Effect of Fermented Red Ginseng Concentrate Intake on Stool Characteristic, Biochemical Parameters, and Gut Microbiota in Elderly Korean Women.

Fermented red ginseng (FRG) has been used as a general stimulant and herbal medicine for health promotion in Asia for thousands of years. Few studies have investigated the effects of FRG containing prebiotics on the gut microbiota. Here, 29 Korean women aged ≥ 50 years were administered FRG for three weeks to determine its effect on stool characteristics, biochemical parameters, and gut microbiome. Gut microbial DNA was subjected to 16S rRNA V3-V4 region sequencing to assess microbial distribution in different stages. Additionally, the stool consistency, frequency of bowel movements, and biochemical parameters of blood were evaluated. We found that FRG intake improved stool consistency and increased the frequency of bowel movements compared to before intake. Biochemical parameters such as glucose, triglyceride, cholesterol, low-density lipoprotein cholesterol, creatinine, alkaline phosphatase, and lactate dehydrogenase decreased and high-density lipoprotein cholesterol increased with FRG intake. Gut microbiome analysis revealed 20 specific bacteria after three weeks of FRG intake. Additionally, 16 pathways correlated with the 20 specific bacteria were enhanced after red ginseng intake. In conclusion, FRG promoted health in elderly women by lowering blood glucose levels and improving bowel movement frequency. The increase in bacteria observed with FRG ingestion supports these findings.

Panax ginseng and its ginsenosides: potential candidates for the prevention and treatment of chemotherapy-induced side effects.

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG.

Fermented Red Ginseng Alleviates Ovalbumin-Induced Inflammation in Mice by Suppressing Interleukin-4 and Immunoglobulin E Expression.

Ginseng (the root of Panax ginseng Meyer) has been reported to have many biologic therapeutic effects, including anti-inflammatory properties, and ginsenosides are considered as one of the factors responsible for these therapeutic effects. To improve their therapeutic action, probiotic bacteria are used to ferment and chemically transform ginsenosides in red ginseng (RG). In this study, we aimed to investigate the beneficial effects of RG fermented by probiotic bacteria (FRG) against ovalbumin (OVA)-induced allergic rhinitis in a mouse model. We induced the mouse model via OVA inhalation; experimental results revealed increased immunoglobulin E (IgE) and interleukin (IL)-4 levels, leading to Th2-type cytokine response. The mice with induced allergy were then orally administered RG and FRG over 2 weeks, as a result of which, IL-4 and IgE levels in bronchoalveolar lavage fluid, nasal fluid, and serum were found to be ameliorated more effectively by FRG than by RG, suggesting that FRG has better immune regulatory effects than RG. FRG also downregulated immune cell levels, such as those of eosinophils and basophils, and significantly decreased the thickness of OVA-induced respiratory epithelium compared to RG. Collectively, the results showed that FRG treatment alleviates inflammation, thereby extending a protective effect to mice with OVA-induced inflammatory allergic rhinitis.

Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis.

Gut dysbiosis is closely connected with the outbreak of psychiatric disorders with colitis. Bifidobacteria-fermented red ginseng (fRG) increases the absorption of ginsenoside Rd and protopanxatriol into the blood in volunteers and mice. fRG and Rd alleviates 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Therefore, to understand the gut microbiota-mediated mechanism of fRG against anxiety/depression, we examined the effects of red ginseng (RG), fRG, ginsenoside Rd, and protopanaxatriol on the occurrence of anxiety/depression, colitis, and gut dysbiosis in mice. Mice with anxiety/depression were prepared by being exposed to two stressors, immobilization stress (IS) or Escherichia coli (EC). Treatment with RG and fRG significantly mitigated the stress-induced anxiety/depression-like behaviors in elevated plus maze, light-dark transition, forced swimming (FST), and tail suspension tasks (TST) and reduced corticosterone levels in the blood. Their treatments also suppressed the stress-induced NF-κB activation and NF-κB+/Iba1+ cell population in the hippocampus, while the brain-derived neurotrophic factor (BDNF) expression and BDNF+/NeuN+ cell population were increased. Furthermore, treatment with RG or fRG suppressed the stress-induced colitis: they suppressed myeloperoxidase activity, NF-κB activation, and NF-κB+/CD11c+ cell population in the colon. In particular, fRG suppressed the EC-induced depression-like behaviors in FST and TST and colitis more strongly than RG. fRG treatment also significantly alleviated the EC-induced NF-κB+/Iba1+ cell population and EC-suppressed BDNF+/NeuN+ cell population in the hippocampus more strongly than RG. RG and fRG alleviated EC-induced gut dysbiosis: they increased Bacteroidetes population and decreased Proteobacteria population. Rd and protopanaxatriol also alleviated EC-induced anxiety/depression and colitis. In conclusion, fRG and its constituents Rd and protopanaxatriol mitigated anxiety/depression and colitis by regulating NF-κB-mediated BDNF expression and gut dysbiosis.

Inducing Intermediates in Biotransformation of Natural Polyacetylene and A Novel Spiro-γ-Lactone from Red Ginseng by Solid Co-Culture of Two Gut Chaetomium globosum and The Potential Bioactivity Modification by Oxidative Metabolism.

The ω-hydroxyl-panaxytriol (1) and ω-hydroxyl-dihydropanaxytriol (2)-are rare examples of polyacetylene metabolism by microbial transformation, and these new metabolites (1, 2) from fermented red ginseng (FRG) by solid co-culture induction of two Chaetomium globosum should be the intermediates of biotransformation of panaxylactone (metabolite A). The metabolic pathway of panaxylactone was also exhibited. The ingredients of red ginseng (RG) also induced the production of rare 6/5/5 tricyclic ring spiro-γ-lactone skeleton (3). The ω-hydroxylation of new intermediates (1, 2) decreases cytotoxicity and antifungal activity against C. globosum compared with that of its bioprecursor panaxytriol. Additionally, compounds 1 and 2 indicated obvious inhibition against nitric oxide (NO) production, with ratios of 44.80 ± 1.37 and 23.10 ± 1.00% at 50 µM. 1 has an equivalent inhibition of NO production compared with the positive drug. So, the microbial biotransformation that occurred in FRG fermented by gut C. globosum can change the original bioactivity of polyacetylene, which gave a basis about the metabolic modification of red ginseng by intestinal fungus fermentation.

Fermented Red Ginseng Alleviates Cyclophosphamide-Induced Immunosuppression and 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis in Mice by Regulating Macrophage Activation and T Cell Differentiation.

A variety of products have been developed with red ginseng (RG, the steamed roots of Panax ginseng Meyer). To clarify the immunomodulating effects of water-extracted RG (wRG), 50% ethanol-extracted RG (eRG), enzyme-treated eRG (ERG) and probiotic-fermented eRG (FRG), we examined their immunopotentiating and immunosuppressive effects in mice with cyclophosphamide (CP)-induced immunosuppression (CI) or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (TC). Oral administration of RG in CI mice significantly increased blood IFN- γ levels. Treatment with RG also increased the tumoricidal effects of CI mouse splenic cytotoxic T (Tc) and NK cells against YAC-1 cells. Treatment with RGs, in particular FRG and wRG, significantly increased Th1 cell differentiation. Treatment with RG except wRG increased Treg cell differentiation. However, wRG alone increased IL-6 and IL-17 expression in the colon of CI mice. Furthermore, RG alleviated colitis in TC mice. FRG most potently suppressed TNBS-induced colon shortening, NF- κ B activation and TNF- α and IL-17 expression and increased IL-10 expression. RGs inhibited TNF- α expression and increased IL-10 expression in lipopolysaccharide-stimulated primary macrophages in vitro while the differentiation of splenic T cells into type 1 T (Th1) and regulatory T (Treg) cells was increased by FRG in vitro. In conclusion, FRG can alleviate immunosuppression and inflammation by inhibiting macrophage activation and regulating Th1 and Treg cell differentiation.

Adjuvant effects of fermented red ginseng extract on advanced non-small cell lung cancer patients treated with chemotherapy.

OBJECTIVE: To investigate the adjuvant therapeutic effects of fermented red ginseng (FRG) extract on non-small cell lung cancer (NSCLC) patients treated with chemotherapy. METHODS: A total of 60 patients with advanced NSCLC were divided into two groups using a random number table, i.e., the gemcitabine plus cisplatin (GP) chemotherapy alone group (26 patients) and the FRG + GP chemotherapy group (34 patients), for 60-day treatment. Patients were then assessed according to the Fatigue Symptom Inventory, Chinese medicine symptoms score, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Karnofsky Performance Status Scale, and Functional Assessment of Cancer Therapy-Lung. In addition, chemotherapy toxicity and tumor biomarkers were measured. RESULTS: For NSCLC patients after chemotherapy, FRG extract significantly improved the FSI score, CM symptoms score, psychological status, physical conditions, and quality of life and reduced chemotherapy toxicity, but the expression levels of carcinoembryonic antigen, cytokeratin-19 fragments, and neuron-specific enolase were not significantly different between the chemotherapy alone and the FRG + chemotherapy groups or between pre- and post-treatments. CONCLUSIONS: This study demonstrated that FRG extract had an adjuvant effect on advanced NSCLC patients treated with chemotherapy. Further studies with a larger sample size will verify the current findings.

Changes in the Ginsenoside Content During Fermentation Using an Appliance for the Preparation of Red Ginseng.

The total amount of ginsenoside in fermented red ginseng (FRG) is increased by microbial fermentation. The aim of this study was to evaluate whether fermentation time and temperature affect the ginsenoside content during fermentation using an appliance for the preparation of red ginseng. The FRG and fermented red ginseng extracts (FRG-e) were prepared using an appliance for the preparation of red ginseng. The temperature was recorded and time points for sampling were scheduled at pre-fermentation (0[Formula: see text]h) and 18, 36, 48, 60 and 72[Formula: see text]h after the addition of the microbial strains. Samples of FRG and FRG-e were collected to identify changes in the ginsenoside contents at each time point during the fermentation process. The ginsenoside content was analyzed using high performance liquid chromatography (HPLC). The levels of ginsenoside Rh1, Rg3, and compound Y, which are known to have effective pharmacological properties, increased more than three-fold in the final products of FRG relative to samples prior to fermentation. Although the ginsenoside constituents of FRG-e decreased or increased and then decreased during fermentation, the total amount of ginsenoside in FRG-e was even higher than those in FRG; the total amounts of ginsenoside in FRG-e and FRG were 8282.8 and 738.0[Formula: see text]mg, respectively. This study examined the changes in composition of ginsenosides and suggests a method to manufacture high-content total ginsenosides according to the fermentation temperature and process time. Reducing the extraction time is expected to improve the decrease of ginsenosides in FRG-e as a function of the fermentation time.

Effect of fermented red ginseng on cytochrome P450 and P-glycoprotein activity in healthy subjects, as evaluated using the cocktail approach.

AIMS: We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P-glycoprotein (P-gp), in healthy volunteers. METHODS: This study was an open-label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). RESULTS: Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least-square mean metabolic ratio (90% CI) was 0.901 (0.830-0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720-0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925-1.197) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.150 (0.860-1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673-0.990) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast ) for fexofenadine (P-gp) was 1.322 (1.112-1.571). CONCLUSION: No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two-week administration of concentrated fermented red ginseng. However, the inhibition of P-gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P-gp substrate drugs.

Fermented Red Ginseng Potentiates Improvement of Metabolic Dysfunction in Metabolic Syndrome Rat Models.

Metabolic syndrome including obesity, dyslipidemia and hypertension is a cluster of risk factors of cardiovascular disease. Fermentation of medicinal herbs improves their pharmacological efficacy. Red ginseng (RG), a widely used traditional herbal medicine, was reported with anti-inflammatory and anti-oxidant activity. Aim in the present study was to investigate that the effects of fermented red ginseng (FRG) on a high-fructose (HF) diet induced metabolic disorders, and those effects were compared to RG and losartan. Animals were divided into four groups: a control group fed a regular diet and tap water, and fructose groups that were fed a 60% high-fructose (HF) diet with/without RG 250 mg/kg/day or FRG 250 mg/kg/day for eight weeks, respectively. Treatment with FRG significantly suppressed the increments of body weight, liver weight, epididymal fat weight and adipocyte size. Moreover, FRG significantly prevented the development of metabolic disturbances such as hyperlipidemia and hypertension. Staining with Oil-red-o demonstrated a marked increase of hepatic accumulation of triglycerides, and this increase was prevented by FRG. FRG ameliorated endothelial dysfunction by downregulation of endothelin-1 (ET-1) and adhesion molecules in the aorta. In addition, FRG induced markedly upregulation of Insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (Glut4) in the muscle. These results indicate that FRG ameliorates obesity, dyslipidemia, hypertension and fatty liver in HF diet rats. More favorable pharmacological effects on HF diet induced metabolic disorders were observed with FRG, compared to an equal dose of RG. These results showed that the pharmacological activity of RG was enhanced by fermentation. Taken together, fermentated red ginseng might be a beneficial therapeutic approach for metabolic syndrome.

Antioxidant and hepatoprotective effects of fermented red ginseng against high fat diet-induced hyperlipidemia in rats / 한국실험동물학회지

This study was performed to investigate the antioxidant and hepatoprotective effects of fermented red ginseng (Panax ginseng C.A. Meyer; FRG) on high-fat diet-induced hyperlipidemia in rats. Sprague-Dawley rats were divided into four groups of seven: normal control, NC; high-fat diet control, HFC; high-fat diet–0.5% FRG, HF-FRGL; and high-fat diet–1% FRG, HF-FRGH. All rats were fed a high-fat diet for eight weeks, except those in the NC group, while rats in the FRG treatment groups received drinking water containing 0.5% or 1% FRG. After eight weeks of treatment, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) in the serum were measured. The concentration of the oxidative stress marker malondialdehyde (MDA), and activity of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in rat liver were evaluated. Histological analysis of the liver was performed using hematoxylin and eosin. The high-fat diet markedly increased serum levels of ALT, AST, TC, TG, and LDL-C and hepatic MDA levels, while administration of FRG to the hyperlipidemic rats resulted in a significant decline in the levels of these parameters. Furthermore, the decline in the levels of serum HDL-C and hepatic SOD, CAT, and GSH-Px induced by the high-fat diet was attenuated by FRG treatment. In addition, histopathological analysis of liver sections suggested that FRG treatment also provided protection against liver damage. These results suggested that FRG improved lipid profiles, inhibited lipid peroxidation, and played a protective role against liver injury in hyperlipidemic rats.

The effect of fermented red ginseng on depression is mediated by lipids.

OBJECTIVES: The cortico-limbic hypothalamic-pituitary-adrenal axis has emerged as an important area for the cause and treatment of depression. The primary aim of this study was to test the hypothesis that hormones, energy sources, and minerals have a causal relationship with depression. The secondary aim was to test whether consumption of fermented red ginseng (FRG) would influence that causal relationship. METHODS: For this study, 93 postmenopausal women were randomly divided into two groups. One group (49 women) was supplied with FRG capsules, and the other group (44 women) with placebo capsules, for 2 weeks. Both before and after the study, the participants filled out the Beck depression inventory questionnaire, and then blood samples were collected. The structural regression model was established. The causative latent variables were hormone (adrenocorticotropic hormone and cortisol), energy (low-density lipoprotein (LDL) cholesterol, total cholesterol, and blood glucose), mineral 1 (potassium, sodium, chloride, and iron), and mineral 2 (magnesium, calcium), and the resultant latent variables were cognitive depression (CD) and somatic depression. The goodness-of-fit statistics of the final model were good (root mean square error of approximation =0.033, comparative fit index =0.877, and Tucker-Lewis index =0.870). RESULTS: The structural regression path of the energy factor on CD showed a significant difference between the FRG group (0.259) and the placebo group (-0.201). The factor loadings of total cholesterol (1.236) and LDL cholesterol (1.000) on the energy factor were much higher than that of glucose (0.166). CONCLUSION: Based on the analysis used in this model, the effect of FRG consumption on CD occurred via the energy factor, which is mainly attributable to cholesterol.