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Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease.

Ginseng root is used extensively in traditional Chinese medicine for its alleged tonic effect and possible curative and restorative properties. There are increasing evidences in the literature on the potential role of ginseng in treating cardiovascular diseases. We herein examine the history of ginseng usage and review the current literature on a myriad pharmacological function of ginseng on the cardiovascular system. From the published studies involving cell cultures and animal models, ginseng is shown to have potential benefits on the cardiovascular system through diverse mechanisms, including antioxidant, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, improving lipid profiles, and involving in glucose metabolism and glycemic control. In addition, the relevant clinical trials regarding the effects of ginseng on the cardiovascular disease are summarized, particularly in managing hypertension and improving cardiovascular function. Finally, the controversies in the literature and the possible adverse interactions between ginseng and other drugs are discussed. This review underscores the potential benefit effects of ginseng on cardiovascular diseases, highlights the gaps in our current research, and emphasizes the necessity for more rigorous systemic investigation.

Antioxidants↗

The effect of Panax ginseng on forced immobility time & immune function in mice.

BACKGROUND & OBJECTIVES: Panax ginseng has been used as a traditional medicine for many years mainly among Asian peoples for developing physical strength. We undertook this study to determine the immune-enhancement effect of P. ginseng using a forced swimming test (FST) and by measuring cytokine production in MOLT-4 cell culture and mouse peritoneal macrophages. METHODS: P. ginseng was orally administered to mice once a day for 7 days. The anti-immobility effect of P. ginseng on the FST and blood biochemical parameters related to fatigue, glucose (Glc); blood urea nitrogen (BUN); latic dehydrogenase (LDH); total protein (TP) and production of cytokines in human T cell line, MOLT-4 cells and mouse peritoneal macrophages were investigated. RESULTS: After two and seven days, the immobility time was decreased in the P. ginsengadministrated mice as compared to the control group; however, this reduction was not significant. In addition, the amount of TP in the blood serum was significantly increased. However, the levels of Glc, BUN, and LDH did not show a significant change. P. ginseng significantly (P<0.05) increased interferon (IFN)-gamma production and expression as compared to control at 48 h in MOLT-4 cells. P. ginseng plus recombinant IFN-gamma instead of P. ginseng alone significantly increased the production of the tumour necrosis factor (TNF)-alpha in the mouse peritoneal macrophages. INTERPRETATION & CONCLUSION: Our results suggest that P. ginseng may be useful for an immune promoter. Further studies are needed to understand the mechanism of its action.

Adjuvants, Immunologic↗

Neuropharmacological studies on Panax ginseng.

Panax ginseng root powder is extensively used in the Far East for a wide variety of clinical ailments and to improve general physical and mental wellbeing. It is now also being used in the Occident because of the adaptogenic activity of the plant. The present investigation was conducted to evaluate the neurophamacological profile of activity of P. ginseng (ginseng), since the available data were meagre and often controversial. Ginseng had a complex profile of activity, sometimes difficult to reconcile on the available neurochemical reports on the plant. Thus, it did not appear to affect pentobarbitone sleep induction or spontaneous motor activity but potentiated amphetamine-induced increase in motility. However, ginseng attenuated the other effects of amphetamine, namely, stereotypy and lethality in aggregated mice. The drug exhibited antinociceptive activity and potentiated the antinociceptive effects of both pentazocine and aspirin. Haloperidol catalepsy was potentiated while the behavioural responses of 5-hydroxytryptophan (5-HTP) and L-DOPA were both attenuated. Ginseng had no anticonvulsant action, nor did it potentiate the anticonvulsant effects of phenobarbitone and diazepam. The drug had per se hyperthermic effect and attenuated the hypothermic response of reserpine and 5-HTP induced hyperthermia. Ginseng exhibited significant aggression-inhibiting effect in doses which had no significant effect on spontaneous motility. The results have been discussed on the neurotransmitter function basis of the experimental paradigms and the likely effect of ginseng on these actions.

Animals↗

Protective role of Panax ginseng extract standardized with ginsenoside Rg3 against acrylamide-induced neurotoxicity in rats.

Acrylamide (ACR) is an industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. ACR was designated as a probable human carcinogen by IARC (1994) and USEPA (1988). Panax ginseng extract has efficacies such as anticancer, antihypertension, antidiabetes and antinociception. The objective of the current study is to evaluate the protective effects of Panax ginseng extract against ACR-induced toxicity in rats. Sixty adult Sprague Dawley female rats were divided into six groups included a control group, a group treated orally with ACR (50 mg kg(-1) body weight; b.w.) for 11 days, a group treated orally with Panax ginseng extract (20 mg kg(-1) b.w.) for 11 days and groups treated orally with Panax ginseng for 11 days before, during or after 11 days of ACR treatment. The results indicated that treatment with ACR alone resulted in a significant increase in lipid peroxidation level and LDH activity in brain homogenate as well as in serum CK activity, whereas it caused a significant decrease in SOD activity and a small but statistically insignificant decrease in Na(+)K(+)-ATPase activity in brain homogenate. Serum serotonin, corticosterone, T3, T4, TSH, estradiol, progesterone and plasma adrenaline were significantly decreased in ACR-treated rats. Treatment with Panax ginseng before, during or after ACR treatment reduced or partially antagonized the effects induced by ACR towards the normal values of controls. It could be concluded that Panax ginseng extract exhibited a protective action against ACR toxicity and it is worth noting that treatment with Panax ginseng extract before or at the same time as ACR treatment was more effective than when administered after ACR treatment.

Acrylamide↗

Proteome analysis of hairy root from Panax ginseng C.A. Meyer using peptide fingerprinting, internal sequencing and expressed sequence tag data.

As an initial step to the comprehensive proteomic analysis of Panax ginseng C. A. Meyer, protein mixtures extracted from the cultured hairy root of Panax ginseng were separated by two-dimensional polyacrylamide gel electrophoresis (2-DE). The protein spots were analyzed and identified by peptide finger printing and internal amino acid sequencing by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and electrospray ionization quadrupole-time of flight mass spectrometry (ESI Q-TOF MS), respectively. More than 300 protein spots were detected on silver stained two-dimensional (2-D) gels using pH 3-10, 4-7, and 4.5-5.5 gradients. Major protein spots (159) were analyzed by peptide fingerprinting or de novo sequencing and the functions of 91 of these proteins were identified. Protein identification was achieved using the expressed sequence tag (EST) database from Panax ginseng and the protein database of plants like Arabidopsis thaliana and Oryza sativa. However, peptide mass fingerprinting by MALDI-TOF MS alone was insufficient for protein identification because of the lack of a genome database for Panax ginseng. Only 17 of the 159 protein spots were verified by peptide mass fingerprinting using MALDI-TOF MS whereas 87 out of 102 protein spots, which included 13 of the 17 proteins identified by MALDI-TOF MS, were identified by internal amino acid sequencing using tandem mass spectrometry analysis by ESI Q-TOF MS. When the internal amino acid sequences were used as identification markers, the identification rate exceeded 85.3%, suggesting that a combination of internal sequencing and EST data analysis was an efficient identification method for proteome analysis of plants having incomplete genome data like ginseng. The 2-D patterns of the main root and leaves of Panax ginseng differed from that of the cultured hairy root, suggesting that some proteins are exclusively expressed by different tissues for specific cellular functions. Proteome analysis will undoubtedly be helpful for understanding the physiology of Panax ginseng.

Databases, Protein↗

Liquid chromatography/mass spectrometry of malonyl-ginsenosides in the authentication of ginseng.

Different negative ion electrospray (ES) source conditions are required to concentrate the ion current in [M-H](-) for malonylated and non-malonylated ginsenosides. However, both can be ionised optimally in a single liquid chromatography/mass spectrometry (LC/MS) analysis by employing switchable voltages in the post-source ion optics of a quadrupole ion trap mass spectrometer. Coupled with automatic MS/MS scanning and post-acquisition neutral loss data analysis, this method provides a means of profiling the malonylated and acetylated ginsenosides in ginseng extracts. Analyses revealed numerous malonylated ginsenosides that could be partially characterised by serial MS/MS experiments. The ratio of mRb(1) to other isomeric forms present and to mRb(2) and mRc appears to show consistent differences among Panax ginseng (Asian ginseng), P. quinquefolius (American ginseng) and P. notoginseng (Sanchi ginseng). The ratio of malonylated to non-malonylated ginsenosides is reduced in the red form of Asian ginseng compared with the white form and there is a concomitant increase in the levels of the corresponding acetylated ginsenosides. The ability to analyse malonylated ginsenosides is an important contribution to the range of chemical characteristics that can be used to authenticate the different species of ginseng and will assist in quality control and standardisation.

Chromatography, Liquid↗

Rapid authentication of ginseng species using microchip electrophoresis with laser-induced fluorescence detection.

Ginseng is one of the most expensive Chinese herbal medicines and the effectiveness of ginseng depends strongly on its botanical sources and the use of different parts of the plants. In this study, a microchip electrophoresis method coupled with the polymerase chain reaction (PCR)-short tandem repeats (STR) technique was developed for rapid authentication of ginseng species. A low viscosity hydroxypropyl methylcellulose (HPMC) solution was used as the sieving matrix for separation of the amplified STR fragments. The allele sizing of the amplified PCR products could be detected within 240 s or less. Good reproducibility and accuracy of the fragment size were obtained with the relative standard deviation for the allele sizes less than 1.0% (n=11). At two microsatellite loci (CT 12, CA 33), American ginseng had a different allele pattern on the electropherograms compared with that of the Oriental ginseng. Moreover, cultivated and wild American ginseng can be distinguished on the basis of allele sizing. This work establishes the feasibility of fast genetic authentication of ginseng species by use of microchip electrophoresis.

Alleles↗

Authentication of traditional Chinese medicine using infrared spectroscopy: distinguishing between ginseng and its morphological fakes.

The quality of pharmaceutical products such as ginseng is important for ensuring consumer safety and efficacy. Ginseng is an expensive herb, and adulteration with other cheaper products may occur. Quality assurance of ginseng is needed since many of its commercial products now come in various formulations such as capsules, powder, softgels and tea. Thus traditional means of authentication via smell, taste or physical appearance are hardly reliable. Herbs like ginseng tend to exhibit characteristic infrared fingerprints due to their different chemical constituents. Here we report for the first time a rapid means of distinguishing American and Asian ginsengs from two morphological fakes--sawdust and Platycodon grandiflorum, via pattern differences and principal component analysis of their infrared spectra. Our results show that ginseng can be distinguished from both sawdust and Platycodon grandiflorum, hence there is a potential of using infrared spectroscopy as a novel analytical technique in the authentication of ginseng.

Drugs, Chinese Herbal↗

Antagonism of the acute pharmacological actions of morphine by panax ginseng extract.

1. The effects of intraperitoneal administration of a standard extract of Panax ginseng alone and in combination with morphine were determined in male Sprague-Dawley rats. 2. Ginseng extract at 200 mg/kg produced analgesia and hypothermia. These effects of ginseng were not reversed by naltrexone. 3. A dose of morphine (8 mg/kg) produced analgesia and hyperthermia. The analgesic response to morphine was antagonized by 25 and 50 mg/kg doses of ginseng but not by 12.5, 100 and 200 mg/kg doses. 4. Morphine-induced hyperthermia was antagonized by 12.5-200 mg/kg doses of ginseng. 5. Administration of morphine (50 mg/kg) produced cataleptic effect which was antagonized by 25 mg/kg of ginseng. 6. The results suggest that ginseng extract at high doses produces analgesia and hypothermia in the rat by a non-opiate mechanism, and antagonizes the acute pharmacological effects of morphine.

Analgesia↗

Medicinal uses of ginseng and related plants in the Soviet Union: recent trends in the Soviet literature.

Soviet scholars were the first to establish the fact that many araliaceous plants are resistogens (adaptogens). In the early 1950's, Soviet researchers pioneered the study of ginseng, which is considered to be the primary resistogen, and some other plants of the "ginseng group". A sizable volume of literature was published as a result of their studies. This article reports the results of Soviet research on the ginseng group for the past three decades, traces the progress of Soviet resistogen studies, and examines their current status. Because of its rarity, ginseng was found to be impractical as a source of raw material for the mass production of medicines. Consequently, Soviet scholars shifted the focus of their research from studying ginseng to other members of the ginseng group in order to find suitable substitutes. Four resistogenic plants were identified, studied and finally introduced into therapeutic practice, between 1955 and 1964. Eleutherococcus or eleuthero ginseng is considered to be the most important of these substitutes.

Humans↗

Anxiolytic activity of Panax ginseng roots: an experimental study.

The putative anxiolytic activity of the white and red varieties of ginseng, the root of Panax ginseng, was investigated in rats and mice using a number of experimental paradigms of anxiety and compared with that of diazepam. Pilot studies indicated that single-dose administration of ginseng had little to no acute behavioural effects, hence the two varieties of ginseng were administered orally at two dose levels twice daily for 5 days, while diazepam (1 mg/kg, i.p.) was administered acutely. White and red varieties of ginseng (20 and 50 mg/kg) showed positive results when tested against several paradigms of experimental anxiety. Both were effective in the open-field and elevated plus-maze tests and reduced conflict behaviour in thirsty rats and footshock-induced fighting in paired mice. Ginseng also attenuated pentylenetetrazole-induced decrease in rat brain MAO activity, confirming its anxiolytic activity since this has been proposed to be an endogenous marker for anxiety. The effects induced by white and red ginseng (50 mg/kg x 5 days) were comparable to those induced by diazepam (1 mg/kg).

Aggression↗

Two-phase partition chromatography using soybean oil eliminates pesticide residues in aqueous ginseng extract.

This study was carried out to develop a cost-, labor- and efficiency-effective elimination method of pesticide residues in ginseng extract. A two-phase partition method between soybean oil and distilled water or aqueous ginseng extract was employed for the elimination of pesticide residues. Content of the pesticides was determined by gas chromatography with electron capture or nitrogen phosphorus detector. A total of 15 pesticides representing four categories (organochlorine, organophosphorus, carbamate, pyrethroid) were spiked (ca. 2 ppm) to 2 ml soybean oil in a test tube and the oil was mixed with 6 ml distilled water or 10% aqueous ginseng extract. The test tubes were then vortexed (2 min) and centrifuged at 3000 rpm for 15 min to separate the oil and aqueous layers. Each layer was harvested and subjected to quantitative analysis of pesticides. The average distribution ratio of the pesticides to the oil layer was 94.4 +/- 6.7% in the mixture of the oil and distilled water, and 105.5 +/- 6.6% in the mixture of the oil and ginseng extract. No significant qualitative and quantitative change of ginsenosides, the active ingredients of Panax ginseng, was observed in the ginseng extract before and after the oil treatment. These results suggest that two-phase partition chromatography between soybean oil and the aqueous phase is a cost-, labor- and efficiency-effective reliable method for the elimination of pesticide residues in ginseng extract.

Chemical Phenomena↗

Identification of anxiolytic ingredients in ginseng root using the elevated plus-maze test in mice.

Ginseng root has been widely used for the management of anxiety and emotional instability, but there is little experimental evidence supporting these clinical applications. We pharmacologically identified the anxiolytic components in ginseng root, using the elevated plus-maze test. Male ICR albino mice and the following drugs were used: diazepam (0.5, 1 and 1.5 mg/kg, p.o.); red ginseng powder (300, 600 and 1200 mg/kg, p.o.); crude saponin and non-saponin ginseng fractions (50, 100 and 200 mg/kg, i.p., for each preparation); and pure ginsenoside Rb1, Rg1, and Ro (2.5, 5 and 10 mg/kg, i.p., for each preparation). Ginseng powder and crude saponin ginseng fraction significantly increased the frequency and duration of open arm entries. Among the three types of pure ginsenoside, only ginsenoside Rb1 significantly increased both the frequency and duration of open arm entries. Our results clearly indicate that ginsenoside Rb1 is one of the active anxiolytic components of ginseng root.

Administration, Oral↗

Effect and putative mechanism of action of ginseng on the formation of glycated hemoglobin in vitro.

As a non-enzymatic, covalent binding between glucose and protein, glycation is a well-known cause of various forms of diabetic complications. This study was undertaken to determine the effect and mechanism of action of ginseng on the formation of glycated protein. A solution containing hemoglobin and glucose was incubated for 5 days by adding ginseng extract or glutathione. The quantitative measurement of glycated hemoglobin was determined using the ion capture component set. The anti-oxidative effect of ginseng and quercetin was determined through the TBA method. The amount of glycated hemoglobin (%GHb) significantly increased with the addition of glucose (27.8 mM) compared to the non-addition group. Nonetheless, this significantly decreased when ginseng extract (2 g/dl) was added and further dropped when glutathione (50 mM) was added. The amount of hemoglobin A1c (%HbA1c), a sub-fraction of glycated hemoglobin, was lower than that of glycated hemoglobin, but it showed a similar tendency. Compared to a non-addition group, the optical density of the organic layer that was separated through the addition of chloroform in oxidized linoleic acid significantly and dose-dependently decreased when ginseng extract or quercetin was added. These results suggest that the inhibitory effect of ginseng on the formation of glycated hemoglobin could be attributed to the anti-oxidative activity of ginseng.

Antioxidants↗

Increase of acetylcholine release by Panax ginseng root enhances insulin secretion in Wistar rats.

The present study was designed to ascertain the effect of Panax ginseng root on plasma glucose and investigate the possible mechanisms for the effect. Ninety minutes after the oral administration of P. ginseng root to fasting Wistar rats, plasma glucose decreased in a dose-dependent manner. Simultaneous with the reduction in plasma glucose, an increase in the plasma level of insulin and C-peptide was also observed. Moreover, disruption of the available synaptic acetylcholine (ACh), using the inhibitor for choline uptake (hemicholinium-3), or the inhibitor for vesicular choline transport (vesamicol), abolished the metabolic actions of P. ginseng root. Conversely, physostigmine, at a concentration sufficient to inhibit acetylcholinesterase, enhanced the metabolic effect of P. ginseng root. It is possible that P. ginseng root mediates the release of ACh from nerve terminals to enhance insulin secretion. Blockade of the actions of P. ginseng root by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP) suggested that the site of action is the muscarinic M(3) receptor. Taken together, the results suggest that P. ginseng root has the ability to increase the release of ACh from nerve terminals in rats so as to stimulate muscarinic M(3) receptors activity located in the pancreatic cells for the secretion of insulin, which in turn lower plasma glucose.

Acetylcholine↗

CO(2)-induced total phenolics in suspension cultures of Panax ginseng C. A. Mayer roots: role of antioxidants and enzymes.

The effects of different concentrations of CO(2) (1%, 2.5% and 5%) on the antioxidant capacity, total phenols, flavonoids, protein content and phenol biosynthetic enzymes in roots of Panax ginseng were studied in bioreactor (working volume 4 l) after 15, 30 and 45 days. CO(2) induced accumulation of total phenolics in a concentration and duration dependent manner. Total phenols, flavonoids and 1,1-diphenyl-2-picrylhydrazyl (DPPH) activity increased 60%, 30% and 20% at 2.5% CO(2) after 45 days compared to control in P. ginseng roots which indicated that phenolics compounds played an important role in protecting the plants from CO(2). Hypothesizing that increasing the phenolic compounds in roots of P. ginseng may increase its nutritional functionality; we investigated whether pentose phosphate pathway (PPP), shikimate/phenylpropanoid pathway enzymes have a role in phenolics mobilization in P. ginseng roots. Fresh weight (FW), dry weight (DW) and growth ratio was increased at 1% and 2.5% CO(2) only after 45 days, however, unaffected after 15 and 30 days. Results also indicated that high CO(2) progressively stimulated the activities of glucose 6 phosphate dehydrogenase (G6PDH, E.C. 1.1.1.49), shikimate dehydrogenase (SKDH, E.C. 1.1.1.25), phenylalanine ammonia lyase (PAL, E.C. 4.3.1.5), cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195), caffeic acid (CA) peroxidase and chlorogenic acid (CGA) peroxidase after 15, 30 and 45 days. Increased CO(2) levels resulted in increases in accumulation of total protein (45%), non-protein thiol (NP-SH) (30%) and cysteine contents (52%) after 45 days compared to control and increased activities of beta-glucosidase (GS, E.C. 3.2.1.21) and polyphenol oxidase (PPO, E.C. 1.10.3.2) in P. ginseng roots indicated that they played an important role in protecting the plants from CO(2). These results strongly suggest that high concentration of CO(2) delivered to ginseng root suspension cultures induced the accumulation of total phenolics possessing high antioxidant properties probably useful for human health. Therefore, roots of P. ginseng are considered as a good source of phenolics compounds with high antioxidants capacity and can be produced on a large scale.

Alcohol Oxidoreductases↗

Electroencephalograph effects of single doses of Ginkgo biloba and Panax ginseng in healthy young volunteers.

Both Ginkgo biloba and Panax ginseng exert a number of physiological effects and have been shown to modulate aspects of cognitive performance. Whilst a number of studies have examined ginkgo's effects on electroencephalograph (EEG) recordings, to date, none have investigated the EEG effects of ginseng. In this double-blind, placebo-controlled, balanced crossover experiment, the effects of single doses of G. biloba (360 mg GK501), P. ginseng (200 mg G115), and an identical placebo, on auditory-evoked potentials, contingent negative variation (CNV), and resting power within the delta, theta, alpha, and beta wavebands, were assessed in 15 healthy volunteers. Each participant was assessed on three separate occasions 4 h after consuming that day's treatment. The order of presentation of the treatments was dictated by a Latin square with 7 days between testing sessions. The results showed that ginseng led to a significant shortening of the latency of the P300 component of the evoked potential. Both ginseng and ginkgo also led to significant reductions in frontal 'eyes closed' theta and beta activity, with additional reduction for ginseng in the alpha waveband. These findings demonstrate for the first time that P. ginseng can directly modulate cerebroelectrical activity, and that these effects are more pronounced than those following G. biloba.

Adult↗

Lipoprotein lipase activation by red ginseng saponins in hyperlipidemia model animals.

The effect of ginseng saponins isolated from red ginseng (a steamed and dried root of Panax ginseng) has been studied in a cyclophosphamide (CPM)-induced hyperlipidemia model in fasted rabbits. In this model, chylomicrons and very low density lipoprotein (VLDL) accumulation was known to occur as a result of reduction in lipoprotein lipase (LPL) activity in the heart and heparin-releasable heart LPL. Oral administration of ginseng saponins at a dose of 0.01 g/kg for 4 weeks was found to reverse the increase in serum triglycerides (TG) and concomitant increase in cholesterol produced by CPM treatment, especially in chylomicrons and VLDL. In addition, ginseng saponins treatment led to a recovery in postheparin plasma LPL activity and heparin-releasable heart LPL activity, which were markedly reduced by CPM treatment. In rats given 15% glycerol/15% fructose solution, postheparin plasma LPL activity declined to two third of normal rats, whereas ginseng saponins reversed it to normal levels. In the present study we first demonstrated that ginseng saponins sustained LPL activity at a normal level or protected LPL activity from being decreased by several factors, resulting in the decrease of serum TG and cholesterol.

Administration, Oral↗