. treatment with Rh2 resulted in induction of apoptotic cells in the tumor in addition to augmentation of the natural killer activity in spleen cells from tumor-hearing nude mice. Thus, particularly in view of the toxicity of CDDP, Rh2 alone would seem to warrant further evaluation for treatment of recurrent or refractory ovarian tumor.

Oh M, Choi YH, Choi S, Chung H, Kim K, Kim SI, Kim DK, Kim ND. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int J Oncol 1999 May;14(5):869-875
Abstract: Ginsenoside Rh2 (G-Rh2) isolated from the root of Panax ginseng has been shown to have anti-cancer proliferation, differentiation and chemopreventive effects in certain cancer cell types. We investigated the mechanism of G-Rh2-induced growth inhibition in MCF-7 human breast carcinoma cells. G-Rh2 significantly inhibited the cell growth in a concentration-dependent manner, which effect was reversible, and induced a G1 arrest in cell cycle progression. G-Rh2 treatment down-regulated the protein level of cyclin D3 but upregulated the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1. The increased levels of p21 were associated with increased binding of p21 and Cdk2 concomitant with marked decrease in Cdk2 and cyclin E-dependent kinase activities with no changes in Cdk2 and cyclin E expression. G-Rh2 markedly reduced the phosphorylated retinoblastoma protein (pRb) and enchanced association of unphosphorylated pRb and the transcription factor E2F-1. These data suggest that G-Rh2 inhibited the growth of MCF-7 cells, by inducing protein expression of p21 and reducing the protein levels of cyclin D which resulted in the down-regulation of cyclin/Cdk complex kinase activity, decreasing phosphorylation of pRb, and inhibiting E2F release.

Park HJ, Park KM, Rhee MH, Song YB, Choi KJ, Lee JH, Kim SC, Park KH. In vitro induction of differentiation by ginsenoides in F9 teratocarcinoma cells. Biol Pharm Bull 1996 Jun;19(6):834-838
Abstract: We investigated the effects of ginsenoside Rb1 (G-Rb1), a major saponin from Panax ginseng C. A. MEYER, on rat liver protein phosphorylation after intraperitoneal administration of CCl4 alone or together with G-Rb1. We found that 118, 63, and 34kDa proteins were prominently phosphorylated in liver homogenates prepared from CCl4-administered rats, while these protein-phosphorylations were inhibited in the homogenate prepared from the G-Rb1 plus CCl4-administration group. When inhibitors of protein kinases were exogenously added to the homogenates from either the CCl4-administered group or the G-Rb1 plus CCl4-administered group, their phosphorylations were inhibited much more by W-7, an inhibitor of Ca2+/calmodulin-dependent protein kinase (CaM-PK), than by H-7, an inhibitor of protein kinase C (C-kinase). Interestingly, only 34kDa was phosphorylated in homogenates prepared from the corn oil-, G-Rb1-, and G-Rb1 plus CCl4-administered groups by the exogenous addition of sodium fluoride (NaF), an inhibitor of glycogen synthase. Additionally, G-Rb1 inhibited the Ca(2+)-accumulation induced by CCl4 both in liver homogenates and microsomes. The above results imply that G-Rb1 inhibits the CCl4-induced protein phosphorylations by modulating CaM-PK rather than C-kinase, and that 34kDa protein may play a different biological role in cellular environment from 118 and 63kDa proteins. Therefore, a study in which G-Rb1 is employed as a modulator of critical CCl4-induced phenomena ranging from the disturbance of Ca2+ concentration to protein phosphorylation may be successfully applicable to investigate the diverse physiological functions of liver.

Xiaoguang C, Hongyan L, Xiaohong L, Zhaodi F, Yan L, Lihua T, Rui H. Cancer chemopreventive and therapeutic activities of red ginseng. J Ethnopharmacol 1998 Feb;60(1):71-78
Abstract: Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 approximately 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system.

Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol 1998 Jun;27(3):359-364
Abstract: BACKGROUND: A number of studies have reported that increased consumption of natural products reduced the risk of cancer. Our previous case-control studies have shown a significant reduction in the risk of cancer development among those who regularly consumed ginseng. We conducted a prospective cohort study to evaluate the preventive effect of ginseng against cancer on a population residing in a ginseng cultivation area on the basis of the result of case-control studies. METHODS: This study was conducted in Kangwha-eup from August 1987 to December 1992. We studied 4634 people over 40 years old who completed a questionnaire on ginseng intake. In an attempt to obtain detailed information about ginseng intake, we asked them to specify their age at initial intake, their frequency and duration of ginseng intake, the kind of ginseng, etc. Multiple logistic regression was used to estimate relative risks (RR) when controlling simultaneously for covariates. RESULTS: Ginseng consumers had a decreased risk (RR = 0.40, 95% confidence interval [CI] : 0.28-0.56) compared with non-consumers. On the type of ginseng, the RR was 0.31 (95% CI: 0.13-0.74) for fresh ginseng extract consumers and 0.34 (95% CI: 0.20-0.53) for consumers of multiple combinations. There was no cancer death among 24 red ginseng consumers. There was a decreased risk with a rise in the frequency of ginseng intake, showing a dose-response relationship. The RR of ginseng consumers were 0.33 (95% CI: 0.18-0.57) in gastric cancer and 0.30 (95% CI : 0.14-0.65) in lung cancer. Among ginseng preparations, fresh ginseng extract consumers were significantly associated with a decreased risk of gastric cancer (RR = 0.33, 95% CI: 0.12-0.88). CONCLUSIONS: These results strongly suggest that Panax ginseng C.A. Meyer has non-organ specific preventive effect against cancer, providing support for the previous case-control studies.

Yun TK, Lee YS, Kwon HY, Choi KJ. Saponin contents and anticarcinogenic effects of ginseng depending on types and ages in mice.Chung Kuo Yao Li Hsueh Pao 1996 Jul;17(4):293-298
Abstract: AIM: To compare the anticarcinogenic effects of fresh, white, and red ginseng (Panax ginseng C A Meyer) roots and their saponins. METHODS: Lung adenoma in newborn N:GP (S) mice was induced by a subcutaneous injection of benzo(a)pyrene 0.5 mg. After weaning, ginseng powders or extracts were given in the drinking water for 6 wk. In the 9th wk the incidence and multiplicity of lung adenoma were counted. RESULTS: Anticarcinogenic effects were found in 6-year-dried fresh ginseng, 5- and 6-year white ginseng, and 4-, 5-, and 6-year-red ginseng powders. Anticarcinogenic effects were also found in 6-year-dried fresh ginseng, 5- and 6-year-white ginseng, and 4-, 5-, and 6-year-red ginseng extracts. The content of major ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 showed a little higher tendency in fresh or white ginsengs than red ginseng. This tendency was increased as the cultivation ages were increased. But there was no relationship was found between ginsenoside contents and preparation types or cultivation ages. CONCLUSION: Long-cultivated ginseng and red ginseng contain a higher amount of anticarcinogenic components.

Yun TK. Experimental and epidemiological evidence of the cancer-preventive effects of Panax ginseng C.A. Meyer. Nutr Rev 1996 Nov;54(11 Pt 2):S71-81