Chemical constituents of
Ginseng contains an extraordinarily complex mixture of chemical constituents that can vary with the species used, the place of origin, and the growing conditions. Various computational analyses which include genomics, transcriptomics, proteomics and bioinformatics have been used to study ginseng plant. A genome-scale metabolic network offers a holistic view of ginsenoside biosynthesis, helps to predict genes associated with the production of pharmacologically vital dammarane-type ginsenosides, and provides insight for improving medicinal values of ginseng by genomics-based breeding. The draft genomic architecture of tetraploid P. ginseng cultivar (cv.) Chunpoong (ChP) by de novo genome assembly, was found to be 2.98 Gbp and consist of 59,352 annotated genes. Presently, bioinformatics exploration of ginseng includes studies on its P-glycoproteins, the impact of cytochrome P-450 on ginseng pharmacokinetics, as well as target prediction and differential gene expression network analyses. This study applauded Betasitosterol and Daucosterin as ginseng bioactive constituents that have several potential pharmacological effects in human, by modulating several proteins which include androgen receptor, HMG-CoA reductase, interlukin-2, and consequently impact the signaling cascade of several kinases such as mitogen-activated protein kinases (MAPKs), as well as many transcription factors such as polycomb protein SUZ12.
Ginseng is a slow-growing, deciduous, perennial plant of the
1.1 Ginseng genomics and biosynthesis of ginsenosides
A genome-scale metabolic network offers a holistic view of ginsenoside biosynthesis, helps to predict genes associated with the production of pharmacologically vital dammarane-type ginsenosides, and provides insight for improving medicinal values of ginseng by genomics-based breeding . The draft genomic architecture of tetraploid
2. Ginsenosides: structure, pharmacokinetics and mechanism
Ginsenosides are specific types of triterpene saponin, a broad group of chemical compounds. Ginsenosides are found nearly exclusively in Panax species (ginseng) and up to now more than 150 naturally occurring ginsenosides have been isolated from different organs of ginseng . Ginsenosides appear to be responsible for most of the activities of ginseng including anti-diabetic, anti-allergic, anticarcinogenic, anti-inflammatory, anti-atherosclerotic, antihypertensive, and immunomodulatory effects as well as anti-stress activity and effects on the central nervous system . The structures of ginsenosides Rb1 and Rg1 are shown in Figure 1.
2.1 Structure of ginsenosides
2.2 ADME of ginsenosides
Absorption, distribution, metabolism and excretion (ADME) describe the pharmacokinetics and pharmacodynamics of a single or more compounds in an organism such as human, mouse etc. The knowledge of pharmacokinetics of ginsenoside and its metabolites is very imperative in designing an optimal dosage regimen and minimizing the adverse effect that may result from ginseng-drugs interaction. The polar ginsenosides include Rg1, Re, Rb1, Rc, Rb2, Rb3, and Rd., while less polar ginsenosides include Rg2, Rg3, Rg5, Rh2, Rk1, and Rs4 [15, 16]. Protopanaxadiol ginsenosides are metabolized to ginsenoside compound K by the intestinal microflora in humans. Ginsenoside compound K (20-
According to Qi et al., , the ginseng saponins have low absorption rate and characterized by extensive metabolism in the gastrointestinal tract, poor membrane permeability, and low solubility of deglycosylated products; and with less than 5% dose bioavailability of the protopanaxadiol (PPD) group of saponins (ginsenosides Ra3, Rb1, Rd., Rg3, and Rh2) and of the protopanaxatriol (PPT) group of saponins (ginsenosides Rg1, Re, Rh1, and R1) were less than 5%. However, PPT saponins have better bioavailability than PPD saponins, which may be due to the fact that PPD saponins degrade faster than PPT saponins. Study on ginseng absorption by HPLC analysis, showed that Rb1 (4.35%) and Rg1 (18.40%) were absorbed, respectively .
Study on the effect of American ginseng and Asian ginseng extracts on gene expression of the hepatic cytochrome P450 enzyme in elderly humans, has shown that protopanaxadiol (PPD), protopanaxatriol (PPT) and their metabolites, moderately inhibited CYP2C9 activity and strongly inhibited CYP3A4 activity [20, 21]. Henderson et al.,  have studied the effects of seven naturally occurring ginsenosides Rb1, Rb2, Rc, Rd., Re, Rf, and Rg1 and eleutherosides B and E (active components of the ginseng root) on the catalytic activity of
|2||betasitosterol, 20(R)-protopanaxatriol, daucosterin,|
|3||isoginsenoside-Rh(3), ginsenoside-Rb(1), -Rb(2), −Rc, −Rd, -Re, − Rg(1), -Rh(1), -Rh(2).|||
|4||Daucosterin; 20(R)-dammarane-3beta,12beta,20,25-tetrol (25-OHPPD); 20(R)-dammarane-3beta,6alpha,12beta,20,25-pentol (25-OH-PPT); 20(S)-protopanaxadiol (PPD); 20(S)-ginsenoside-Rh(2) (Rh2); 20(S)-ginsenoside-Rg(3) (Rg3); 20(S)-ginsenoside-Rg(2) (Rg2); 20(S)-ginsenoside-Rg(1) (Rg1); 20(S)-ginsenoside-Rd (Rd); 20(S)-ginsenoside-Re (Re);|
|5||Panaxadione, ginsenosides Rd., Re, and Rg2|||
|1||Rb1||protects hippocampal neuron, enhance insulin/IGF-1 signaling, inhibited GSK-3β-mediated C/EBP homologous protein (CHOP) signaling||[29, 30, 31, 32]|
|2||Rb2||Down-regulation of matrix metalloproteinase|
|3||Rg1||Downregulation of nuclear factor-kappa B (NF-𝜅B)/nitric oxide (NO) signaling pathway, increases the expression of insulin growth factor I receptor (IGF-IR)||[34, 35]|
|4||Rd||Phosphoinositide-3-kinase/AKT and phosphoextracellular signal-regulated protein kinase (ERK) 1/2 pathways, suppress poly(ADP-ribose) polymerase-1, protein tyrosine kinase activation, the upregulation of the endogenous antioxidant system and GAP-43 expression||[5, 36, 37]|
|5||Re||PREVENT the reduction of H(+)-ATPase activity|||
|6||Rg3||Modulation of three modules of MAP kinases, P-gp (P-glycoprotein) inhibition, modulation of Ephrin receptor pathway, inhibits NMDA receptor by increasing the concentration of glycine, suppression of TPA-induced cyclooxygenase-2 (COX-2) expression||[39, 40, 41, 42]|
3. Bioinformatics analyses of ginsenosides
A study has proposed a novel method to explore underlying mechanisms of multiple actions of multiple constituents of Ginseng (
In the study conducted by Yan et al.  to identify immunomodulatory biomarkers in an immune cell induced by ginseng, microarray assays were carried out to identify differentially expressed genes associated with American ginseng (
In their study, Zhu et al. , have reported two major
Bioinformatics network analysis has been used to analyzed a combination of ginseng and arginine regimen, ginseng and lingzhi as well as ginseng and gingko regimens [45, 46], in order to understand potential impact of drug–drug interaction (agonism or antagonism) based on common pathways.
In silicotarget prediction and gene expression network of key ginseng constituents
The ligands (Ginsenoside Rb1, Rc, Rg3, Re, F1, C; Betasitosterol, Panaxadione, Daucosterin (also known as Sitogluside or Eleutheroside A), and 20(R)-protopanaxatriol) were subjected to
|S.No||Constituents||Target Genes||% probability||Possible effect|
|1||Ginsenoside Rb1, Rg3, Rc, Re, F1, C,||PTAFR, IL2, STAT3, VEGFA, FGF1, FGF2, HPSE, PSEN1, PSENEN, NCSTN, BCL2L1||10||Immunomodulatory, anti-haemostatic, anti-cancer|
|2||Panaxadione||PRKCA, HSD11B1, CYP19A1, SIRT2, PTPN1, CCR1, VDR, PTPN11, NR1I2, REN, BACE1, NR3C1, INSR, ITK, F2R||20||Anti-inflammatory, anti-diabetic|
|3||Betasitosterol||AR, HMGCR, CYP51A1, NPC1L1, NR1H3, CYP19A1, CYP17A1, RORC, ESR1, ESR2||35–70||Anti-depressive, neuroprotection, anti-cancer|
|4||Daucosterin||STAT3, IL2||20–60||Immunomodulatory, anti-cancer, anti-inflammatory|
|5||20(R)-protopanaxatriol||PTPN1, CYP2C19, CHRM2, SLC6A2, SLC6A4, AR, ACHE, HSD11B1, ESR1, CYP19A1, ATP12A, NR1H3, HMGCR, CYP51A1, NPC1L1||20||Anti-depressive, anti-hypertension|
The genes that were targeted by Betasitosterol (Table 3) have greater than 30% probability (35–70%), Daucosterin targeted Interleukin-2 (IL2) with 60% probability, while others were less than 30%. The best target of Betasitosterol is Androgen Receptor (AR), followed by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, Cytochrome P450 51, Niemann-Pick C1-like protein 1, LXR-alpha, Cytochrome P450 19A1, Cytochrome P450 17A1, Nuclear receptor ROR-gamma and others.
This study shows that SUZ12 has the highest score as transcription factor influenced by the ginseng, this is followed by STAT3, RUNX1, FOS, VDR, RCOR1, SPI1 and EGR1 (Figures 2 and 3). The kinases that were impacted by the action of ginseng active constituents include MAPK1, MAPK14, AKT1, CDK1, ABL1, ERK1 and ERK2 (Figure 4). Moreover, major intermediate proteins JUN, RARA, NCOR1, MYC, RB1, HDAC2, CSNK2A1 and others (Figure 5).
Zhang et al.  have reported ginsenoside, stigmasterol, β-sterol, β-elemene and β-selinene, kaempferol, panaxynol, ginsenoyne A, fumarine, girinimbin, elemicin, dauricine, and maltol, as part of secondary metabolites produced by ginseng. However, network analysis of ginseng-associated targets ginseng in treatment of depression which could occur in post-COVID19 period, identified AKT1, CASP3, NOS3, TNF, and PPARG as the core genes in protein–protein interaction network, and that ginsenoside Re, ginsenoside Rg1, frutinone A and kaempferol were the key ingredients in ginseng for immune-regulation .
Based on curated data on UniProt database (www.uniprot.org), androgen receptor (Uniprot ID: P10275) involves in positive regulation of MAPK cascade, NF-kappaB transcription factor activity, insulin-like growth factor receptor signaling pathway, and transcription by RNA polymerase II and III, as well as negative regulation of transcription by RNA polymerase II, epithelial cell proliferation, and extrinsic apoptotic signaling pathway. HMG-CoA reductase (UniProt ID: P04035) involves in positive regulation of ERK1 and ERK2 cascade, stress-activated MAPK cascade, cardiac muscle cell apoptotic process, smooth muscle cell proliferation, and cholesterol homeostasis, as well as negative regulation of MAP kinase activity, wound healing, and striated muscle cell apoptotic process, and it also give response to ethanol. Interleukin-2 (UniProt ID: P60568) involves in positive regulation of inflammatory response, transcription by RNA polymerase II, tyrosine phosphorylation of STAT protein, interferon-gamma production, B cell and activated T cell proliferation and immunoglobulin secretion, as well as negative regulation of inflammatory response, heart contraction, B cell apoptotic process, and lymphocyte proliferation, and it also give response to ethanol.
A comprehensive review of betasitosterol has reported several therapeutic potentials which include antioxidant, antipyretic, anti-inflammatory, anti-arthritic, and antimicrobial activities, as well as anti-cancer, anti-diabetic, antihyperlipidemic, anti-atherosclerosis, anti-pulmonary tuberculosis, angiogenic, immune modulation and anti-HIV effects .
Knowledge of bioinformatics has not been fully applied to the study of ginseng in proportionality to the acclaimed medicinal properties from the ethnobotanical use.
This study has applauded Betasitosterol and Daucosterin as ginseng bioactive constituents that have several potential pharmacological effects in human, by modulating several proteins which include androgen receptor, HMG-CoA reductase, interlukin-2, and consequently impact the signaling cascade of several kinases such as Mitogen-activated protein kinases (MAPKs), as well as many transcription factors such as Polycomb protein SUZ12. Moreover, difference in pharmacological outcome of aqueous ginseng extract and ethanolic ginseng extract would necessitate holistic approach of extraction. Furthermore, chemical biology and
This research has no acknowledgment.
Conflict of interest
The authors declare no conflict of interest.