Network Pharmacology of Red Ginseng (Part I): Effects of Ginsenoside Rg5 at Physiological and Sub-Physiological Concentrations

Abstract

Numerous in vitro studies on isolated cells have been conducted to uncover the molecular mechanisms of action of Panax ginseng Meyer root extracts and purified ginsenosides. However, the concentrations of ginsenosides and the extracts used in these studies were much higher than those detected in pharmacokinetic studies in humans and animals orally administered with ginseng preparations at therapeutic doses. Our study aimed to assess: (a) the effects of ginsenoside Rg5, the major “rare” ginsenoside of Red Ginseng, on gene expression in the murine neuronal cell line HT22 in a wide range of concentrations, from 10−4 to 10−18 M, and (b) the effects of differentially expressed genes on cellular and physiological functions in organismal disorders and diseases. Gene expression profiling was performed by transcriptome-wide mRNA microarray analyses in HT22 cells after treatment with ginsenoside Rg5. Ginsenoside Rg5 exhibits soft-acting effects on gene expression of neuronal cells in a wide range of physiological concentrations and strong reversal impact at high (toxic) concentration: significant up- or downregulation of expression of about 300 genes at concentrations from 10−6 M to 10−18 M, and dramatically increased both the number of differentially expressed target genes (up to 1670) and the extent of their expression (fold changes compared to unexposed cells) at a toxic concentration of 10−4 M. Network pharmacology analyses of genes’ expression profiles using ingenuity pathway analysis (IPA) software showed that at low physiological concentrations, ginsenoside Rg5 has the potential to activate the biosynthesis of cholesterol and to exhibit predictable effects in senescence, neuroinflammation, apoptosis, and immune response, suggesting soft-acting, beneficial effects on organismal death, movement disorders, and cancer.

Challenges in phytotherapy research

“…At low concentrations, only a high affinity of the ligand-receptor infection may contribute to the comparatively “selective” effect. In contrast, in high concentrations, the interactions with other proteins may be toxic and less effective ( Panossian et al, 2021a ; Panossian et al, 2021b ; Panossian et al, 2021c ).…”

Network Pharmacology Approach for Medicinal Plants: Review and Assessment

“…The prediction of disease-related genes is a preliminary step to explore the molecular mechanism of medicinal herbs for treating multiple diseases and disorders [ 81 , 82 ]. Additionally, instead of relying on literature data, the target gene can also be obtained through real experiments; for example, researchers have now analyzed the transcriptome-wide gene expression microarray profiles of isolated cells in response to the exposure to plant extracts, their combinations, or purified compounds, followed by ingenuity pathway analyses in silico to elucidate their mechanisms of action and activated molecular networks behind predicted therapeutic effectiveness in various health conditions [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ].…”

Network Pharmacology Approach for Herbal Drugs Intended for the Therapy of Diseases: A Comprehensive Review

“…The estimation of disease-related genes is a first step in investigating the molecular mechanism of plants and herbs for treating a wide range of diseases and disorders" [31]. "Furthermore, rather than relying on literature data, researchers have now analysed the transcriptome-wide gene expression microarray profiles of isolated tissues in response to exposure to plant extracts, their combinations, or purified compounds, accompanied by innovative pathway assessments In silico to illustrate their mechanisms of action and activated molecular networks behind estimated therapeutic effects in various health conditions" [32].…”