Ginsenoside Re

Eur J Pharmacol . 2016 Dec 15;793:101-108.

Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells[Pubmed: 27840193]

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition. Reducing the Aβ load may be a new perspective for AD treatment. Ginsenoside Re is an extract from Panax notoginseng, which is a well-known traditional Chinese medicine that has been used for the treatment of various diseases for years. Ginsenoside Re has been reported to decrease Aβ in Alzheimer's disease animal models, but the mechanism has not been fully elucidated. In the present study, we investigated the mechanism of Ginsenoside Re. Our results showed that Ginsenoside Re decreased the Aβ levels in N2a/APP695 cells. Aβ peptides are generated by β-secretase (β-site amyloid precursor protein cleaving enzyme 1 (BACE1)) and γ-secretase. We found that Ginsenoside Re decreased the BACE1 mRNA and protein levels and inhibited BACE1 activity in the N2a/APP695 cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates the activity of the BACE1 promoter, and activating PPARγ can inhibit BACE1. The results also showed that Ginsenoside Re significantly increased the PPARγ protein and mRNA levels. These effects of Ginsenoside Re on BACE1 could be effectively inhibited by the PPARγ antagonist GW9662. These findings indicate that Ginsenoside Re inhibits BACE1 through activation of PPARγ, which ultimately reduces the generation of Aβ1-40 and Aβ1-42. Therefore, Ginsenoside Re may be a promising agent for the modulation of Aβ-related pathology in AD.

Antimicrob Agents Chemother . 2015 Sep;59(9):5654-63.

Protective effect of ginsenosides Rg1 and Re on lipopolysaccharide-induced sepsis by competitive binding to Toll-like receptor 4[Pubmed: 26149990]

We previously demonstrated that ginsenosides Rg1 and Re enhanced the immune response in C3H/HeB mice but not in C3H/HeJ mice carrying a mutation in the Tlr4 gene. The results of the present study showed that both Rg1 and Re inhibited mRNA expression and production of proinflammatory mediators that included tumor necrosis factor α, interleukin-1β, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase from lipopolysaccharide (LPS)-stimulated macrophages. Rg1 was found to be distributed both extracellularly and intracellularly but Re was located only extracellularly to compete with LPS for binding to Toll-like receptor 4. Preinjection of Rg1 and Re into rats suppressed LPS-induced increases in body temperature, white blood cell counts, and levels of serum proinflammatory mediators. Preinjection of Rg1 and Re into mice prevented the LPS-induced decreases in total white blood cell counts and neutrophil counts, inhibited excessive expression of multiple proinflammatory mediators, and successfully rescued 100% of the mice from sepsis-associated death. More significantly, when administered after lethal LPS inoculation, Rg1, but not Re, still showed a potent antisepsis effect and protected 90% of the mice from death. The better protection efficacy of Rg1 could result from its intracellular distribution, suggesting that Rg1 may be an ideal antisepsis agent.

Int J Mol Med. 2012 Jan;29(1):73-80.

Ginsenoside Re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice.[Pubmed: 21971952 ]

Ginsenoside Re is a protopanaxatriol-type saponin isolated from Panax ginseng berry. Although anti-diabetic and anti-hyperlipidemic effects of Re have been reported by several groups, its mechanism of action is largely unknown until now. Here, we examine anti-diabetic and anti-hyperlipidemic activities of Re and action mechanism(s) in human HepG2 hepatocytes and high-fat diet fed C57BL/6J mice.
METHODS AND RESULTS:
Re suppresses the hepatic glucose production via induction of orphan nuclear receptor small heterodimer partner (SHP), and inhibits lipogenesis via suppression of sterol regulatory element binding protein-1c (SREBP-1c) and its target gene [fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1)] transcription. These effects were mediated through activation of AMP-activated protein kinase (AMPK), and abolished when HepG2 cells were treated with an AMPK inhibitor, Compound C. C57BL/6J mice were randomly divided into five groups: regular diet fed group (RD), high-fat diet fed group (HFD) and the HFD plus Re (5, 10, 20 mg/kg) groups. Re treatment groups were fed a high-fat diet for 6 weeks, and then orally administered Re once a day for 3 weeks. The in vitro results are likely to hold true in an in vivo experiment, as Re markedly lowered blood glucose and triglyceride levels and protected against hepatic steatosis in high-fat diet fed C57BL/6J mice.
CONCLUSIONS:
In conclusion, the current study suggest that Ginsenoside Re improves hyperglycemia and hyperlipidemia through activation of AMPK, and confers beneficial effects on type 2 diabetic patients with insulin resistance and dyslipidemia.

Cardiovasc Ther., 2012, 30(4):e183–8.

Ginsenoside Re: pharmacological effects on cardiovascular system.[Pubmed: 21884006]

Ginsenosides are the bioactive constituents of ginseng, a key herb in traditional Chinese medicine. As a single component of ginseng, Ginsenoside Re (G-Re) belongs to the panaxatriol group. Many reports demonstrated that G-Re possesses the multifaceted beneficial pharmacological effects on cardiovascular system. G-Re has negative effect on cardiac contractility and autorhythmicity. It causes alternations in cardiac electrophysiological properties, which may account for its antiarrhythmic effect. In addition, G-Re also exerts antiischemic effect and induces angiogenic regeneration. In this review, we first outline the chemistry and the pharmacological effects of G-Re on the cardiovascular system.

Life Sci. 2014 Oct 12;115(1-2):15-21.

Ginsenoside Re enhances small-conductance Ca(2+)-activated K(+) current in human coronary artery endothelial cells.[Pubmed: 25242515 ]

Ginsenosides, active components in ginseng, have been shown to increase nitric oxide (NO) production in aortic endothelial cells. This effect was reversed by tetraethylammonium (TEA) inhibition of endothelial Ca(2+)-activated K(+) (KCa) channels. The objectives of this study, therefore, were to test 1) whether vasorelaxing Ginsenoside Re could affect KCa current, an important regulator of NO production, in human coronary artery endothelial cells (HCAECs); and 2) whether small-conductance KCa (SKCa) channel was the channel subtype involved.
METHODS AND RESULTS:
Ionic currents of cultured HCAECs were studied using whole-cell patch clamp technique. Ginsenoside Re dose-dependently increased endothelial outward currents, with an EC50 of 408.90±1.59nM, and a maximum increase of 36.20±5.62% (mean±SEM; p<0.05). Apamin, an SKCa channel inhibitor, could block this effect, while La(3+), a nonselective cation channel (NSC) blocker, could not. When NSC channel, inward-rectifier K(+) channel, intermediate-, and large-conductance KCa channels were simultaneously blocked, Ginsenoside Re could still increase outward currents significantly (35.49±4.22%; p<0.05); this effect was again abolished by apamin. Repeating the experiments when Cl(-) channel was additionally blocked gave similar results. Finally, we demonstrated that Ginsenoside Re could hyperpolarize HCAECs; this effect was reversed by apamin. These data clearly indicate that Ginsenoside Re increased HCAEC outward current via SKCa channel activation, and NSC channel was not involved.
CONCLUSIONS:
This is the first report to demonstrate that Ginsenoside Re could increase SKCa channel activity in HCAECs. This can be a mechanism mediating ginseng's beneficial actions on coronary vessels.

Mol Pharmacol. 2006 Dec;70(6):1916-24.

Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormones.[Pubmed: 16985185 ]

Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that Ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes.
METHODS AND RESULTS:
In this study, we provide compelling evidence that Ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, Ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that Ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment.
CONCLUSIONS:
Thus, Ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.

Int Immunopharmacol. 2010 May;10(5):626-31.

Ginsenoside Re enhances survival of human CD4+ T cells through regulation of autophagy.[Pubmed: 20230918 ]

In the present study, we examined the effects of Ginsenoside Re (Re) on cytokine expression, cytokine-dependent autophagy and cell survival in human CD4(+) T cells.
METHODS AND RESULTS:
When CD4(+) T cells isolated from human peripheral blood were treated with Re, LC3 and monodansylcadaverine (MDC), representative markers of autophagy, were decreased in a dose-dependent manner. Interestingly, Re suppressed the production of interferon-gamma (IFN-gamma) and immunity-related GTPase family M (IRGM) in CD4(+) T cells whereas no changes in other autophagy-related signaling molecules (ERK, p38 and AKT-mTOR-p70S6k) were found. Concomitantly, we observed that Re increased the proliferation of CD4(+) T cells with decreased cell death.
CONCLUSIONS:
Our results demonstrate that Ginsenoside Re enhanced viability of CD4(+) T cells through the regulation of IFN-gamma-dependent autophagy activity.

Am J Chin Med. 2016;44(2):401-13.

Ginsenoside Re Attenuates Neuroinflammation in a Symptomatic ALS Animal Model.[Pubmed: 27080948 ]

Ginsenoside Re (G-Re), one of the most active ingredients of ginseng, has pharmacological activities that affect a number of targets. To investigate the effects of G-Re on neuroinflammation, we used G-Re (2.5[Formula: see text][Formula: see text]g/g) at the Joksamni acupressure point (ST36) once every other day for one week. To evaluate G-Re function in symptomatic human-superoxide dismutase 1 (hSOD1[Formula: see text] transgenic mice, immunohistochemistry and Western blot analysis were performed with the spinal cord of symptomatic hSOD1(G93A) transgenic mice.
METHODS AND RESULTS:
Here, we report that G-Re exhibits potent neuroprotective effects against neuroinflammation in a murine model of ALS. G-Re treatment reduced the loss of motor neurons and active-microglia-related expression of Iba-1 in the spinal cord of symptomatic hSOD1(G93A) transgenic mice. In addition, compared with age-matched hSOD1(G93A) mice, G-Re-treated hSOD1(G93A) mice showed a significant reduction in expression of pro-inflammatory proteins such as CD14 and TNF-[Formula: see text] protein related to TLR4 signaling pathway. G-Re administration also led to a decrease in cell death-related phospho-p38 protein levels, and had an antioxidative effect by reducing HO1 expression.
CONCLUSIONS:
Together, our data suggest that G-Re could have potent anti-neuroinflammatory effects on ALS by inhibiting the TLR4 pathway.

Pharmacol. Biochem., 2012, 101(1):93-8.

Ginsenoside Re attenuates diabetes-associated cognitive deficits in rats.[Pubmed: 22197711 ]

This study was designed to investigate the effect of Ginsenoside Re (Re) on cognitive functions, oxidative stress and inflammation in streptozotocin-induced diabetic rats.
METHODS AND RESULTS:
Diabetic rats were treated with Re (40mg/kg) for 8weeks, blood glucose and body weight were measured monthly and weekly, respectively. Cognitive performances were evaluated with Morris water maze. Brain was obtained for measurements of TNF-α and malondialdehyde (MDA) contents in both temporal cortex and hippocampus, blood was collected for assays of TNF-α, MDA and reduced glutathione (GSH) levels. Learning and memory abilities were significantly (both P<0.01) impaired in diabetic rats, accompanied by the marked (all P<0.01) elevations of TNF-α and MDA levels in temporal cortex and hippocampus. Increment of MDA and decrement of GSH in serum also occurred with significant differences (both P<0.01). Chronic treatment with Re markedly (P<0.05) improved the cognition of diabetic rats, evidenced by the decreased escape latency and the increased percentage of time spent in the target quadrant. Furthermore, Re treatment remarkably (P<0.05) reduced the levels of TNF-α and MDA in both brain areas of diabetic rats. Decline of MDA level and elevation of GSH level in serum were also seen in Re-treated diabetic rats, coupled with decrease in serum glucose level, all with statistically significant differences.
CONCLUSIONS:
Our findings firstly provide the first evidence that Ginsenoside Re can remarkably attenuate diabetes-associated cognitive decline, secondly confirm the involvement of oxidative stress and inflammation in the development of cognitive impairment caused by diabetes, finally point toward the potential of Ginsenoside Re as an adjuvant therapy to conventional anti-hyperglycemic regimens as well as diabetes-associated cognitive decline.