Ginsenoside Re

The roots of Panax ginseng C. A. Mey.

Ginsenoside Re is an extract from Panax notoginseng. Ginsenoside Re decreases the β-amyloid protein (Aβ). Ginsenoside Re plays a role in antiinflammation through inhibition of JNK and NF-κB.

In Vitro:Ginsenoside Re is a well-known traditional Chinese medicine, which decreases the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA and protein levels and inhibits BACE1 activity in the N2a/APP695 cells. Ginsenoside Re also significantly increases the PPARγ protein and mRNA levels.To prevent Ginsenoside Re from having a cytotoxic effect on the N2a/APP695 cells, the cell viability is first determined by the MTT assay. The N2a/WT and N2a/APP695 cells are treated with increasing concentrations of Ginsenoside Re (0-200 µM) for 24 h. Ginsenoside Re concentrations under 100 µM do not affect the viability of the N2a/WT and N2a/APP695 cells, whereas the 150 µM Ginsenoside Re concentration markedly decreases the survival rate of the N2a/WT and N2a/APP695 cells. Incubation with Ginsenoside Re at a 200 µM concentration for 24 h reduces the viability of the N2a/WT and N2a/APP695 cells by 15.58% and 26.82%, respectively. These data indicate that Ginsenoside Re treatment within the range of 0-100 µM for 24 h is safe for the N2a/WT and N2a/APP695 cells (P>0.05)[1].

In Vivo:Ginsenoside Re reduces insulin resistance in 3T3-L1 adipocytes and high-fat diet (HFD) rats through inhibition of JNK and NF-κB activation[2]. Intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 20 mg/kg is lethal to mice, and 70% to 80% of the mice die within 60 h. However, pretreatment of the mice with Rg1 or Ginsenoside Re increases their survival rates in a dose-dependent manner. With the doses of Rg1 or Ginsenoside Re increase from 2.5 to 5 mg/kg, the survival rate is elevated from 60% to 90% (Rg1) or from 30% to 40% (Ginsenoside Re). All the mice administered Rg1 at a minimal dose of 10 mg/kg are protected from death compared to 80% survival of mice treated with an equal dose of Ginsenoside Re. To protect all the mice, 20 mg/kg Ginsenoside Re is needed. To investigate the anti-inflammatory potential of Rg1 and Ginsenoside Re, 1 mg/kg Rg1 or Ginsenoside Re is injected into rats and then challenged the animals with LPS. The injection procedure itself causes a transient stress-induced increase in body temperature of ~1.2°C in each group. Thereafter, LPS-challenged rats without pretreatment develope a robust biphasic fever, with the first peak reaching ~1.5°C at 2 h and the second peak reaching 1.8°C at 4 h. In contrast, the temperature changes for the Rg1-, Ginsenoside Re-, and TAK-242-treated groups are only 0.9, 1.2, and 0.8°C at 2 h and 1.3, 1.4, and 1.0°C at 4 h, respectively. Pretreatment with Rg1, Ginsenoside Re, or TAK-242 significantly attenuates LPS-induced alterations in body temperature[3].

References:
[1]. Cao G, et al. Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells. Eur J Pharmacol. 2016 Dec 15;793:101-108. [2]. Zhang Z, et al. Ginsenoside Re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-kappaB. Mol Endocrinol. 2008 Jan;22(1):186-95. [3]. Su F, et al. Protective effect of ginsenosides Rg1 and Re on lipopolysaccharide-induced sepsis by competitive binding to Toll-like receptor 4. Antimicrob Agents Chemother. 2015 Sep;59(9):5654-63.

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

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

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, which cause paralysis and respiratory dysfunction. There is currently no permanently effective drug for patients with ALS. 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. 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. Together, our data suggest that G-Re could have potent anti-neuroinflammatory effects on ALS by inhibiting the TLR4 pathway.

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

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

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. 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. 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.

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

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

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. 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. Our results demonstrate that Ginsenoside Re enhanced viability of CD4(+) T cells through the regulation of IFN-gamma-dependent autophagy activity.

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

Pharmacol Biochem Behav. 2012 Mar;101(1):93-8.

OBJECTIVE: This study was designed to investigate the effect of Ginsenoside Re (Re) on cognitive functions, oxidative stress and inflammation in streptozotocin-induced diabetic rats. RESEARCH DESIGN AND METHOD: 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-alpha and malondialdehyde (MDA) contents in both temporal cortex and hippocampus, blood was collected for assays of TNF-alpha, MDA and reduced glutathione (GSH) levels. RESULTS: 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-alpha 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-alpha 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.

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]

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

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. 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. 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.

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

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

AIMS: 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. MAIN METHODS: Ionic currents of cultured HCAECs were studied using whole-cell patch clamp technique. KEY FINDINGS: 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. SIGNIFICANCE: 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.

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

Cardiovasc Ther. 2012 Aug;30(4):e183-8.

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.

Ginsenoside Re (Ginsenoside B2) is an extract from Panax notoginseng. Ginsenoside Re decreases the β-amyloid protein (Aβ). Ginsenoside Re plays a role in antiinflammation through inhibition of JNK and NF-κB.

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