Panax ginseng (roots and its extract) is well known as the most important herbal medicine in the Orient, particularly in Korea, China, Japan and also in North America (typically in cooler climates) for more 2000 years, as a medicinal plant with mysterious powers, traditionally used to revitalize the body and mind, increased physical strength, prevent aging and increased vigor. But now it seems that the scientists have discovered new important application. Among the several kinds of Panax ginseng products, Korean red ginseng has the most potent multiple pharmacological actions for treating various human diseases as cardiovascular disease, diabetes mellitus, rheumatoid arthritis, against stress, fatigue, cancer, hypertension, atherosclerotic disorders , ischemic injury, sexual dysfunction,…
The botanical classifications of Korean ginseng are as follows:
Phylum: Embryophyta Siphonogama
The genus name Panax is a compound of the Greek words “pan” and “axos”. “Pan” means “all” and “axos” means “treat”, which represents “treats all diseases”.
It is compound by ginsenosides, eleutherosides, sterols, flavonoids, peptides, vitamins, polyacetylenes, minerals, b-elemine and choline.
Active components of Korean Ginseng
The key active ingredients of ginseng are known to be a compound carbohydrate (a compound of alcohol or phenol and sugar) called saponin or ginsenosides. This property excites and suppresses the central nervous system, adjusts metabolism, lowers blood glucose, improves muscular activities, stimulates the endocrine system and maintains hormone levels properly.
The name saponin is derived from the phenomenon in which fine foam comes from its solution like a piece of soap. In general, glycosides form a very high polarization compound that causes hemolysis.
Ginsenoside-Rg1 (C42H72O14 2H2O)
Ginsenoside-Rb1 (C54H92O23 3H2O)
Ginsenoside-Rf (C42H72O14 2H2O)
Based on their chemical structures, saponin compounds are divided into three groups such as protopanaxadiol (PD), protopanaxatriol (PT), and oleanane.
Korean ginseng has better pharmacological efficacy compared with other ginseng, because it has ginsenosides Ra1, Ra2, Ra3, malonyl- G-Rb1, malonyl-G-Rb2, malonyl-G-Rc, malonyl-GRd, Rs1, Rs2, Rs3, Rg3, Rg5, Rh2, K-R2, Rf, Rf2, 20®- G-Rg2, Rg6, 20®-G-Rh1, 20(E)-G-F4, Rh4, K-R1, and polyacetyleneginsenoside-Ro.
Figure SEQ Figura \* ARABIC 1. Structure of ginsenosides.
Figure SEQ Figura \* ARABIC 2. Chemical structures of 20(S)-ginsenosides Rg3, ginsenosides Rh2, Rg1, Re and Rc.
Non-saponin active components
Korean ginseng has important substances other than ginsenoside that show anti-tumor, anti-oxidative, anti-diabetic and anti-inflammatory effects, and even hematosis action.
These components are panaxydol, panaxynol and panaxytriol, have showed anti-tumor and anti oxidative effects.
Phenol compounds such as maltol show anti-aging effects as a lipid per-oxidation inhibitor. Maltol is a phenol compound specific to Korean red ginseng. Carbohydrates are extracted in a water solution, and make up 60%–70% of total extracts. Monosaccharide, disaccharide, and trisaccharide and polysaccharide display a hypoglycemic effect, increased immune system and anti-ulcerative activity.
Pharmacological effects of Korean ginseng
Scientifically proven pharmacological effects of Korean ginseng are as follows:
Efficacy of improving cerebral functions
Korean ginseng (extract and saponin component) is found to have efficacy to increase attention, learning skill, to improve memory, intellectual ability and to reduce memory loss.
Ginseng saponin and ginsenoside Rh2 reduce high blood glucose. Korean ginseng includes insulin secretion stimulating activity and insulin-like activity substance.
Efficacy of adjusting blood pressure
It is rumored that taking ginseng leads to high blood pressure. Recently, facts about the biochemical and pharmacological activities of ginseng related to blood pressure control are being gradually revealed by modern medical studies of effective ingredients and the efficacy of ginseng.
Korean red ginseng can exert an antihypertensive effect, elevating NO concentration and reducing cardiac frequency.
Efficacy of anti-fatigue and anti-stress
It is observed that Korean ginseng enforces the power, increases resistance to stress and prevents against the fatigue.
Ginsenoside Rb1 is the component, at least a major component, in ginseng with anti-stress activity: Rb1 may block stress response at a very early stage and consequently prevents adverse effects of stress.
Panax ginseng extract has potential protective effects against the oxidative stress.
Efficacy of improving liver functions
Korean ginseng has the activity of prompting the detoxification of toxic substances, protecting the liver from damage, and generating and promoting the regeneration and recovery of the liver. It has also an anti-hepatitis activity.
Efficacy of relieving pain
Korean ginseng was found to have an action inhibiting the Ca channel that exists on sensory neurons and is related to the pain transmission neuron.
Efficacy on climacteric disorders
Tests showed that the administration (3 g/day, 2 months) of Korean red ginseng in climacteric disorders was efficient.
Efficacy of improving male sexual dysfunctions
Korean red ginseng was evaluated as effective for the improvement of sexual function and for defends males against sexual behavior disorders caused by stress. A clinical test indicated that the group who were given Korean red ginseng showed better effects in erectile function, sexual desire and satisfaction of patients.
Efficacy of inhibiting AIDS virus (HIV) growth
AIDS is a chronic disease, and an examination of the anti-HIV activity of Korean red ginseng components revealed that HIV growth inhibition activity was observed in crude saponin components.
The possibility that the occurrence of the deleted nef gene might be associated with long-term intake of Korean red ginseng.
Efficacy of anti-oxidation and anti-aging activity
Korean ginseng has the anti-oxidation effect of inhibiting the increase in harmful free radical formation and lipid peroxidation.
Efficacy of increasing immunization functions
Korean ginseng extracts have the ability to revive cellular immune response.
Efficacy of preventing cancer and activate antitumor
Studies of Korean ginseng intake and cancer cases show that those who take Korean ginseng are less likely to contract various cancers such as cancer of the stomach, liver , lung, breast, skin melanoma and human ovarian carcinoma, than those who do not take it.
- Efficacy of inhibiting cancer cell growth
Saponin and non-saponin ingredients of ginseng contain activity inhibiting a variety of cancer cell growth.
It was suggested that ginsenoside Rp1 can be used for anticancer action.
- Efficacy of inhibiting the metastasis of cancer cells
Efficacy of inhibiting metastasis of cancer was observed for example in lung tumor.
- Efficacy of increasing anti-tumor activity of anticancer drug
Combination of Korean ginseng with mitomycin C increased the anti-cancer effect of Korean ginseng in comparison to the treatment of the anti-tumor drug (mitomycin C) alone.
- Efficacy of inhibiting tolerance formation and reducing
side effects of anti-tumor drugs
Efficacy of increasing cytotoxicity against tumor cells and reducing the side effects of anti-tumor drugs with the combination of Korean ginseng with anti-tumor drugs by inhibiting resistance formation that is a hindrance to anti-tumor chemotherapy.
Figure SEQ Figura \* ARABIC 3. Schematic overview of ginsenosides-mediated genomic and non-genomic pathways. Ginsenosides possess a steroid- like skeleton composed of four trans-rings with different degrees of glyco-substitution. They are amphipathic in nature and can exhibit their actions at different cellular locations; such as the plasma membrane, cytosol and nucleus. Through the nongenomic pathway (indicated by red arrows), (i) they can initiate their actions by binding with the transmembrane receptors (e.g. ATPase pump, ion transporters and channels, voltage-gated channels and G-proteins) and subsequently activating the associated downstream signaling cascades. Moreover, they can intercalate into the plasma membrane resulting in an alteration of membrane fluidity and a trigger of a series of cellular responses. (ii) binding with steroid hormone receptors (SHRs) including glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and mineralocorticoid receptor (MR) present inside or outside the nucleus by using their hydrophobic backbone is another alternative to trigger downstream cellular responses. Those activated (phosphorylated) SHRs can activate the target molecules through a signaling cascade that brings about various cellular responses. (iii) the ligand-bound SHRs can translocate into the nucleus, where they regulate gene transcription by binding with the specific Response Elements (XRE). This is the so called 'genomic pathway' (indicated by blue arrows). Consequently, the altered gene products can affect the final cellular responses.
Figure SEQ Figura \* ARABIC 4. Schematic overview of ginsenoside Rg1-mediated angiogenic action in HUVEC. Ginsenoside Rg1, which acts as a functional ligand of glucocorticoid receptor (GR) (either cytosol GR or membrane-bound GR-mGR), promotes angiogenesis through both non-genomic and genomic pathways. Through the non-genomic pathway, it increases nitric oxide (NO) production via the PI3K-Akt pathway: GR → phosphatidylinositol-3 kinase (PI3K)/Akt pathway → endothelial nitric oxide synthase (eNOS) pathway. Rg1 also increases vascular endothelial growth factor (VEGF) production through the GR → PI3K/Akt → GSK3β → β-catenin/TCF pathway. Gene expression profiling data indicated that Rg1 could increase the expression of a group of genes (e.g. Rho A, RhoB, IQGAP1, LAMA4, CALM2 and Vav2) which are related to cell-cell adhesion, migration and cytoskeletal remodeling.
Cytocrome P450 is an enzymatic family of hemoprotein located primarly in hepatocytes. They are involved in the organism detossification, because they are able to act on hexogen substrate (drugs and external toxines) and on endogen one. The most important isoforms of CyP450 involved in drugs metabolism are CYP3A4, CYP2D6, CYP2C9, CYP1A2 e CYP2E1.
Herbal remedies may interact with medicinal drugs, altering the pharmacokinetic characteristics, so studies on effects on CYP450 have been tested.
Elevated cytochrome P450 activity, translated into a more rapid metabolic rate, may result in a decrease in drug plasma concentrations to sub therapeutic levels and total loss of the pharmacological effect.
Conversely, suppression of cytochrome P450 activity may trigger a rise in plasma drug levels leading to an undesirable exaggerated pharmacological effect and the appearance of toxic symptoms commensurate with overdose. However, the reported effects of ginseng on P450 activities in the clinical trials are somewhat contradictory, but now we know that ginseng can interacts with some drugs.
P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain.
Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents, as ginsenosides.
Recent research has focused on their value in human cancer prevention and treatment. Scientists have discovered new ginseng applications, for example it seems to be an antitumor herb.
Recent studies showed that the combination of 5-FU ( one of the most widely used chemotherapeutic agents in first-line therapy for colorectal cancer) and Panaxadiol significantly enhanced the percentage of apoptotic cells in human colorectal cancer ( through the regulation of cell cycle transition and the induction of apoptotic cells) when compared with the corresponding cell groups treated by 5-FU alone.
Scientists have found that 25-hydroxyprotopanaxadiol(25-OH-PPD), but not 25-hydroxyprotopanaxatriol(25-OH-PPT), from Panax ginseng has an anti-cancer activity in vitro: it inhibited prostate cancer cell growth and proliferation, induced apoptosis, and led to arrest in the G1 phase of the cell cycle.
Ginseng seems to inhibit benzoapirene, a carcinogenic compound involved in bladder cancer, acting, probably, a chemo preventive action.
The chemo preventive effect of Panax ginseng may be due, in part, to ginsenosides’s ability to compete with aryl hydrocarbon receptors (that play an important roles in carcinogenesis, development, differentiation).
It is wrong to think that natural therapies cannot have adverse effects; in fact it is known that herbal medicines can give serious clinical interactions when co-administered with prescription medicines. For example, ginseng may interact with Warfarin, an anticoagulant drug; it induces a decrease of protrombine time.
Ginseng, moreover, may interacts with oral hypoglycemic drugs, so, without a check on glucose hematic levels, it may induce hypoglycemia.
Ginseng can also give similar effects to the estrogenic ones, because its compounds have a chemical structure like testosterone, estrogens and glucocorticoides. So it must not to be used in pregnancy and in women that use substitutive hormonal therapy.
It seems to interacts with imatinib through CYP3A4, increasing hepatotoxic effects. So, it is necessary to check liver function.
It may increase haematic digossina level, and it may hind with antidepressive effects (as phenelzine).
Moreover, simultaneous administration of ginseng with anti-HIV drugs may cause significant elevation in plasma drug levels, for example it may interact with ritonavir.
Figure 6. Chemical structure of ritonavir
Ginseng may cause insomnia, headache, and tremulousness, irritability. These events are not so frequent and they occurred only if ginseng is somministrated at elevated dosages and for long time. It is important to take ginseng for no more than 45-60 days consecutively.
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