Ginsenoside Rb1

Ginsenoside Rb1, a main constituent of the root of Panax ginseng, inhibits Na+, K+-ATPase activity with an IC50 of 6.3±1.0 μM. Ginsenoside also inhibits IRAK-1 activation and phosphorylation of NF-κB p65 .

In Vitro:Rat brain microsomal Na+, K+-ATPase activity is inhibited significantly and rapidly by Ginsenoside Rb1. The IC50 of Ginsenoside Rb1 for Na+,K+-ATPase is 6.3±1.0 μM. The inhibition is enhanced with increasing the concentration of Ginsenoside Rb1 or decreasing that of Na+ and K+. Kinetic analysis reveals that Ginsenoside is an uncompetitive inhibitor with respect to ATP[1]. Ginsenoside Rb1 significantly inhibits the activation of interleukin-1 receptor-associated kinase-1 (IRAK-1), IKK-β, NF-κB, and MAP kinases (ERK, JNK, and p-38); however, interaction between LPS and Toll-like receptor-4, IRAK-4 activation and IRAK-2 activation are unaffected[2]. Ginsenoside Rb1 is an ingredient of a Chinese medicine Panax ginseng. Ginsenoside Rb1 is a major bioactive compound in the regulating pregnane X receptor (PXR)/NF-κB signaling. Ginsenoside Rb1 is the compound with potent anti-inflammatory activity in ginseng saponin extract (GSE). The concentration for Ginsenoside Rb1 (10 μM) is optimized from a preliminary study to ensure sufficient anti-inflammatory activity and without apparent cytotoxicity. Ginsenoside Rb1 significantly reduces TNF-α-induced upregulation of IL-1β and iNOS mRNA levels, and restores the mRNA levels of PXR and CYP3A4 in LS174T cells. TNF-α causes a significant reduction in PXR protein levels and increase in the ratio of phosphorylated to total NF-κB p65, both of which are significantly abrogated by Ginsenoside Rb1[3].

In Vivo:Ginsenoside Rb1 at the both doses of 30 mg/kg and 60 mg/kg significantly attenuates the histological lung injury. Ginsenoside Rb1 at the dose of 30 mg/kg and 60 mg/kg both significantly attenuates the histological intestine injury[4]. Ginsenoside Rb1 (Rb1), an ingredient of a Chinese medicine Panax ginseng, has beneficial effects on mesentery microvascular hyperpermeability induced by Lipopolysaccharide (LPS) and the underlying mechanisms. In some rats, Ginsenoside Rb1 (5 mg/kg per hour) is administrated through the left jugular vein 30 min after LPS infusion. Ginsenoside Rb1 decreases caveolae number in endothelial cells of microvessels. Ginsenoside Rb1 ameliorates microvascular hyperpermeability after the onset of endotoxemia and improves intestinal edema through inhibiting caveolae formation and junction disruption, which is correlated to suppression of NF-κB and Src activation[5].

References:
[1]. Cao J, et al. Inhibitory effects of ginsenoside Rg1 and Rb1 on rat brain microsomal Na+,K+-ATPase activity. Zhongguo Yao Li Xue Bao. 1990 Jan;11(1):10-4. [2]. Joh EH, et al. Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation--the key step of inflammation. Biochem Pharmacol. 2011 Aug 1;82(3):278-86. [3]. Zhang J, et al. Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium-Induced Colitis. Drug Metab Dispos. 2015 Aug;43(8):1181-9. [4]. Jiang Y, et al. Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice. Oxid Med Cell Longev. 2015;2015:843721. [5]. Zhang Y, et al. Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway. Am J Physiol Gastrointest Liver Physiol. 2014 Feb 15;306(4):G289-300.

Effects of ginsenosides-Rb1 on exercise-induced oxidative stress in forced swimming mice.[Pubmed:25422546]

Pharmacogn Mag. 2014 Oct;10(40):458-63.

BACKGROUND: The fleshy root of Panax ginseng C.A. Meyer (ginseng) is one of the most well-known and valued herbs in traditional Chinese medicine. Ginsenosides are considered mainly responsible for the pharmacological activities of ginseng. The purpose of this study was to investigate the effects of ginsenoside-Rb1 (G-Rb1) on swimming exercise-induced oxidative stress in male mice. MATERIALS AND METHODS: A total of 48 animals were randomly divided into four groups, with twelve mice in each group. The first, second and third groups were designed as G-Rb1 treatment groups, got 25, 50 and 100 mg/kg bodyweight of G-Rb1, respectively. The fourth group was designed as the control group, got physiologic saline. The mice were intragastrically administered once daily for 4 weeks. The weight-loaded forced swimming test was conducted on the final day of experimentation. Then the exhaustive swimming time, blood lactate, serum creatine kinase (CK), malondialdehyde (MDA) and antioxidant enzymes in liver of mice were measured. RESULTS: The results showed that G-Rb1 could prolong the exhaustive swimming time and improve exercise endurance capacity of mice, as well as accelerate the clearance of blood lactate and decrease serum CK activities. Meanwhile, G-Rb1 could decrease MDA contents and increase superoxide dismutase, catalase, glutathione peroxidase activities in liver of mice. CONCLUSIONS: The study suggested that G-Rb1 possessed protective effects on swimming exercise-induced oxidative stress in mice.

Ginsenoside Rb1 attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the JNK and p38 signaling pathways.[Pubmed:25912763]

Vascul Pharmacol. 2015 Oct;73:86-95.

BACKGROUND: Abdominal aortic aneurysm (AAA), a life-threatening vascular disease, accounts for approximately 10% of the morbidity in people over 65 years old. No satisfactory approach is available to treat AAA. Ginsenosides Rb1 and Rg1 are primary ingredients of Panax notoginseng for the treatment of cardiovascular diseases, but their impact on AAA is unknown. METHODS AND RESULTS: An AAA model was established using an Ang II infusion in ApoE(-/-) mice. After continuous stimulation of Ang II for 28 days, suprarenal aortic aneurysms developed in 77% mice and 12% mice died suddenly due to AAA rupture. Administration of Ginsenoside Rb1 (20 mg/kg/day), but not ginsenoside Rg1, significantly reduced the incidence and mortality of AAA. Ginsenoside Rb1 treatment dramatically suppressed Ang II-induced diameter enlargement, extracellular matrix degradation, matrix metalloproteinase (MMP) production, inflammatory cell infiltration, and vascular smooth muscle cell (VSMC) dysfunction. Mechanistic studies indicated that the protective effects of Ginsenoside Rb1 were associated with the inactivation of JNK and p38 MAPK signaling pathways. A specific activator of JNK and p38, anisomycin, nearly abolished Ginsenoside Rb1-driven suppression of MMP secretion by VSMCs. CONCLUSIONS: Ginsenoside Rb1, as a potential anti-AAA agent, suppressed AAA through inhibiting the JNK and p38 signaling pathways.

Anti-Asthmatic Effects of Ginsenoside Rb1 in a Mouse Model of Allergic Asthma Through Relegating Th1/Th2.[Pubmed:25832478]

Inflammation. 2015 Oct;38(5):1814-22.

The aim of the study was to investigate the anti-asthma effects of Ginsenoside Rb1 (Rb1) and its possible mechanisms. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2 mg/kg), and Rb1 (10 and 20 mg/kg). Airway resistance (RI) was measured; histological studies were evaluated by the hematoxylin and eosin (HE) staining; Th1/Th2, ovalbumin (OVA)-specific serum, and bronchoalveolar lavage fluid (BALF) IgE levels were evaluated enzyme-linked immunosorbent assay (ELISA); and T-bet/GATA3 proteins were evaluated by Western blot. Our study demonstrated that Rb1 inhibited OVA-induced increases in RI and eosinophil counts; interleukin (IL)-4 was recovered, and IFN-gammalevel increased in bronchoalveolar lavage fluid. Histological studies demonstrated that Rb1 substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot studies demonstrated that Rb1 substantially inhibited GATA3 and increased T-bet. These findings suggest that Rb1 may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.

Ginsenosides Rb1 and Rg1 Stimulate Melanogenesis in Human Epidermal Melanocytes via PKA/CREB/MITF Signaling.[Pubmed:24799945]

Evid Based Complement Alternat Med. 2014;2014:892073.

Reduced or defective melanin skin pigmentation may cause many hypopigmentation disorders and increase the risk of damage to the skin triggered by UV irradiation. Ginsenosides Rb1 and Rg1 have many molecular targets including the cAMP-response element-binding protein (CREB), which is involved in melanogenesis. This study aimed to investigate the effects of ginsenosides Rb1 and Rg1 on melanogenesis in human melanocytes and their related mechanisms. The effects of Rb1 and Rg1 on cell viability, tyrosinase activity, cellular melanin content and protein levels of tyrosinase, microphthalmia-associated transcription factor (MITF), and activation of CREB in melanocytes were assessed. Results showed that Rb1 or Rg1 significantly increased cellular melanin content and tyrosinase activity in a dose-dependent manner. By contrast, the cell viability of melanocytes remained unchanged. After exposure to Rb1 or Rg1, the protein levels of tyrosinase, MITF, and phosphorylated CREB were significantly increased. Furthermore, pretreatment with the selective PKA inhibitor H-89 significantly blocked the Rb1- or Rg1-induced increase of melanin content. These findings indicated that Rb1 and Rg1 increased melanogenesis and tyrosinase activity in human melanocytes, which was associated with activation of PKA/CREB/MITF signaling. The effects and mechanisms of Rb1 or Rg1 on skin pigmentation deserve further study.

Cardioprotection of ginsenoside Rb1 against ischemia/reperfusion injury is associated with mitochondrial permeability transition pore opening inhibition.[Pubmed:26740222]

Chin J Integr Med. 2016 Jan 6. pii: 10.1007/s11655-015-2433-6.

OBJECTIVE: To investigate the role of Ginsenoside Rb1 (Gs-Rb1) in cardioprotection against ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury and to explore whether the cardioprotective action is mediated via attenuating the formation of mitochondrial permeability transition pore (mPTP). METHODS: A Langendorff-perfused model of rat heart was employed. I/R injury was induced by breaking off perfusion for 40 min then reperfusion for 60 min. Gs-Rb1 (100 mumol/L) were administrated for 10 min before I/R. Infarct size was estimated by the 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) released from effluents were measured. Transmission electron microscopy was performed to assess morphological difference between cardiac mitochondrial isolated from I/R rats and Gs-Rb1 pretreated rats. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt, and its downstream target glycogen synthase kinase 3beta (GSK-3beta). Incubation isolated cardiac mitochondria with Gs-Rb1, Ca(2+)-induced opening of the mPTP was assessed by the reduction of absorbance at 520 nm (A520). Neonatal rat cardiomyocytes were subjected to hypoxia 9 h followed by reoxygenation 4 h to induce H/R injury. After pretreated with different concentration of Gs-Rb1 (6.25, 25, 100 mumol/L ), cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) method. The membrane potential was estimated by Rh123 fluorescence. mPTP opening was measured using the probe calcein-AM. RESULTS: Gs-Rb1 100 mumol/L significantly reduced the infarct size of hearts (26.39%+/-11.67% vs. I/R group 56.68%+/-5.88%, P<0.01). Compared with the I/R group, Gs-Rb1 pretreatment decreased LDH and CK levels in the coronary effluent (P<0.05 or P<0.01) as well as attenuated destructive ultrastructure induced by I/R. The protective effect of Gs-Rb1 involved in phosphorylating protein kinase B/PKB (Akt) and GSK-3beta. In mitochondria isolated from rat hearts, significant inhibition of Ca(2+)-induced swelling was observed in samples that were pretreated with Gs-Rb1 (6.25, 25, 100, 400 mumol/L) for 10 min. When cardiomyocytes were isolated from neonatal rat and subjected to H/R, cell viability was increased with treatment of Gs-Rb1 (6.25, 25, 100 mumol/L ). Gs-Rb1 inhibited mPTP opening and restored subsequent loss of mitochondrial membrane potential. CONCLUSION: Gs-Rb1 presents cardioprotective effect against I/R or H/R injury which involves in activating Akt, phosphorylating GSK-3beta and inhibiting mPTP opening.

[Ginsenoside Rb1 upregulates expressions of GLUTs to promote glucose consumption in adiopcytes].[Pubmed:25850283]

Zhongguo Zhong Yao Za Zhi. 2014 Nov;39(22):4448-52.

Previous studies have shown that Ginsenoside Rb1 (Rb1), one of active components in ginseng, can activate insulin signaling pathway and promote translocation of glucose transporters (GLUTs) to increase glucose uptake in adipocytes. However, the effect of Rb1 on the expressions of GLUTs remains unknown. In this study, the effects of Rb1 on GLUT1 and GLUT4 were observed in 3T3-L1 adipocytes and epididymal adipose tissue of db/db obese diabetic mice. Male db/db mice were treated with Rb1 by intraperitoneal injection at the dosage of 20 mg x kg(-1) for 14 d. Rb1 reduced HOMA-IR significantly (P < 0.05, n = 5), and FBG and FINS sowed declining trend after treatment with Rb1. Rb1 recovered the expressions of GLUT1 and GLUT4 and phosphorylation of AKT in adipose tissue of db/db mice. In vitro, glucose consumption in 3T3-L1 adipocytes treated with 10 micromol x L(-1) Rb1 for 24 h was elevated (P < 0.05, n=3), and mRNA of GLUT1 and GLUT4 were up-regulated (P < 0.05, n=3) and proteins of GLUT1 and GLUT4 were also increased. AKT was activated in adipocytes treated with Rb1 for 3 h. It can be concluded that Ginsenoside Rb1 can up-regulate the expression of GLUTs in adipose tissue, in addition to activate insulin signalling pathway, which may partially account for its insulin sensitizing activity and regulating effect of glucose metabolism.

Neuroprotective effects of ginsenosides on neural progenitor cells against oxidative injury.[Pubmed:26935530]

Mol Med Rep. 2016 Apr;13(4):3083-91.

Ginsenosides exhibit various neuroprotective effects against oxidative stress. However, which ginsenoside provides optimal effects for the treatment of neurological disorders as a potent antioxidant remains to be elucidated. Therefore, the present study investigated and compared the neuroprotective effects of the Rb1, Rd, Rg1 and Re ginsenosides on neural progenitor cells (NPCs) following tert-Butylhydroperoxide (t-BHP)-induced oxidative injury. Primary rat embryonic cortical NPCs were prepared from E14.5 embryos of Sprague-Dawley rats. The oxidative injury model was established with tBHP. A lactate dehydrogenase assay and terminal deoxynucleotidyl transferase dUTP nickend labeling staining were used to measure the viability of the NPCs pretreated with ginsenosides under oxidative stress. Reverse transcriptionquantitative polymerase chain reaction analysis was used to determine the activation of intracellular signaling pathways triggered by the pretreatment of ginsenosides. Among the four ginsenosides, only Rb1 attenuated tBHP toxicity in the NPCs, and the nuclear factor (erythroizdderived 2)like 2/heme oxygenase1 pathway was found to be key in the intracellular defense against oxidative stress. The present study demonstrated the anti-oxidative effects of Ginsenoside Rb1 on NPCs, and suggested that Rb1 may offer potential as a potent antioxidant for the treatment of neurological disorders.