Decoding the Cure-all Effects of Ginseng

Abstract

Ginseng has been known as a "cure–all" traditional medicine to treat various illnesses and as an adaptogen to relieve stress. However, the known active compounds of ginseng are small–molecule metabolites. Here we report ginsentides, which are disulfide–dense, super–stable and cell–penetrating peptides with 31—33 amino acids, as active compounds and adaptogens that restore homeostasis in response to stress. Using mass spectrometry–based target identification and functional studies, we show that ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via the PI3K/Akt signaling pathway. Ginsentides were also found to alleviate α1–adrenergic receptor overactivity by reversing phenylephrine–induced constriction of the aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40, inhibit P2Y12 receptors, reduce platelet aggregation, and thrombus formation in the lung. Orally administered ginsentides were effective in anti–stress behavior using animal models of tail suspension and forced swimming tests. Together, these results suggest that ginsentides interact with multiple systems to restore homeostasis by reversing stress–induced physiological changes and provide new insights into the panacea medicinal effects of ginseng.

Ginsentide TP1 Protects Hypoxia-Induced Dysfunction and ER Stress-Linked Apoptosis

“…Taken together, our data indicate that TP1 limits ROS generation and maintains NO bioavailability to prevent endothelial activation under hypoxic conditions. Bioactive ginsenosides are known to counteract redox regulation, promote NO production, and prevent ROS generation; thus, they protect cells against oxidative damage [25,[43][44][45]. Consistent with these reported effects, we found that treatment with the ginsenosides Rb1 and Rg1 reduced the intracellular ROS levels of both normoxic and hypoxic ECs, comparable with the impact of TP1 treatment (Figure S12A,B).…”

“…The cellular uptake of Cy3labeled TP1 (Cy3-TP1) in live cells was observed using confocal microscopy to minimize artifacts in localizing labeled peptides under fluorescence microscopy [28]. The live-cell images of human umbilical vein/vascular endothelium (HUVEC-CS) cells after incubation with 1 µM Cy3-TP1 for 1 h revealed that Cy3-TP1 was internalized and distributed throughout the cytoplasm, whereas LysoTracker counterstaining showed that Cy3-TP1 also accumulated in lysosomes (Figure 1C) due its internalization through energy-dependent endocytosis as observed in our previous studies [25].…”

“…Despite an abundance of ginseng research, ginsenosides alone cannot adequately explain the "cure-all" effect of ginseng in its ethnomedicinal uses [46,47]. Recently, we reported that the cell-penetrating cystine-dense microprotein TP1 coordinates multiple systems to exert anti-stress and cardiovascular benefits [25]. This report shows that ginsentide TP1 differing from the two key ginsenosides, Rb1 and Rg1, plays an important adaptogenic role in maintaining protein homeostasis in hypoxic cells and suppressing ER-stress-induced apoptosis.…”

Ginsentide-like Coffeetides Isolated from Coffee Waste Are Cell-Penetrating and Metal-Binding Microproteins

“…This report identifies, in coffee waste, a panel of novel coffeetides which belong to the ginsentide family. Ginsentides show high potential to treat chronic metabolic and cardiovascular diseases [ 39 ]. Our study showed that coffeetide cC1a, at its N-terminus, contains a metal-binding domain where cC1a binds to the Fe 3+ ion.…”

“…Thus far, only ginsentides, which are cell-penetrating microproteins, have been characterized. Functionally, ginsentides could be the major active compounds responsible for the “cure-all” effect of ginseng because they coordinate multiple physiological systems to relax blood vessels and relieve stress [ 39 , 40 ].…”