Yasushi Mizumaki, Masanori Kurimoto, Yutaka Hirashima, Michiharu Nishijima, Hironaga Kamiyama, Shoichi Nagai, Akira Takaku, Kazuyuki Sugihara, Mineo Shimizu and Shunro Endo
Panax ginseng is a traditional Chinese herb with a wide range of therapeutic benefits. Recent studies focusing on its effect on the central nervous system have revealed that ginseng has neurotrophic effects including differentiation of neurons. However, most studies involve use of the water-soluble fraction called saponin, and little is known about the effect of the lipophilic fraction. In the present study, we have shown that the lipophilic fraction of ginseng at a concentration of between 0.1 and 50 µg/ml can induce neurite outgrowth of PC12 cells in a dose-dependent manner. Nearly all cells showed morphological differentiation in response to the lipophilic fraction. This morphological differentiation of PC12 cells appeared to be similar to that of NGF. The lipophilic fraction of ginseng also induced neurite extension and promoted survival of rat cortical neurons at a concentration of between 0.025 and 1 µg/ml. These neurotrophic effects on PC12 cells and cortical neurons were not inhibited by K252b, which selectively blocks neurotrophin actions by inhibiting trk-type receptor tyrosine phosphorylation. This suggests that trks do not participate in the neurotrophic action of the lipophilic fraction. However, the effects were completely attenuated by sphingosine, polymyxin B or staurosporin, known inhibitors of protein kinase C (PKC) and calmodulin-dependent kinases. Our results suggest that the lipophilic fraction of ginseng exerts its neurotrophic effects via PKC-dependent pathways.
Author Keywords: Ginseng; Lipophilic fraction; Neurotrophic factor; PKC
Neuroscience classification codes: Development and regeneration, Neurotrophic factors: biological effects
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 523-524, February-March 2003, Pages 63-74
Panax ginseng C.A. Meyer has been the most highly recognized medicinal herb in the Orient. The prolonged administration of red ginseng extract significantly inhibits the incidence of hepatoma and also proliferation of pulmonary tumors induced by aflatoxin B1 and urethane. Statistically significant anticarcinogenic effects were in aged or heat treated extracts of ginseng and red ginseng made by steaming in a 9 weeks medium-term anticarcinogenicity test using benzo[a]pyrene. In case-control studies, odds ratios (OR) of the cancer of lip, oral cavity and pharynx, larynx, lung, esophagus, stomach, liver, pancreas, ovary, and colorectum were significantly reduced. As to the type of ginseng, the ORs for cancer were reduced in user of fresh ginseng extract intakers, white ginseng extract, white ginseng powder, and red ginseng. In a cohort study with 5 years follow-up conducted in a ginseng cultivation area, ginseng users had a decreased relative risk (RR) compared with non-users. The relative risks (RRs) of ginseng users were decreased in gastric cancer and lung cancer. These findings strongly suggest that Panax ginseng C.A. Meyer cultivated in Korea has non-organ specific cancer preventive effects against various cancers. To investigate the active components for cancer prevention, several fractions of fresh and red ginseng and four semi-synthetic ginsenoside Rh1, Rh2, Rg3 and Rg5, the major saponin components in red ginseng, were prepared among the ginsenosides. By using Yun´s model, Rg3 and Rg5 showed statistically significant reduction of lung tumor incidence and Rh2 had a tendency to decrease the incidence. In conclusion, these results strongly suggested that Panax ginseng C.A. Meyer cultivated in Korea is a non-organ specific cancer preventive against human cancers and also indicated that the anticarcinogenicity or human cancer preventive effect of Panax ginseng is due to ginsenoside Rg3, Rg5 and Rh2.
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≈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.
Author Keywords: Red ginseng; Transplantable tumor; T lymphocyte proliferation; Tumorigenesis; Lipid peroxidation
Hai Rim Shin1 Joon Youn Kim1 , Taik Koo Yun2, Gareth Morgan3 and Harri Vainio3
Department of Preventive Medicine, College of Medicine, Dong-A University, 3Ga-1 Dong-Dae-Shin-Dong, Seo-Gu, Pusan, Korea, 602-714
Laboratory of Experimental Pathology, Korea Atomic Energy Research Institute, Korea Cancer Center Hospital, Seoul, Korea
Unit of Chemoprevention, International Agency for Research on Cancer, Lyon, France
Abstract Objective: We have reviewed the potential cancer-preventive and other relevant properties of Panax ginseng C. A. Meyer, which has been traditionally used as a natural tonic in Oriental countries.
Data identification and study selection: Publications on Panax ginseng and its relation to cancer were obtained from the Medline database (1983-1998) and by checking reference lists to find earlier reports. The reports cover experimental models and human studies on cancer-preventive activity, carcinogenicity and other beneficial or adverse effects. In addition, possible mechanisms of chemoprevention by ginseng were considered.
Results: Published results from a cohort and two case-control studies in Korea suggest that the intake of ginseng may reduce the risk of several types of cancer. When ginseng was tested in animal models, a reduction in cancer incidence and multiplicity at various sites was noted. Panax ginseng and its chemical constituents have been tested for their inhibiting effect on putative carcinogenesis mechanisms (e.g., cell proliferation and apoptosis, immunosurveillance, angiogenesis); in most experiments inhibitory effects were found.
Conclusion: While Panax ginseng C. A. Meyer has shown cancer-preventive effects both in experimental models and in epidemiological studies, the evidence is currently not conclusive as to its cancer-preventive activity in humans. The available evidence warrants further research into the possible role of ginseng in the prevention of human cancer and carcinogenesis.cancer-preventive activity - experimental models - ginseng - mechanisms of anti-carcinogenesis
Ali Karadeniz, Mustafa Cemekand Nejdet Simsek
Cadmium is an environmental and industrial cumulative pollutant that affects many organs, specially the liver. The protective effect of Spirulina platensis and Panax ginseng on cadmium-induced oxidative stress and hepatotoxicity was evaluated in adult female Wistar albino rats. At the end of the 1-month experimental period, all animals were fasted for 12 h and liver samples were taken for the determination of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels. S. platensis and P. ginseng treatments showed marked decrease lipid peroxidation and increase of the endogenous antioxidants levels. The cadmium-induced histopathological changes were also minimized with the tested extracts. These results suggest that S. platensis and P. ginseng might play a role in reducing the toxic effect of cadmium and its antioxidant properties seem to mediate such a protective effect.
Keywords: Spirulina platensis; Panax ginseng; Cadmium; Hepatic damage; Rat
Soo Lim, Ji Won Yoon, Sung Hee Choi, Bong Jun Cho, Jun Tae Kim, Ha Soon Chang, Ho Seon Park, Kyong Soo Park, Hong Kyu Lee, Young-Bum Kim and Hak Chul Jang
Received 25 September 2007;
accepted 2 July 2008.
Available online 6 December 2008.
Extracts of ginseng species show antihyperglycemic activity. We evaluated the antihyperglycemic and antiobesity effects of ginsam, a component of Panax ginseng produced by vinegar extraction, which is enriched in the ginsenoside Rg3. Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, were assigned into 1 of 3 groups (n = 8 each): controls (isotonic sodium chloride solution, 5 mL/d), rats given 300 mg/(kg d) ginsam, and rats given 500 mg/(kg d) ginsam. An intraperitoneal 2-hour glucose tolerance test was performed at the end of the 6-week treatment. After 8 weeks, body and liver weights, visceral fat measured by computed tomography, and fasting glucose and insulin concentrations and lipid profiles were recorded. Insulin-resistant rats treated with ginsam had lower fasting and postprandial glucose concentrations compared with vehicle-treated rats. Importantly, overall glucose excursion during the intraperitoneal 2-hour glucose tolerance test decreased by 21.5% (P < .01) in the treated rats, indicating improved glucose tolerance. Plasma insulin concentration was significantly lower in ginsam-treated rats. These changes may be related to increased glucose transporter 4 expression in skeletal muscle. Interestingly, when the data from both ginsam-treated groups were combined, body weight was 60% lower in the ginsam-treated rats than in the controls (P < .01). Liver weight and serum alanine aminotransferase concentrations were also lower in the ginsam-treated rats. These effects were associated with increased peroxisome proliferator-activated receptor γ expression and adenosine monophosphate-activated protein kinase phosphorylation in liver and muscle. Our data suggest that ginsam has distinct beneficial effects on glucose metabolism and body weight control in an obese animal model of insulin resistance by changing the expression of genes involved in glucose and fatty acid metabolism.
Ying Wei, Chao-Mei Ma and Masao Hattori
Three artificial triterpenoids, (20R)-20,25-epoxy-dammaran-2-en-6α,12β-diol (1), (20R)-20,25-epoxy-3-methyl-28-nordammaran-2-en-6α,12β-diol (2) and isodehydroprotopanaxatriol (3), were isolated from an acidic hydrolysate of Panax ginseng C.A. Meyer, along with three known triterpenes, (20R)-panaxadiol (4), (20R)-panaxatriol (5) and oleanolic acid (6). Compounds 1-3 and 6 showed inhibitory activity against HIV-1 protease with IC50 of 10.5, 10.3, 12.3 and 6.3 µM, respectively. The results indicated that acid treatment of Ginseng extract could produce diverse structures with interesting bioactivity.
Three artificial triterpenoids were isolated along with three known ones, from an acidic hydrolysate of Panax ginseng. Four of them showed inhibitory activity on HIV protease.
Keywords: Panax ginseng; Araliaceae; Triterpenoid; (20R)-20,25-Epoxy-dammaran-2-en-6α,12β-diol; (20R)-20,25-Epoxy-3-methyl-28-nordammaran-2-en-6α,12β-diol; Isodehydroprotopanaxatriol; HIV-1 protease inhibitor
Fay Ng, Heedong Yun, Xiaoguang Lei, Samuel J. Danishefsky, Jed Fahey, Katherine Stephenson, Charles Flexner and Lawrence Lee
Panaxytriol is a nutraceutical-based active constituent of Korean red ginseng and is reported to exhibit potent anti-tumor properties. Its activity may be in part due to its induction of phase 2 chemoprotective enzymes. Its unique properties may have important implications in cancer therapeutics. Graphical abstract
The medicinal herb, Panax notoginseng, has been used for thousands of years in traditional Chinese medicine and possesses anti-fibrosis properties. Epithelial-myofibroblast transition (EMT) plays an important role in renal tubulointerstitial fibrosis. The present study was designed to examine whether ginsenoside Rg1, a major active component isolated from Panax notoginseng, has an ability to block this phenotypic transition in rat renal tubular epithelial cells (NRK-52E) induced by transforming growth factor-β1 (TGF-β1). The morphology of tubular epithelial-myofibroblast transition was observed through light microscope and transmission electron microscopy. α-SMA and E-cadherin are two markers of tubular epithelial-myofibroblast transition, their protein expressions were assessed by immunohistochemistry and western blot analysis. Gene expression of α-SMA as well as the two major extracellular matrix components collagen I and fibronectin was measured by real-time PCR analysis. Enzyme-linked immunosorbent assay was used to quantitatively detect collagen I and fibronectin in the supernatant. Our results revealed that ginsenoside Rg1 obviously blocked morphologic transformation in NRK-52E induced by TGF-β1. Meanwhile, ginsenoside Rg1 inhibited the expression of α-SMA and the loss of E-cadherin, subsequently decreased the levels of collagen I and fibronectin in a dose-dependent manner. In addition, western blot analysis indicated that ginsenoside Rg1 inhibited the expression of P-ERK1/2 in NRK-52E induced by TGF-β1. These results suggest that ginsenoside Rg1 can restrain the process of EMT maybe via suppressing the expression of P-ERK1/2 in vitro.
Keywords: Ginsenoside Rg1; Transforming growth factor-β1 (TGF-β1); Renal fibrosis; Epithelial-myofibroblast transition (EMT); Extracellular matrix (ECM); Extracellular signal-regulated kinase (ERK)
Fig. 1. Chemical structure of ginsenoside Rg1.
Fig. 2. Effect of ginsenoside Rg1 on phenotypic transformation of tubular epithelial to myofibroblasts in NRK-52E induced by TGF-β1. (a-c) Phase contrast microscopy 200×: (a) control group; (b) TGF-β1 10 ng/ml group; (c) TGF-β1 10 ng/ml plus ginsenoside Rg1 40 ng/ml group (after incubated for 72 h). (d-g) Transmission electron microscopy 4200×: (d) control group; (e-f) TGF-β1 10 ng/ml group; (g) TGF-β1 10 ng/ml plus ginsenoside Rg1 40 ng/ml group (after incubated for 72 h).
Fig. 3. Time-course of α-SMA, collagen I and fibronectin mRNA expression in NRK-52E induced by TGF-β1. It was demonstrated that α-SMA mRNA level increased rapidly and up to maximum in 48 h upon the stimulation of TGF-β1, and then declined but still kept at a relatively high level. This increase was followed by significant augmentation of collagen I and fibronectin mRNA, both of which appeared progressively throughout the time course.
Fig. 4. Western blot analysis of α-SMA and E-cadherin expression in NRK52E cells. (a) Western blot analysis of α-SMA and E-cadherin expression in NRK52E cells. The NRK52E cells were stimulated with TGF-β1 (10 ng/ml) at 24 h, 48 h, 72 h, 96 h, and 120 h. (b) Ginsenoside Rg1 decreased α-SMA expression at 72 h in a dose-dependent manner. Ginsenoside Rg1 largely restored the E-cadherin protein staining at 72 h in a dose-dependent manner.
Fig. 5. Effect of ginsenoside Rg1 on expression of α-SMA and E-Cadherin in NRK52E cells detected by immunohistochemistry. (a-c) Immunohistochemical analysis of α-SMA expression 200×: (a) control group; (b) TGF-β1 10 ng/ml group; (c) TGF-β1 10 ng/ml plus ginsenoside Rg1 40 ng/ml group (after incubated for 72 h). (d-f) Immunohistochemical analysis of E-cadherin expression 400×: (d) control group; (e) TGF-β1 10 ng/ml group; (f) TGF-β1 10 ng/ml plus ginsenoside Rg1 40 ng/ml group (after incubated for 72 h).
Fig. 6. Western blot analysis of P-ERK1/2 expression in NRK52E cells. (a) Western blot analysis of P-ERK1/2 expression in NRK52E cells. The NRK52E cells were stimulated with TGF-β1 (10 ng/ml) at 15 min, 30 min, 60 min, 120 min, and 240 min. (b) Ginsenoside Rg1 decreased P-ERK1/2 expression at 60 min in a dose-dependent manner.
Oligonucleotide primer sets for real-time PCR.
For, Rev and Pro indicate forward, reverse and probe, respectively. All primers and TaqMan probes were purchased from Sangon Biotech (Shanghai, China).
Effect of ginsenoside Rg1 on α-SMA, collagen I and fibronectin mRNA expression in NRK52E cells (relative expression ratio).
♣ p < 0.05 vs. control group.
◊ p > 0.05 vs. control group.
* p < 0.05 vs. TGF-β1 10 ng/ml.
♦ p > 0.05 vs. TGF-β1 10 ng/ml.
Immunohistochemical analysis of the expression of α-SMA and E-Cadherin in NRK52E cells (positive-stained cells %).
♣ p < 0.05 vs. control group.
◊ p > 0.05 vs. control group.
* p < 0.05 vs. TGF-β1 10 ng/ml.
Effect of Rg1 on TGF-β1-induced collagen I and fibronectin protein expression detected by ELISA.
♣ p < 0.05 vs. control group.
◊ p > 0.05 vs. control group.
* p < 0.05 vs. TGF-β1 10 ng/ml.
Corresponding author at: Department of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxuexiang, Wuhou, Chengdu 610041, China.
A new compound, named quinquefoloside-Lc (1), together with nine known compounds, was isolated from leaves of Panax quinquefolium, and its structure was elucidated as 3β,12β,20S-trihydroxy-25-methoxydammar-23-ene 3-O-β-d-glucopyranosyl (1 → 2) β-d-glucopyranosyl-20-O-β-d-xylopyanosyl (1 → 6) β-d-glucopyranoside (1), on the basis of MS, 1D-and 2D-NMR experiments as well as by chemical degradation. The cytotoxicity of these compounds against human breast cancer MCF-7 cell line was also tested by MTT method.
A new compound, named Quinquefoloside-Lc (1), together with nine known compounds, was isolated from leaves of Panax quinquefolium, and its structure was elucidated as 3β, 12β, 20S-trihydroxy-25-methoxydammar-23-ene 3-O-β-d-glucopyranosyl (1 → 2)β-d-glucopyranosyl-20-O-β-d-xylopyanosyl(1 → 6)β-d-glucopyranoside (1), on the basis of MS, 1D-and 2D-NMR experiments as well as by chemical degradation. The cytotoxicity of these compounds against human breast cancer MCF-7 cell line was also tested by MTT method. The structure of Quinquefoloside-Lc (1) was shown as follows.
Keywords: Qinquefoloside; Ginsenoside; Saponin; Anti-cancer
Fig. 1. Structure of compound 1.
Fig. 2. Key HMBC and NOESY correlations of compound 1.
Schwann cells (SCs), the glial cells of the peripheral nerve system, play a key role in the regeneration of injured peripheral nerves. However, problems with the use of SCs to repair peripheral nerves include attenuated biologic properties and impaired function with ageing. Panaxydol (PND) effectively protects neurons against injury in degenerative diseases. We investigated the protective role of PND in SCs through immunocytochemistry and ELISA assay. PND promoted the expression and secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) by SCs in a dose-dependent manner at doses of 2.5-20 and 5.0-20 µM, respectively. The effects on both factors were maximal at 10 µM. PND also enhanced the synthesis of actin, a key component of the cytoskeleton. When we examined mitochondria in SCs with probes marked with rhodamine-123, fluorescence intensity was stronger in the PND group than in a control group, indicating a stabilized mitochondrial transmembrane potential. PND modified cytoskeleton dynamics and induced SCs to secrete and express neurotrophic factors (NTFs), and to resist high energy consumption in a dose-dependent manner. It exerted its maximum effect at 10 µM. PND treatment of SCs might be promising strategies for the application of these cells in repairing PNS injury by enhancing the biological properties.
Keywords: Schwann cell; Panaxydol; Neurotrophic factors; Cytoskeleton; Mitochondrial transmembrane potentials
Abbreviations: BDNF, brain-derived neurotrophic factor; DMSO, dimethyl sulfoxide; NTF, neurotrophic factor; NGF, nerve growth factor; PBS, phosphate-buffered saline; PND, panaxydol; PNS, peripheral nervous system; SCs, Schwann cells
Jing He, Wen-Long Ding, Feng Li, Rong Xia, Wen-Jin Wang and Hao Zhu
Ritu Shukla and Madhu Kuma
Liver, being primary site for biotransformation of foreign compounds is vulnerable to various chemical assaults. Ginseng has a wide range of pharmacological and therapeutical action. In the present study an attempt has been made to study the cadmium chloride (CdCl2) induced toxicity in liver and its possible protection by panax ginseng Swiss albino mice were divided into four groups: (i) Control group - only vehicle (double distilled water) (ii) inseng treated group - 10 mg/kg b.wt. orally (iii) CdCl2 treated group - 1.0 mg/kg b.wt. CdCl2 i.p. (iv) Combination group - Ginseng root extract (10 mg/kg b.wt.) and CdCl2 (1.0 mg/kg b.wt.). Activities of alkaline phosphatase, GOT, GPT were measured in serum and lipid peroxidation (LPO) and GSH content were measured in liver. The results indicated a significant increase in LPO, GOT, GPT activities and decrease in GSH and serum alkaline phosphatase activities after CdCl2 treatment. Ginseng alone did not show any significant alterations except a significant decrease in LPO level. Combined treatment of Ginseng and CdCl2 showed significant decrease in LPO, GOT, GPT and elevation in GSH and serum alkaline phosphatase as compared to CdCl2 treated group. Thus, Ginseng is found to be protective against cadmium-induced hepatic injuries.
Keywords: Cadmium; Ginseng; LPO; GSH; SGOT; SGPT
Life Sciences, Volume 71, Issue 7, 5 July 2002, Pages 759-769
Hyung-Chul Lee, Sang-Gu Hwang, Young-Gu Lee, Hyung-Ok Sohn, Dong-Wook Lee, Seok-Youn Hwang, Yi-Swong Kwak, Jae-Joon Wee, Woo-Hong Joo, Yong-Kweon Cho, Ja-Young Moon
The effects of the subchronic administration of Panax ginseng extracts were examined on the hepatic cytochrome P450-dependent monooxygenase system of guinea pigs pre-exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Panax ginseng extracts were intraperitoneally administered to guinea pigs at 100 mg/kg/day for 14 days from 1 week after a single intraperitoneal injection of 1 µg of TCDD/kg of body weight. TCDD treatment increased the total cytochrome P450 content 2.86-fold, and this was remarkably inhibited by the administration of Panax ginseng extracts. Treatment with ginseng extract alone also decreased the contents of cytochrome P450 by 33%, but both TCDD and ginseng extracts had no effect on cytochrome b5 content. The administration of TCDD resulted in a 1.73-fold increase in microsomal NADPH-cytochrome P450 reductase activity in the guinea pig liver, and this was significantly inhibited by ginseng extracts, but treatment with ginseng extracts alone had no effect on its activity, and no statistical changes in the activity of NADPH-cytochrome b5 reductase were observed in guinea pig liver due to TCDD and/or ginseng extract administration. Compared to the control, ECOD activity remarkably (1.76-fold) increased after TCDD administration, but this increase was completely inhibited by treatment with ginseng extract. Treatment with ginseng extract alone resulted in a 50% reduction of ECOD activity. TCDD administration remarkably induced benzphetamine demethylation (BPDM) activity, while ginseng extract also slightly increased the enzyme´s activity, but the induction attributed to ginseng extracts was not statistically significant. Even though administration of ginseng extracts slightly inhibited TCDD-induced BPDM activity, the inhibition was not statistically significant. These results indicate that ginseng extract exerts different effect on the induction of P450 isozymes. From these results, we suggest that Panax ginseng extracts may act as an inhibitor of CYP1A rather than that of CYP2B.