Ginsenoside Rg2

Korean J Physiol Pharmacol. 2013 Apr;17(2):133-7.

Ginsenoside rg2 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell.[Pubmed: 23626475]

Vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), P- and E-selectin play a pivotal role for initiation of atherosclerosis. Ginsenoside, a class of steroid glycosides, is abundant in Panax ginseng root, which has been used for prevention of illness in Korea. In this study, we investigated the mechanism(s) by which Ginsenoside Rg2 may inhibit VCAM-1 and ICAM-1 expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC).
METHODS AND RESULTS:
LPS increased VCAM-1 and ICAM-1 expression. Ginsenoside Rg2 prevented LPS-mediated increase of VCAM-1 and ICAM-1 expression. On the other hand, JSH, a nuclear factor kappa B (NF-κB) inhibitor, reduced both VCAM-1 and ICAM-1 expression stimulated with LPS. SB202190, inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and wortmannin, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced LPS-mediated VCAM-1 but not ICAM-1 expression. PD98059, inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) did not affect VCAM-1 and ICAM-1 expression stimulated with LPS. SP600125, inhibitor of c-Jun N-terminal kinase (JNK), reduced LPS-mediated ICAM-1 but not VCAM-1 expression. LPS reduced IkappaBα (IκBα) expression, in a time-dependent manner within 1 hr. Ginsenoside Rg2 prevented the decrease of IκBα expression stimulated with LPS. Moreover, Ginsenoside Rg2 reduced LPS-mediated THP-1 monocyte adhesion to HUVEC, in a concentration-dependent manner.
CONCLUSIONS:
These data provide a novel mechanism where the Ginsenoside Rg2 may provide direct vascular benefits with inhibition of leukocyte adhesion into vascular wall thereby providing protection against vascular inflammatory disease.

Chem Biol Interact. 2012 Jan 5;195(1):35-42.

Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3β via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells.[Pubmed: 22062806]

Panax ginseng is known to have anti-diabetic activity, but the active ingredients have not been fully explored yet. Here, we test whether Ginsenoside Rg2 has an inhibitory effect on hepatic glucose production and determine its mechanism of action.
METHODS AND RESULTS:
Ginsenoside Rg2 significantly inhibits hepatic glucose production and induces phosphorylations of liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3β (GSK3β) in time- and concentration-dependent manners in human HepG2 hepatoma cells, and these effects were abolished in the presence of compound C, a selective AMPK inhibitor. In addition, phosphorylated form of cAMP-response element-binding protein (CREB), a key transcription factor for hepatic gluconeogenesis, was decreased in time- and concentration-dependent manners. Next, gene expression of orphan nuclear receptor small heterodimer partner (SHP) was also examined. Ginsenoside Rg2 markedly enhanced the gene expression of SHP and its direct interaction with CREB, which results in disruption of CREB·CRTC2 complex. Consequently, expressions of relevant genes such as peroxisome proliferation-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were all significantly suppressed and these effects were also reversed in the presence of compound C. In conclusion, our results propose that
CONCLUSIONS:
Ginsenoside Rg2 suppresses the hepatic glucose production via AMPK-induced phosphorylation of GSK3β and induction of SHP gene expression. Further studies are warranted to elucidate a therapeutic potential of Ginsenoside Rg2 for type 2 diabetic patients.

Progress in Modern Biomedicine, 2010,10(06):1069-75.

Ginsenoside Rg2 attenuates learning and memory loss through an anti-apoptotic property in a rat model of multi-infarct dementia.[Reference: WebLink]

We evaluated the neurorestorative effects of Ginsenoside Rg2,one of the main bioactive components of Panax ginseng,in a rat model of multi-infarct dementia (MID).
CONCLUSIONS:
A MID rat model was established as produced by multiple cerebral infarctions induced by means of a thrombo-inducer.Y-maze learning performance was assessed after thrombo-induction.Results: Immunocytochemical techniques were employed to assess cell apoptosis as measured by protein expressions of glutamate,calpainⅡ,caspase-3 and bax.Learning and memory performance were impaired by thrombo-inductor induced MID and the expression of glutamate,calpainⅡ,caspase-3 and bax were increased in this MID rat model.After Ginsenoside Rg2 (2.5,5 or 10 mg/kg) or nimodipine (50μg/kg) treatment,learning and memory performance was increased and the expression of glutamate,calpain Ⅱ,caspase-3 and bax were decreased in this MID model.
CONCLUSIONS:
These findings suggest that Ginsenoside Rg2 improved learning and memory through mechanisms related to anti-apoptosis in MID rats.These results also indicate that Ginsenoside Rg2 may represent a potential neurorestorative treatment strategy for vascular dementia or other ischemic insults.

2016 Jan;40(1):9-17.

A UPLC/MS-based metabolomics investigation of the protective effect of ginsenosides Rg1 and Rg2 in mice with Alzheimer's disease[Pubmed: 26843817]

Abstract Background: Alzheimer's disease (AD) is a progressive brain disease, for which there is no effective drug therapy at present. Ginsenoside Rg1 (G-Rg1) and G-Rg2 have been reported to alleviate memory deterioration. However, the mechanism of their anti-AD effect has not yet been clearly elucidated. Methods: Ultra performance liquid chromatography tandem MS (UPLC/MS)-based metabolomics was used to identify metabolites that are differentially expressed in the brains of AD mice with or without ginsenoside treatment. The cognitive function of mice and pathological changes in the brain were also assessed using the Morris water maze (MWM) and immunohistochemistry, respectively. Results: The impaired cognitive function and increased hippocampal Aβ deposition in AD mice were ameliorated by G-Rg1 and G-Rg2. In addition, a total of 11 potential biomarkers that are associated with the metabolism of lysophosphatidylcholines (LPCs), hypoxanthine, and sphingolipids were identified in the brains of AD mice and their levels were partly restored after treatment with G-Rg1 and G-Rg2. G-Rg1 and G-Rg2 treatment influenced the levels of hypoxanthine, dihydrosphingosine, hexadecasphinganine, LPC C 16:0, and LPC C 18:0 in AD mice. Additionally, G-Rg1 treatment also influenced the levels of phytosphingosine, LPC C 13:0, LPC C 15:0, LPC C 18:1, and LPC C 18:3 in AD mice. Conclusion: These results indicate that the improvements in cognitive function and morphological changes produced by G-Rg1 and G-Rg2 treatment are caused by regulation of related brain metabolic pathways. This will extend our understanding of the mechanisms involved in the effects of G-Rg1 and G-Rg2 on AD. Keywords: Alzheimer's disease; ginseng; ginsenoside Rg1; Ginsenoside Rg2; metabolomics.

Mol Cells. 2003 Feb 28;15(1):34-9.

Effects of ginsenosides on glycine receptor alpha1 channels expressed in Xenopus oocytes.[Pubmed: 12661758]

Ginsenosides, major active ingredients of Panax ginseng, are known to regulate the excitatory ligand-gated ion channel activity. Recent reports showed that ginsenosides attenuate nicotinic acetylcholine and NMDA receptor channel activity. However, it is not known whether ginsenosides also affect the inhibitory ligand-gated ion channel activity.
METHODS AND RESULTS:
We investigated the effect of ginsenosides on human glycine alpha1 receptor channel activity expressed in Xenopus oocytes using a two-electrode voltage clamp technique. Treatment of ginsenoside Rf enhances glycine-induced inward peak current (IGly) with dose dependent and reversible manner but ginsenoside Rf itself did not elicit membrane currents. The half-stimulatory concentrations (EC50) of ginsenoside Rf was 49.8 +/- 8.9 microM. Glycine receptor antagonist strychnine completely blocked the inward current elicited by glycine plus ginsenoside Rf. Cl- channel blocker 4,4'-disothiocyanostilbene-2,2'-disulfonic acid (DIDS) also blocked the inward current elicited by glycine plus ginsenoside Rf. We also tested the effect of eight individual ginsenosides (i.e., Rb1, Rb2, Rc, Rd, Re, Rg1, Ginsenoside Rg2, and Ro) in addition to ginsenoside Rf. We found that five of them significantly enhanced the inward current induced by glycine with the following order of potency: Rb1 > Rb2 > Ginsenoside Rg2 > or = Rc > Rf > Rg1 > Re.
METHODS AND RESULTS:
These results indicate that ginsenosides might regulate gylcine receptor expressed in Xenopus oocytes and this regulation might be one of the pharmacological actions of Panax ginseng.

Int J Clin Exp Med. 2015 Nov 15;8(11):19938-47.

Protective effects of ginsenoside Rg2 against H2O2-induced injury and apoptosis in H9c2 cells.[Pubmed: 26884906]

Ginsenoside Rg2 is one of the major active components of ginseng and has many biological activities. This study aimed to investigate the protective effects of Ginsenoside Rg2 against H2O2-induced injury and apoptosis in H9c2 cells.
METHODS AND RESULTS:
The results showed that pretreatment with Ginsenoside Rg2 not only increased cell viability, but also decreased lactate dehydrogenase (LDH) release. Ginsenoside Rg2 inhibited the decrease of SOD, GSH-PX activities and the increase of MDA content induced by H2O2. Meanwhile, the levels of ROS generation and cardiomyocyte apoptosis in Ginsenoside Rg2 group significantly reduced when compared with the model group. Western blot analyses demonstrated that Ginsenoside Rg2 up-regulate level of Bcl-2 expression and down-regulate levels of Bax, Caspase-3, -9 expression.
CONCLUSIONS:
These findings indicated that Ginsenoside Rg2 could protect H9c2 cells against H2O2-induced injury through its actions of anti-oxidant and anti-apoptosis.

Naunyn Schmiedebergs Arch Pharmacol. 2010 Jul;382(1):89-101.

Effects of ginsenoside Rg2 on the ultraviolet B-induced DNA damage responses in HaCaT cells.[Pubmed: 20508917]

Our previous study demonstrated the increase in the repair of UVB damage by mRg2, a mixture of ginsenosides containing 60% Rg2 in NIH3T3 cells. In the present study, the effects of purified Ginsenoside Rg2( Rg2) on the repair and apoptosis in ultraviolet B (UVB)-exposed HaCaT cells were investigated on gene expression levels.
METHODS AND RESULTS:
When cells were exposed to UVB and post-incubated in normal medium for 24 h, the cell viability decreased to about 50% of that in nontreated control. When Rg2 was post-incubated, however, the UVB-induced cytotoxicity was significantly prevented in an Rg2 concentration- and time-dependent manner. The apoptotic nuclear fragmentation resulting from UVB exposure was also significantly protected by the Rg2 post-incubation. Microarray analysis showed that the genes stimulated by the Rg2-alone treatment include those involved in p53 signaling pathway such as GADD45alpha, GADD45beta, and cell communication genes. RT-PCR analysis showed that the Rg2-alone treatment slightly upregulated the p53 and GADD45 transcript and protein levels by about 1.5-fold as compared with the nontreated control. The mRNA levels of p53 and GADD45 in cells exposed to UVB and post-incubated with Rg2 for 24 h decreased in an Rg2 concentration-dependent manner as compared with that post-incubated in normal medium. However, the mRNA level of the UVB-exposed cells post-incubated with 5 microM retinol was essentially the same as that post-incubated in normal medium. Time course experiment showed that the mRNA levels of p53 and GADD45 in UVB-exposed cells were upregulated by post-incubation with 50 microM Rg2 until 6 and 9 h, respectively, and then gradually decreased until 24 h. By Western blot analysis, it was also revealed that the Rg2 post-incubation decreases the expression of p53, phospho-p53, GADD45, and ATM in UVB-exposed cells. Time course analysis also indicated that these decreased expressions were due to the earlier upregulation of p53 and GADD45 proteins. When UVB-exposed cells were post-incubated with Rg2 for 24 h after UVB exposure, the level of remaining cyclobutane pyrimidine dimers decreased in both Rg2 concentration- and time-dependent manner.
CONCLUSIONS:
All these results suggest that Rg2 protects cells against UVB-induced genotoxicity by increasing DNA repair, in possible association with modulation of protein levels involved in p53 signaling pathway.