• Journal of Ginseng Research
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• v.44 no.5
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• pp.690-696
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• 2020

Background: As the main metabolites of ginsenosides, 20(S, R)-protopanaxadiol [PPD(S, R)] and 20(S, R)-protopanaxatriol [PPT(S, R)] are the structural basis response to a series of pharmacological effects of their parent components. Although the estrogenicity of several ginsenosides has been confirmed, however, the underlying mechanisms of their estrogenic effects are still largely unclear. In this work, PPD(S, R) and PPT(S, R) were assessed for their ability to bind and activate human estrogen receptor α (hERα) by a combination of in vitro and in silico analysis. Methods: The recombinant hERα ligand-binding domain (hERα-LBD) was expressed in E. coli strain. The direct binding interactions of ginsenosides with hERα-LBD and their ERα agonistic potency were investigated by fluorescence polarization and reporter gene assays, respectively. Then, molecular dynamics simulations were carried out to simulate the binding modes between ginsenosides and hERα-LBD to reveal the structural basis for their agonist activities toward receptor. Results: Fluorescence polarization assay revealed that PPD(S, R) and PPT(S, R) could bind to hERα-LBD with moderate affinities. In the dual luciferase reporter assay using transiently transfected MCF-7 cells, PPD(S, R) and PPT(S, R) acted as agonists of hERα. Molecular docking results showed that these ginsenosides adopted an agonist conformation in the flexible hydrophobic ligand-binding pocket. The stereostructure of C-20 hydroxyl group and the presence of C-6 hydroxyl group exerted significant influence on the hydrogen bond network and steric hindrance, respectively. Conclusion: This work may provide insight into the chemical and pharmacological screening of novel therapeutic agents from ginsenosides.

• Proceedings of the Ginseng society Conference
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• 2002.10a
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• pp.317-334
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• 2002

Ginsenosides are metabolized (deglycosylated) by intestinal bacteria to active forms after oral administration. 20(S)-Protopanaxadiol $20-O-{\beta}-D-glucopyranoside$ (M1) and 20(S)-protopanaxatriol (M4) are the main intestinal bacterial metabolites (IBMs) of protopanaxadiol- and protopanaxatriol-type glycosides. M1 was selectively accumulated into the liver soon after its intravenous (i.v.) administration to mice, and mostly excreted as bile; however, some M1 was transformed to fatty acid ester (EMl) in the liver. EM1 was isolated from rats in a recovery dose of approximately $24mol\%.$ Structural analysis indicated that EM1 comprised a family of fatty acid mono-esters of M1. Because EM1 was not excreted as bile as Ml was, it was accumulated in the liver longer than M1. The in vitro cytotoxicity of M1 was attenuated by fatty acid esterification, implying that esterification is a detoxification reaction. However, esterified M1 (EM1) inhibited the growth of B16 melanoma more than Ml in vivo. The in vivo antitumor activity paralleled with the pharmacokinetic behavior. In the case of M4, orally administered M4 was absorbed from the small intestine into the mesenteric lymphatics followed by the rapid esterification of M4 with fatty acids and its spreading to other organs in the body and excretion as bile. The administration of M4 prior to tumor injection abrogated the enhanced lung metastasis in the mice pretreated with 2-chloroadenosine more effectively than in those pretreated with anti-asialo GMl. Both EM1 and EM4 did not directly affect tumor growth in vitro, whereas EM1 promoted tumor cell lysis by lymphocytes, particularly non-adherent splenocytes, and EM4 stimulated splenic NK cells to become cytotoxic to tumor cells. Thus, the esterification of IBM with fatty acids potentiated the antitumor activity of parental IBM through delay of the clearance and through immunostimulation. These results suggest that the fatty acid conjugates of IBMs may be the real active principles of ginsenosides in the body.

• The Journal of Traditional Korean Medicine
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• v.15 no.1
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• pp.97-105
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• 2006

To study on antioxidant effects in the liver of 40-week-old mouse, the sample were orally pretreated 5mg/kg/day for 5 days with red ginseng saponin components(total saponin, protopanaxadiol saponin, protopanaxatriol saponin, ginsenoside-Rd, ginsenoside-Re, compound-K) for 5 days. The ability of saponin to protect the mouse liver from oxidative damage was examined by determining the activity of superoxide dismutase(SOD), glutathione peroxidase(GPx) and the contents of glutathione, the level of malondialdehyde, The only protopanaxadiol among the ginseng saponin fractions was significantly increased the hepatic SOD activity(p<0.01). The red ginseng saponin induced a slight increase of GPx activity, especially ginsenoside Rd, compound K and protopanaxatriol treatments significantly increased its activity. The content of glutathione was significantly increased by total saponin, protopanaxadiol and ginsenoside Rd(p<0.01), but the oxidized glutathione level was lowered in all the red ginseng saponin. Finally, the level of malondialdehyde was significantly decreased by ginsenoside Rd and protopanaxadiol. In conclusion, protopanaxadiol and ginsenoside Rd among the saponin fraction were especially increased in the activity of hepatic antioxidative enzyme and decreased the lipid peroxidation that was expressed in term of MDA formation. This comprehensive antioxidant effects of red ginseng saponin seems to be by a certain action of saponin other than a direct antioxidant action.

• Journal of Life Science
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• v.26 no.12
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• pp.1422-1430
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• 2016

This study was performed to investigate the modulatory effects of two prototypes of Panax ginseng saponin fractions, 20(S)-protopanaxadiol saponins (PDS) and 20(S)-protopanaxatriol saponins (PTS), on the induction of inflammatory mediators in lipopolysaccharide (LPS)-treated RAW264.7 murine macrophage cells. For this purpose, RAW264.7 cells were treated with LPS ($10{\mu}g/ml$) before, after, or simultaneously with PDS or PTS ($150{\mu}g/ml$), and the released level of nitric oxide (NO) and expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were evaluated. When RAW264.7 cells were treated with LPS and ginseng saponin fractions simultaneously for 24 hr, PTS, compared to PDS, more strongly attenuated the NO production induced by LPS treatment. When the cells were pretreated with LPS for 2 hr followed by PDS or PTS treatment for 24 hr, both ginseng saponins strongly reduced NO release. The pretreatment of RAW264.7 cells with PDS or PTS for 2 hr followed by LPS treatment for 24 hr significantly attenuated the LPS-induced production of NO. PTS showed stronger inhibitory potency to NO generation than PDS. Our western blot experiment showed that both PDS and PTS ($150{\mu}g/ml$) also significantly down-regulated the expressions of iNOS and COX-2 induced by LPS treatment. Our results suggest that both PDS and PTS possess strong protective effects against LPS-stimulated inflammation and that their protective effects are mediated by the suppression of NO synthesis via down-regulation of pro-inflammatory enzymes, iNOS, and COX-2 in the RAW264.7 cells.

• Journal of Ginseng Research
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• v.33 no.4
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• pp.316-323
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• 2009

Ginseng saponins have various pharmacological effects on the immune system. 20(S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT) are the species of ginseng saponin metabolites that are formed by human intestinal bacteria and detected in circulation. The effects of PPD and PPT on the inflammatory mediator release from the activated mast cells were tested. Histamine release was evaluated in activated guinea pig lung mast cells, and the secretion of interleukin-4 (IL-4), interleukin-8 (IL-8), and the tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) was assessed in an HMC-1 cell after treating it with ginseng saponin metabolites. The results are as follows. PPT, at its maximum concentration of $100\;{\mu}M$, completely abolished the secretion of IL-4 from the PMA-stimulated HMC-1 cell. It also inhibited IL-8 secretion from the same cells by about 40-50% of the PMA-treated DMSO control. PPD, at its maximum concentration of $100\;{\mu}M$, showed a tendency to induce histamine release from the guinea pig lung mast cells. It inhibited the secretion of IL-4 (by 89% of the PMA-treated DMSO control) in the PMA-stimulated HMC-1 cell, but did have a significant effect on the IL-8 release from the same cell. Both PPD and PPT showed no effects, however, on the release of TNF-${\alpha}$ from the PMA-stimulated HMC-1 cell. These results suggest that PPD and PPT are from the ginseng metabolites that are responsible for the immunomodulating activity of ginseng extracts when they are taken orally.

• YAKHAK HOEJI
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• v.16 no.3
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• pp.129-136
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• 1972

Two anti-infalmmatory glycosides, Panax saponin A, $C_{47}H_{72}O_{14}$ center dot $2H_{2}O$, m.p. $208-10^{\circ}$ and C, m.p. $196-202^{\circ}$, were isolated from the methanol extract of Panax ginseng. The anti-inflammatory activity of Panax saponin A was found to have delayed and prolonged characteristics. The partial structure of Panax saponin A was established to be ${\beta}{\betha}$'20S-protopanaxatriol-diglucoside. One of glucose residues was bound to the 20S-hydroxyl group of aglycone.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.226-226
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• 1994

천연의 Triterpene이나 Steroid의 01igo당 배당체는 항균작용, 소염작용, 항암작용등의 유용한 생리활성을 가지는것이 많다. 따라서 이들 화합물군으로 부터 신의약품이 개발될 가능성이 매우크다 하겠다. 그러나 천연물은 그 작용이 약하거나 순수하게 다량 분리하기가 쉽지않다. 생리활성이 강하고, 부작용이 적은 배당체를 이용가능한 양만큼 다량을 순수하게 얻기 위하여는 합성의 기법이 절대적으로 필요하다. 이를 위하여 연구자는 천연의 총배당체 (배당체혼합물)로부터 aglycone을 얻고 여기에 g1ycosidation 반응으로 당을 결합시킴으로써 천연 또는 비 천연성 배당체를 합성하고 생리활성을 검토, 신물질을 창출하고자 한다. Aglycone으로는 Ginsenosides의 aglycone인 20(s)-protopanaxadiol 및 20(S)-protopanaxatriol, Soyasapogenol B, Oleanlic acid를 사용하고, 목표로하는 생리활성은 항암작용, 항군작용, alcohol 흡수 저해작용을 지향한다.

• Journal of Ginseng Research
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• v.22 no.3
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• pp.200-205
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• 1998

Isolated rabbit jejunal segments were used to study the effects of ginseng total saponins (GTS) , protopanaxatriol saponins (PT) and protopanaxadiol saponins (PD) on intestinal contractility. GTS, PT and PD caused a dose-dependent decrease in intestinal spontaneous movements, and PT was the most efficacious of them. The effect of GTS, PT and PD were not blocked by pretreatment with phentolamine (10-6 M), yohimbine (10-6 M), d1-propranolol (10-6 M), naloxone(10-6∼10-5M), Nu-nitro-L-arginine methyl ester (10-4 M), methylene blue (10-5M), and N-ethylmaleimide (10-4 M). However, pretreatment with tetraethylammonium chloride (3-10 mM) antagonized the effect of GTS, PT and PD. Furthermore, 4-amlnopyridine (1 mM) also inhibited the effect of GTS, PT and PD. The results suggest that GTS, PT and PD inhibited the spontaneous movements in isolated rebait jejunum by causing hyperpolarization through an activation of K+ channels directly.

• Journal of Ginseng Research
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• v.33 no.3
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• pp.165-176
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• 2009

Korean ginseng, which contains ginsenosides and polysaccharides as its main constituents, is orally administered to humans. Ginsenosides and polysaccharides are not easily absorbed by the body through the intestines due to their hydrophilicity. Therefore, these constituents which include ginsenosides Rb1, Rb2, and Rc, inevitably come into contact with intestinal microflora in the alimentary tract and can be metabolized by intestinal microflora. Since most of the metabolites such as compound K and protopanaxatriol are nonpolar compared to the parental components, these metabolites are easily absorbed from the gastrointestinal tract. The absorbed metabolites may express pharmacological actions, such as antitumor, antidiabetic, anti-inflammatory, anti-allergic, and neuroprotective effects. However, the activities that metabolize these constituents to bioactive compounds differ significantly between individuals because all individuals possess characteristic indigenous strains of intestinal bacteria. Recently, ginseng has been fermented with enzymes or microbes to develop ginsengs that contain these metabolites. However, before using these enzymes and probiotics, their safety and biotransforming activity should be assessed. Intestinal microflora play an important role in the pharmacological action of orally administered ginseng.

• Korean Journal of Pharmacognosy
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• v.17 no.2
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• pp.139-147
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• 1986

Ginseng saponins(GS), protopanaxadiol saponins(PD) and protopanaxatriol saponins (PT) were tested for the inhibition of the development of morphine tolerance and dependence antagonism of morphine analgesia and the loss of morphine tolerance and dependence in mice The results were as follows: 1. Inhibition of the development of morphine tolerance and dependence. 2. Antagonism of morphine analgesia. 3. Increase in the loss of morphine tolerance and dependence. Antagonism of morphine by ginseng saponins and its reversal by L-DOPA and 5-HTP suggest some possibility that catecholamines and serotonin levels might be associated with the results.