Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions

Abstract

Ginseng has gained its popularity as an adaptogen since ancient days because of its triterpenoid saponins, known as ginsenosides. These triterpenoid saponins are unique and classified as protopanaxatriol and protopanaxadiol saponins based on their glycosylation patterns. They play many protective roles in humans and are under intense research as various groups continue to study their efficacy at the molecular level in various disorders. Ginsenosides Rb1 and Rg1 are the most abundant ginsenosides present in ginseng roots, and they confer the pharmacological properties of the plant, whereas ginsenoside Rg3 is abundantly present in Korean Red Ginseng preparation, which is highly known for its anticancer effects. These ginsenosides have a unique mode of action in modulating various signaling cascades and networks in different tissues. Their effect depends on the bioavailability and the physiological status of the cell. Mostly they amplify the response by stimulating phosphotidylinositol-4,5-bisphosphate 3-kinase/protein kinase B pathway, caspase-3/caspase-9-mediated apoptotic pathway, adenosine monophosphate-activated protein kinase, and nuclear factor kappa-light-chain-enhancer of activated B cells signaling. Furthermore, they trigger receptors such as estrogen receptor, glucocorticoid receptor, and N-methyl-d-aspartate receptor. This review critically evaluates the signaling pathways attenuated by ginsenosides Rb1, Rg1, and Rg3 in various tissues with emphasis on cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders.

Keywords: PPD; Rg3; ginsenoside; review; signaling.

Fig. 1

Structure of ginsenosides Rg1, Rb1, and Rg3.

Fig. 2

Effect of ginsenosides Rb1, Rg1, and Rg3 on endothelial cells. Bax, Bcl-2-associated X protein; Bcl2, B-cell lymphoma 2; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; GR, glucocorticoid receptor; HIF1-α, hypoxia-inducible factor 1-alpha; MAPK, mitogen-activated protein kinase; PI3K/AKT, phosphatidylinositol 3-kinase/AKT; VEGF, vascular endothelial growth factor.

Fig. 3

Ginsenoside Rg3 and its stereoisomer 20(S)-Rg3 differentially attenuate cancer cell growth. IAP, inhibitors of apoptosis proteins; IKK, IκB kinase; NF-κB, nuclear factor κB.

Fig. 4

Mechanism of cancer prevention by ginsenosides Rb1 and Rg1. AhR, aryl hydrocarbon receptor; ER, estrogen receptor; PEDF, pigment epithelium derived factor; TGF-β1, transforming growth factor β1; XRE, xenobiotic responsive elements.

Fig. 5

Enhancing glucose uptake in muscle cells and insulin sensitive cells by ginsenosides Rb1, Rg1, and Rg3. AMPK, 5′ AMP-activated protein kinase; Bcl2, B-cell lymphoma 2; CHOP, CCAAT enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2; ER, estrogen receptor; GLUT1, glucose transporter 1; GLUT4, glucose transporter 4; IRS-1, insulin receptor substrate 1; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase; PI3K, phosphatidylinositol 3 kinase; PKB, protein kinase B.

Fig. 6

Action of ginsenosides in neurodegeneration, ischemic injury, and secretion of neurotrophic factors. BDNF, brain-derived neurotrophic factor; cAMP, adenosine monophosphate; CREB, cAMP response element binding; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; GDNF, glial cell-derived neurotrophic factor; NGF, nerve growth factor; PKA, protein kinase A; PPAR-γ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; Trk, tropomyosin-related kinase.