Rare ginsenosides: A unique perspective of ginseng research

Abstract

Background: Rare ginsenosides (Rg3, Rh2, C-K, etc.) refer to a group of dammarane triterpenoids that exist in low natural abundance, mostly produced by deglycosylation or side chain modification via physicochemical processing or metabolic transformation in gut, and last but not least, exhibited potent biological activity comparing to the primary ginsenosides, which lead to a high concern in both the research and development of ginseng and ginsenoside-related nutraceutical and natural products. Nevertheless, a comprehensive review on these promising compounds is not available yet.

Aim of review: In this review, recent advances of Rare ginsenosides (RGs) were summarized dealing with the structurally diverse characteristics, traditional usage, drug discovery situation, clinical application, pharmacological effects and the underlying mechanisms, structure-activity relationship, toxicity, the stereochemistry properties, and production strategies.

Key scientific concepts of review: A total of 144 RGs with diverse skeletons and bioactivities were isolated from Panax species. RGs acted as natural ligands on some specific receptors, such as bile acid receptors, steroid hormone receptors, and adenosine diphosphate (ADP) receptors. The RGs showed promising bioactivities including immunoregulatory and adaptogen-like effect, anti-aging effect, anti-tumor effect, as well as their effects on cardiovascular and cerebrovascular system, central nervous system, obesity and diabetes, and interaction with gut microbiota. Clinical trials indicated the potential of RGs, while high quality data remains inadequate, and no obvious side effects was found. The stereochemistry properties induced by deglycosylation at C (20) were also addressed including pharmacodynamics behaviors, together with the state-of-art analytical strategies for the identification of saponin stereoisomers. Finally, the batch preparation of targeted RGs by designated strategies including heating or acid/ alkaline-assisted processes, and enzymatic biotransformation and biosynthesis were discussed. Hopefully, the present review can provide more clues for the extensive understanding and future in-depth research and development of RGs, originated from the worldwide well recognized ginseng plants.

Keywords: Bioactivity; Biotransformation; Panax; Production strategy; Rare ginsenosides; Stereospecific property.

Graphical abstract

Fig. 1

An overview of the research trends of rare ginsenosides based on publications up to 2021. (A) The annual numbers of publication; (B) Publications of individual rare ginsenosides; (C) Types of diseases involved.

Fig. 2

Structures of RGs identified in Panax species. (A) Representative skeletons of RGs with different side-chain variation; (B) Moiety of Va-type side-chain variation; (C) Moiety of Vb-type side-chain variation; (D) Glycosyl substitution.

Fig. 3

Bioactivities of representative RGs from Panax species. (A) Targeting the FXR/TGR5 bile acids signaling pathways by RGs in cardiovascular diseases ; (B) Mechanism of RGs on steroid hormone receptors; (C) Mechanism of RGs on ADP P2Y12 receptors; (D) Targeting the PD-1/PD-L1 signaling pathways by RGs in cancers.

Fig. 4

Structure-activity relationship of rare ginsenosides.

Fig. 5

The interaction pattern between ginsenosides and gut microbiota.

Fig. 6

The potential transformation pathway of ginsenosides during physical and chemical processing.

Fig. 7

The potential transformation pathway of rare ginsenosides mediated by biotransformation (A) and biosynthesis (B).