Red Panax Ginseng Studies
- Ginseng mediates its anti-cancer activity by inhibiting the expression of DNMTs and reactivating methylation-silenced genes in colorectal cancer.
Developing safe and effective therapeutic modalities remains a critical challenge for improving the prognosis of patients with colorectal cancer (CRC). In this regard, targeting epigenetic regulation in cancers has recently emerged as a promising therapeutic approach. Since several natural compounds have recently been shown to be important epigenetic modulators, we hypothesized that Ginseng might exert its anti-cancer activity by regulating DNA methylation alterations in CRC. In this study, a series of cell culture studies were conducted, followed by their interrogation in patient-derived 3D organoid models to evaluate Ginseng’s anti-cancer activity in CRC. Genome-wide methylation alterations were interrogated by undertaking MethylationEpic BeadChip microarrays. First, 50% inhibitory concentrations (IC50) were determined by cell viability assays, and subsequent Ginseng treatment demonstrated a significant anti-cancer effect on clonogenicity and cellular migration in CRC cells. Treatment with Ginseng potentiated cellular apoptosis through regulation of apoptosis-related genes in CRC cells. Furthermore, Ginseng treatment downregulated the expression of DNA methyltransferases (DNMTs) and decreased the global DNA methylation levels in CRC cells. The genome-wide methylation profiling identified Ginseng-induced hypomethylation of transcriptionally silenced tumor suppressor genes. Finally, cell culture-based findings were successfully validated in patient-derived 3D organoids. In conclusion, we demonstrate that Ginseng exerts its anti-tumorigenic potential by regulating cellular apoptosis via the downregulation of DNMTs and reversing the methylation status of transcriptionally silenced genes in CRC. [Okuno K, Pratama MY, Li J, et al. Ginseng mediates its anti-cancer activity by inhibiting the expression of DNMTs and reactivating methylation-silenced genes in colorectal cancer. Carcinogenesis. 2023; May 3. bgad025. - Study of red ginseng preparation HRG80 for relieving muscle pain/soreness and supporting the neuromuscular performance of elite weightlifters in intense resistance exercise: an open-label, randomized, crossover trial.
This study aimed to assess the efficacy of new Panax ginseng C.A.Mey preparation of increased bioavailability in fatigue assessed as relief of muscle soreness and improving the neuromuscular performance of healthy subjects following a bout of intense resistance exercise. The effects of the hydroponically cultivated red ginseng root powder HRG80TM (RG) γ-Cyclodextrin -based chewable tablets and cyclodextrin-free RG capsules were compared in an open label, randomized, crossover trial on 20 elite weightlifters. The RG treatments for 10 days have a statistically significant effect on the relief of the muscle’s soreness compared to the control. No statistically significant difference was observed in the effects of two capsules vs. one tablet suggesting that γ Cyclodextrin based chewable tablets of red ginseng preparation HRG80 are almost 4-fold active of cyclodextrin-free HRG80 capsules. Furthermore, the effect of tablets vs. control was significant on the 5th day of the treatment, while the effect of capsules vs. control was observed three days later—on the 8th day. However, in push-ups on the uneven bars (PUB) test of neuromuscular performance, the capsule intake results in increased physical performance compared to tablets or control with maximal effect on the 7th day of treatment. The results of this study provide evidence for the efficacy of γ-cyclodextrin-based chewable tablets containing 100 mg of red ginseng HRG80TM for relief of muscle soreness and supporting the neuromuscular performance of healthy subjects in intense resistance exercise. [Hovhannisyan AS, Mosinyan DN, Hayrumyan SA, Panossian AG. Study of red ginseng preparation HRG80 for relieving muscle pain/soreness and supporting the neuromuscular performance of elite weightlifters in intense resistance exercise: an open-label, randomized, crossover trial. Phys Med Rehabil Int. 2022;9(3):1-7. - Effects of red and white ginseng preparations on electrical activity of the brain in elderly subjects: a randomized, double-blind, placebo-controlled, three-armed cross-over study.
Abstract: Background: Recently, the superior efficacy of hydroponically cultivated red ginseng preparation HRG80® compared to wild growing white ginseng (WG) in preventing stress‐induced symptoms related to the daily work situation of healthy subjects was reported. The aim of this study was to compare the effects of HRG80®, WG, and placebo on the electrical activity in the brain of elderly human subjects during relaxation and mental challenges. Methods: Changes in the electroencephalogram (EEG) frequency ranges of 17 different brain regions were measured after single and repeated administration of HRG80®, WG, and placebo across a four‐week randomized, doubleblind, placebo‐controlled three‐armed cross‐over trial. Results: Both red and white ginseng preparations had a strong impact on brain activity, with different effects on various brain regions depending on the mental load during relaxation and cognitive tasks associated with memory, attention, and mental performance. Both ginseng preparations exhibited significant effects on spectral powers compared to placebo, reflecting an activating action. The spectral changes in the quantitative EEG induced by HRG80® indicated an improvement in mood as well as calming effects, evidenced by the modulation of β2 waves, representing changes in GABA‐ergic neurotransmission. HRG80® attenuated δ/θ powers during relaxation, suggesting the potential improvement of pathologically enhanced spectral power in aging. Conclusion: The results of this study suggest that both hydroponically cultivated red and wild growing white ginseng have similar beneficial effects on the cognitive functions of elderly subjects, as reflected by electric brain activity, but their modes of action on the brain are different. [Dimpfel W, Mariage PA, Panossian AG. Effects of red and white ginseng preparations on electrical activity of the brain in elderly subjects: a randomized, double-blind, placebo-controlled, three-armed cross-over study. Pharmaceuticals. 2021;14:182. - Efficacy of Panax ginseng Meyer herbal preparation HRG80 in preventing and mitigating stress-induced failure of cognitive functions in healthy subjects: a pilot, randomized, double-blind, placebo-controlled crossover trial.
Background: The aim of this pilot study was to compare the efficacy of hydroponically
cultivated red Panax ginseng Meyer root preparation (HRG80) and traditionally harvested six-year old white P. ginseng standard preparation (PGS) with placebo in preventing symptoms of stress. Methods: The effects of HRG80, PGS, and placebo capsules were studied in 50 tired healthy subjects in a three-arm, randomized, double-blinded, placebo-controlled crossover trial. Efficacy-outcome measures included the accuracy of processing the d2 test for cognitive functions, obtained accuracy score in a computerized memory test, and the perceived-stress (PS) score. Results: A statistically significant interaction effect between time and treatment (p < 0.0001) was observed in the attention d2 and memory tests, indicating that HRG80 treatment was more beneficial than that with a placebo. The effects of PGS were better than those of the placebo, but the difference was not statistically significant. There was significant difference between the effects of HRG80 and PGS (p < 0.0001) that were observed after single (Day 1) and repeated administrations on Days 5 and 12 of treatment. Conclusion: Overall, HRG80 treatment was significantly superior compared to that with the PGS and placebo regarding attention, memory, and PS scores after single and repeated administrations for 5 and 12 days. [Mariage PA, Hovhannisyan A, Panossian AG. Efficacy of Panax ginseng Meyer herbal preparation HRG80 in preventing and mitigating stress-induced failure of cognitive functions in healthy subjects: a pilot, randomized, double-blind, placebo-controlled crossover trial. Pharmaceuticals. 2020;13:57.] - Panax ginseng Meyer herbal preparation HRG80 for preventing and mitigating stress-induced failure of cognitive functions in healthy subjects.
A large body of evidence suggests that ginsenoside metabolites contribute substantially to the pharmacological effects of ginseng. These metabolites (rare ginsenosides) are present in minor amounts in white Ginseng and in larger amounts in steam processed red Ginseng. A recent study aimed to obtain evidence that rare ginsenosides significantly contribute in the overall efficacy of Ginseng. The efficacy of two Ginseng preparations containing approximately the same amounts of major ginsenosides but substantially different (7.8-fold) amounts of rare ginsenosides was compared in a three-arm, randomized, double-blinded, placebo-controlled, crossover trial. A hydroponically cultivated red Panax ginseng Meyer root preparation (HRG80®) was compared with traditionally harvested 6-year old white P. ginseng (WG) and placebo for their ability to prevent symptoms of stress such as fatigue, impaired memory, reduced concentration, and attention deficit related to daily work in healthy subjects. The effects of HRG80® (daily dose: 418 mg of red ginseng powder, 63.5.mg of ginsenosides, and 52 mg of rare ginsenosides), PGS Arkopharma (daily dose: 764 mg of white ginseng powder, 19.8 mg of ginsenosides, and 6.1 mg of rare ginsenosides), and placebo capsules, taken orally once a day for 14 days in 50 tired but otherwise healthy subjects, were studied. The efficacy outcomes included the accuracy of processing in the d2 test for cognitive functions, an accuracy score obtained using a computerized memory test, and the perceived stress score. A statistically significant interaction effect between time and treatment was observed in the d2 attention and memory tests, indicating that HRG80 was more beneficial than placebo. The effects of WG were better than those of placebo, but the difference was not statistically significant. There was a significant difference between the effects of HRG80 and WG, which was observed after both single (day 1) and repeated administration (days 5 and 12). Importantly, the effective therapeutic daily dose of HRG80 (418 mg) was at least 10-fold lower than the commonly used effective dose red ginseng (4500–9000 mg per day). [Lemerond T, Panossian AG. Panax ginseng Meyer herbal preparation HRG80 for preventing and mitigating stress-induced failure of cognitive functions in healthy subjects. J Altern Complement Integr Med. 2020;6:100.] - Panax ginseng preparations enhance long term potentiation in rat 1 hippocampal slices by glutamatergic NMDA and kainate receptor 2 mediated transmission.
Background: Root of the Korean red ginseng (Panax ginseng C.A. Meyer) is used in traditional medicinal systems to enhance cognitive function. In this study we compared the effects of HRG80 with a standard Ginseng preparation (SGP) on the excitability of pyramidal cells in the hippocampus of rats by using hippocampal long-term potentiation. The aim of the study: The aim of this study was to compare the effects of HRG80 with SGP on the excitability of pyramidal cells in the hippocampus of rats, and to elucidate a possible mechanism of their action by using hippocampal long-term potentiation, a memory model based on modulation of glutamatergic neurotransmission. Methods: Red Ginseng preparations were orally administered at daily doses of 10 mg/kg, 25 mg/kg, and 50 mg/kg to rats for 1 week before ex vivo analysis of the excitability of hippocampus slices was performed the following day. Hippocampal slices were stimulated in vitro with single stimuli (SS) or theta burst stimuli (TBS) in order to activate the Schaffer Collaterals targeting pyramidal cells in the presence or absence of six various glutamatergic receptor antagonists. Results: Both P. ginseng preparations induced a dose dependent increase in the population spike in the presence of SS as well as in the presence of TBS leading to long-term potentiation (LTP) compared to the placebo (glucose 1% 1 ml/kg). Comparison of the efficacy of both P. ginseng preparations revealed a superior action of HRG80 Ginseng, reached considerably and statistically significantly higher population spike peak amplitudes than SGP in the presence of both stimulation modi. Only glutamatergic NMDA and Kainate receptor antagonists selectively reversed the actions of HRG80 and SGP. Conclusions: Ginseng HRG80 preparation from hydroponically cultivated roots is more active than SGP. Ginseng induced higher excitability of pyramidal cells by modulation of ionotropic glutamate NMDA and Kainate receptor mediated transmission. [Dimpfel W, Schombert L, Panossian AG. Panax ginseng preparations enhance long term potentiation in rat 1 hippocampal slices by glutamatergic NMDA and kainate receptor 2 mediated transmission. J Altern Complement Integr Med. 2020;6:106.] - Network pharmacology of red ginseng (part 1): effects of ginsenoside Rg5 at physiological and sub-physiological concentrations.
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. [Panossian A, Abdelfatah S, Efferth T. Network pharmacology of red ginseng (part 1): effects of ginsenoside Rg5 at physiological and sub-physiological concentrations. Pharmaceuticals. 2021;14(10):999.] - Network pharmacology of red ginseng (part 2): the differential effects of red ginseng and ginsenoside Rg5 in cancer and heart diseases as determined by transcriptomics.
Panax ginseng C.A.Mey. is an adaptogenic plant traditionally used to enhance mental and physical capacities in cases of weakness, exhaustion, tiredness, or loss of concentration, and during recovery. According to ancient records, red ginseng root preparations enhance longevity with long-term intake. Recent pharmacokinetic studies of ginsenosides in humans and our in vitro study in neuronal cells suggest that ginsenosides are effective when their levels in blood is low—at concentrations from 10−6 to 10−18 M. In the present study, we compared the effects of red ginseng root preparation HRG80TM(HRG) at concentrations from 0.01 to 10,000 ng/mL with effects of white ginseng (WG) and purified ginsenosides Rb1, Rg3, Rg5 and Rk1 on gene expression in isolated hippocampal neurons. The aim of this study was to predict the effects of differently expressed genes on cellular and physiological functions in organismal disorders and diseases. Gene expression profiling was performed by transcriptome-wide mRNA microarray analyses in murine HT22 cells after treatment with ginseng preparations. Ingenuity pathway downstream/upstream analysis (IPA) was performed with datasets of significantly up- or downregulated genes, and expected effects on cellular function and disease were identified by IPA software. Ginsenosides Rb1, Rg3, Rg5, and Rk1 have substantially varied effects on gene expression profiles (signatures) and are different from signatures of HRG and WG. Furthermore, the signature of HRG is changed significantly with dilution from 10,000 to 0.01 ng/mL. Network pharmacological analyses of gene expression profiles showed that HRG exhibits predictable positive effects in neuroinflammation, senescence, apoptosis, and immune response, suggesting beneficial soft-acting effects in cancer, gastrointestinal, and endocrine systems diseases and disorders in a wide range of low concentrations in blood. [Panossian A, Abdelfatah S, Efferth T. Network Pharmacology of Ginseng (Part II): The Differential Effects of Red Ginseng and Ginsenoside Rg5 in Cancer and Heart Diseases as Determined by Transcriptomics. Pharmaceuticals. 2021; 14(10):1010.] - An open-label, pilot trial of HRG80™ red ginseng in chronic fatigue syndrome, fibromyalgia, and post-viral fatigue.
Abstract: Chronic fatigue syndrome and fibromyalgia (CFS/FMS) affect 2.1% of the world’s population and ~10–25% of people who have had COVID-19. Previous clinical data suggested that a unique Panax ginseng (C.A. Meyer, family Araliaceae) root extract (HRG80 Red Ginseng) often resulted in marked improvement. We aimed to study this hydroponic form of red ginseng root, containing high levels of rare ginsenosides, for improving energy, cognition, and stamina. This open-label prospective study included participants with severe CFS/FMS who took a daily supplement of red ginseng capsules (200–400 mg) or tablets (100–200 mg) for one month. A total of 188 subject patients completed the one-month treatment trial. Of these, 60.1% rated themselves as improved, with 13.3% rating themselves as being much better. In this group, the mean composite score improved from 11.9 to 18.8 (p < 0.001), with a 67% average increase in energy, 44% average increase in overall well-being, 48% average improvement in mental clarity, 58% average composite improvement in the previous three measurements (primary outcome measure), 46% average improvement in sleep, 33% average decrease in pain, and 72% average increase in stamina. Our study showed that this unique red ginseng root powder resulted in a marked improvement in people with CFS and fibromyalgia. This included the subgroup with post-viral CFS/FMS. [Teitelbaum J, Goudie S. An open-label, pilot trial of HRG80™ red ginseng in chronic fatigue syndrome, fibromyalgia, and post-viral fatigue. Pharmaceuticals. 2022;15:43. - Effect of γ -cyclodextrin on the dissolution of ginsenosides Rg5 and Rk1 from red ginseng chewable tablets.
Abstract. This study aimed to assess the water solubility of Ginsenosides Rg5 and Rk1 released from chewable tablets containing Red Ginseng preparation HRG80 incorporated γ-cyclodextrin (GCD) complex compared with γ-cyclodextrin free drug preparation. The dissolution rate of Ginsenosides Rg5 and Rk1 was increased three times after γ-cyclodextrin inclusion. The relative solubility of Ginsenosides Rg5 and Rk1 calculated from the ratio of Area under the curve AUC 0 – 90 min was correspondingly 221% and 227%. This study for the first reports that Red Ginseng preparation HRG80 inclusion into GCD significantly improves (increases) the water solubility of active constituents Ginsenosides Rg5 and Rk1. [Ginosyan G, Prazyan A, Davinyan A, Hovhannisyan A. Effect of γ -cyclodextrin on the dissolution of ginsenosides Rg5 and Rk1 from red ginseng chewable tablets. Glob J Pharmaceu Sci. 2022;9(4):555766.]
