Bioconversion, Pharmacokinetics, and Therapeutic Mechanisms of Ginsenoside Compound K and Its Analogues for Treating Metabolic Diseases.

Rare ginsenoside compound K (CK) is an intestinal microbial metabolite with a low natural abundance that is primarily produced by physicochemical processing, side chain modification, or metabolic transformation in the gut. Moreover, CK exhibits potent biological activity compared to primary ginsenosides, which has raised concerns in the field of ginseng research and development, as well as ginsenoside-related dietary supplements and natural products. Ginsenosides Rb1, Rb2, and Rc are generally used as a substrate to generate CK via several bioconversion processes. Current research shows that CK has a wide range of pharmacological actions, including boosting osteogenesis, lipid and glucose metabolism, lipid oxidation, insulin resistance, and anti-inflammatory and anti-apoptosis properties. Further research on the bioavailability and toxicology of CK can advance its medicinal application. The purpose of this review is to lay the groundwork for future clinical studies and the development of CK as a therapy for metabolic disorders. Furthermore, the toxicology and pharmacology of CK are investigated as well in this review. The findings indicate that CK primarily modulates signaling pathways associated with AMPK, SIRT1, PPARs, WNTs, and NF-kB. It also demonstrates a positive therapeutic effect of CK on non-alcoholic fatty liver disease (NAFLD), obesity, hyperlipidemia, diabetes, and its complications, as well as osteoporosis. Additionally, the analogues of CK showed more bioavailability, less toxicity, and more efficacy against disease states. Enhancing bioavailability and regulating hazardous variables are crucial for its use in clinical trials.

Multi-layered effects of Panax notoginseng on immune system.

Recent research has demonstrated the immunomodulatory potential of Panax notoginseng in the treatment of chronic inflammatory diseases and cerebral hemorrhage, suggesting its significance in clinical practice. Nevertheless, the complex immune activity of various components has hindered a comprehensive understanding of the immune-regulating properties of Panax notoginseng, impeding its broader utilization. This review evaluates the effect of Panax notoginseng to various types of white blood cells, elucidates the underlying mechanisms, and compares the immunomodulatory effects of different Panax notoginseng active fractions, aiming to provide the theory basis for future immunomodulatory investigation.

Ginsenoside CK cooperates with bone mesenchymal stem cells to enhance angiogenesis post-stroke via GLUT1 and HIF-1α/VEGF pathway.

The transplantation of bone marrow mesenchymal stem cells (MSCs) in stroke is hindered by the restricted rates of survival and differentiation. Ginsenoside compound K (CK), is reported to have a neuroprotective effect and regulate energy metabolism. We applied CK to investigate if CK could promote the survival of MSCs and differentiation into brain microvascular endothelial-like cells (BMECs), thereby alleviating stroke symptoms. Therefore, transwell and middle cerebral artery occlusion (MCAO) models were used to mimic oxygen and glucose deprivation (OGD) in vitro and in vivo, respectively. Our results demonstrated that CK had a good affinity for GLUT1, which increased the expression of GLUT1 and the production of ATP, facilitated the proliferation and migration of MSCs, and activated the HIF-1α/VEGF signaling pathway to promote MSC differentiation. Moreover, CK cooperated with MSCs to protect BMECs, promote angiogenesis and vascular density, enhance neuronal and astrocytic proliferation, thereby reducing infarct volume and consequently improving neurobehavioral outcomes. These results suggest that the synergistic effects of CK and MSCs could potentially be a promising strategy for stroke.

Ginsenoside compound K acts via LRP1 to alleviate Amyloid ß42-induced neuroinflammation in microglia by suppressing NF-κB.

BACKGROUND: Alzheimer's disease (AD), has caused a mass of disability and mortality in elder populations, which increases global health burden. There are still limited effective disease-modifying drugs. Alleviating microglia-evoked neuroinflammation has become a promising treatment strategy for AD. Ginsenoside Compound K has been demonstrated to exhibit anti-inflammatory and neuroprotective benefits. Here we measured the effects of Ginsenoside Compound K in inhibiting amyloid-induced microglia inflammation and the possible molecular mechanisms and target of action in vitro. METHODS: The cytotoxicity of all chemical reagents on BV2 cells were evaluated using the MTT assay. qRT-PCR and ELISA were carried out to detect the inflammatory cytokines levels. Western blot was utilized to determine the effect of Ginsenoside Compound K on the nuclear factor-κB (NF-κB) p65 nuclear translocation. Antagonist Receptor Associated Protein (RAP) was used to verify the engagement of low-density lipoprotein receptor-related protein 1(LRP1). RESULTS: Ginsenoside Compound K diminished inflammatory cytokine production and reversed NF-κB p65 nuclear translocation induced by Aß42 oligomers. LRP1 expression was up-regulated by Ginsenoside Compound K. When LRP1 was blocked by antagonist RAP, the protective effect of Ginsenoside Compound K was massively eliminated. CONCLUSION: These observations provide evidence for anti-inflammatory effect of Ginsenoside Compound K through NF-κB pathway via LRP1 activation, and support further evaluation of Ginsenoside Compound K as a potential effective modulator for AD.

Ginsenoside Compound K Ameliorates Development of Diabetic Kidney Disease through Inhibiting TLR4 Activation Induced by Microbially Produced Imidazole Propionate.

Diabetic kidney disease (DKD) is a common and devastating complication in diabetic patients, which is recognized as a large and growing problem leading to end-stage kidney disease. As dietary-mediated therapies are gradually becoming more acceptable to patients with DKD, we planned to find active compounds on preventing DKD progression from dietary material. The present paper reports the renoprotective properties and underlying mechanisms of ginsenoside compound K (CK), a major metabolite in serum after oral administration of ginseng. CK supplementation for 16 weeks could improve urine microalbumin, the ratio of urinary albumin/creatinine and renal morphological abnormal changes in db/db mice. In addition, CK supplementation reshaped the gut microbiota by decreasing the contents of Bacteroides and Paraprevotella and increasing the contents of Lactobacillu and Akkermansia at the genus level, as well as reduced histidine-derived microbial metabolite imidazole propionate (IMP) in the serum. We first found that IMP played a significant role in the progression of DKD through activating toll-like receptor 4 (TLR4). We also confirmed CK supplementation can down-regulate IMP-induced protein expression of the TLR4 signaling pathway in vivo and in vitro. This study suggests that dietary CK could offer a better health benefit in the early intervention of DKD. From a nutrition perspective, CK or dietary material containing CK can possibly be developed as new adjuvant therapy products for DKD.

Ginsenoside CK inhibits obese insulin resistance by activating PPARγ to interfere with macrophage activation.

Obesity is often accompanied by chronic low-grade inflammation, which aggravates the disorder of lipid metabolism and leads to insulin resistance (IR). Macrophage activation plays an important role in inflammation. Ginsenoside Compound K (CK) is an active metabolite of ginsenoside Rb1, which is adopting to an anti-inflammatory effective substance. In order to clarify the mechanism of ginsenoside CK on the regulation of macrophage activation in adipose tissue, the macrophage model was incubated with the supernatant of hypertrophic adipocytes, and the co-culture models of Raw264.7 and 3T3-L1 were established. The levels of related cytokines, macrophage polarization and protein expression in inflammatory signaling pathway were measured. The results showed that ginsenoside CK significantly inhibited the increase of MCP-1 and TNF-α induced by the supernatant of hypertrophic adipocytes, promoted the expression of IL-10, inhibited the activation of inflammatory macrophages and increased the expression of anti-inflammatory macrophages. Similarly, ginsenoside CK inhibited the migration of Raw264.7, blocked the activation of NF-κB, and up-regulated the expression of PPARγ. In addition, ginsenoside CK also promotes the expression of IRS-1 in insulin signal pathway. The experimental results proved that ginsenoside CK plays a crucial role in alleviating inflammation and insulin resistance in obesity, and inhibits macrophage activation through the key protein PPARγ.

Evaluating the protective effects of individual or combined ginsenoside compound K and the downregulation of soluble epoxide hydrolase expression against sodium valproate-induced liver cell damage.

Sodium valproate (SVP) is one of the most commonly prescribed antiepileptic drugs. However, SVP is known to induce hepatotoxicity, which limits its clinical application for treating various neurological disorders. Previously, we found that ginsenoside compound K (G-CK) demonstrated protective effects against SVP-induced hepatotoxicity by mitigating oxidative stress and mitochondrial damage, as well as downregulating the expression of soluble epoxide hydrolase (sEH) in rats. This study aimed to assess the effect of G-CK on SVP-induced cytotoxicity in human hepatocytes (L02 cell line), as well as the effect of the downregulation of sEH expression on both the hepatotoxicity of SVP and the hepatoprotective effects of G-CK. We observed that G-CK significantly ameliorated the decrease of cell viability, elevated ALT, AST and ALP activities, significant oxidative stress, and loss of mitochondrial membrane potential induced by SVP in L02 cells. G-CK also inhibited the SVP-mediated upregulation of sEH expression. Transfection of the L02 cells with siRNA-sEH led to a partial improvement in the L02 cytotoxicity caused by SVP by mitigating cellular oxidative stress without recovering the reduced mitochondrial membrane potential. Furthermore, the combination of siRNA-sEH and G-CK had better inhibitory effects on the SVP-induced changes of all detection indices except mitochondrial membrane potential than G-CK alone. Together, our results demonstrated that the combination of siRNA-sEH and G-CK better suppressed the SVP-induced cytotoxicity in L02 cells compared to either G-CK or siRNA-sEH alone.

Ginsenoside compound K- a potential drug for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease, if prescription of effective delayed, the articular disturbances may lead to disability. Ginsenoside compound K (GCK) is the main degradation product of oral ginsenosides in the human intestine. Numerous researches in vitro and in vivo have recorded the anti-arthritic effect of GCK, we discuss the mechanisms from the following three aspects, including anti-inflammatory, immune-regulatory, and bone-protective, respectively, in this review, and the anti-arthritic mechanism of GCK may be related to the effect on TNF-α-TNFR2, glucocorticoid receptor (GR) and ß-arrestin1/2. We also describe the anti-anemia effect of GCK to open the possibility that GCK can be used as an effective disease-modifying anti-rheumatic drug (DMARD).

Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis.

Atherosclerosis, a chronic multifactorial disease, is closely related to the development of cardiovascular diseases and is one of the predominant causes of death worldwide. Normal vascular endothelial cells play an important role in maintaining vascular homeostasis and inhibiting atherosclerosis by regulating vascular tension, preventing thrombosis and regulating inflammation. Currently, accumulating evidence has revealed that endothelial cell apoptosis is the first step of atherosclerosis. Excess apoptosis of endothelial cells induced by risk factors for atherosclerosis is a preliminary event in atherosclerosis development and might be a target for preventing and treating atherosclerosis. Interestingly, accumulating evidence shows that natural medicines have great potential to treat atherosclerosis by inhibiting endothelial cell apoptosis. Therefore, this paper reviewed current studies on the inhibitory effect of natural medicines on endothelial cell apoptosis and summarized the risk factors that may induce endothelial cell apoptosis, including oxidized low-density lipoprotein (ox-LDL), reactive oxygen species (ROS), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), homocysteine (Hcy) and lipopolysaccharide (LPS). We expect this review to highlight the importance of natural medicines, including extracts and monomers, in the treatment of atherosclerosis by inhibiting endothelial cell apoptosis and provide a foundation for the development of potential antiatherosclerotic drugs from natural medicines.

In vitro modulatory effects of ginsenoside compound K, 20(S)-protopanaxadiol and 20(S)-protopanaxatriol on uridine 5'-diphospho-glucuronosyltransferase activity and expression.

We explored the inhibitory effect of ginsenoside compound K (CK), 20(S)-protopanaxadiol (PPD), and 20(S)-protopanaxatriol (PPT) on six uridine 5'-diphospho-glucuronosyltransferase (UGT) enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) activities in human liver microsomes (HLMs) and 10 UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17) activities in recombinant UGT isoforms.PPD was a potent inhibitor of UGT1A3 activity with half-maximal inhibitory concentration values of 5.62 and 3.38 µM in HLMs and recombinant UGT1A3, respectively. UGT1A3 inhibition by CK and PPD was competitive with inhibitory constant (Ki) values of 17.4 and 1.21 µM, respectively, and inhibition by PPT was non-competitive with a Ki value of 8.07 µM in HLMs. PPD exhibited more than 3.4-fold selectivity for UGT1A3 inhibition compared with other UGT isoforms inhibition, while CK and PPT showed more than 2.16- and 2.21-fold selectivity, respectively.PPD did not significantly increase the mRNA expression of UGT1A1, 1A3, 1A4, 1A9, and 2B7 in hepatocytes.Given the low plasma concentrations of PPD in healthy human subjects and the absence of induction potential on UGT isoforms, we conclude that PPD cause no pharmacokinetic interactions with other co-administered drugs metabolised by UGT1A3.

Polymorphic Characterization, Pharmacokinetics, and Anti-Inflammatory Activity of Ginsenoside Compound K Polymorphs.

Polymorphism exhibits different physicochemical properties, which can impact the bioavailability and bioactivity of solid drugs. This study focused on identifying the polymorphs of ginsenoside compound K (CK) and studying their different behaviors in pharmacokinetics (PK) and pharmacodynamics (PD). Four CK polymorphs (form I, II, III, and IV) from organic solvents were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD). A feasible LC-MS/MS method was exploited to determine the PK parameters. Form II displayed the most exposure, followed by form I, III, and IV. Notably, all forms showed sex dimorphism, and the bioavailability in the female group was about two-fold higher than in the male group. The PD properties were investigated in carrageenan-induced acute paw inflammation, and form II at 20 mg/kg showed significant inhibition of edema by 42.7%. This study clarified the polymorphic, PK, and PD characters of four crystal forms of CK, and the data suggested that form II had the best efficacy for drug development.

[The Effects of Ginsenoside Compound K on PDGF-BB-Induced PASMCs Proliferation and Phenotypic Conversion of Pulmonary Arterial Smooth Muscle Cells].

OBJECTIVE: To explore the inhibitory effects of ginsenoside compound K (CK) on pulmonary arterial smooth muscle cells (PASMCs) proliferation and phenotypic conversion in vitro and investigate its related mechanisms. METHODS: PASMCs cultured in vitro were examined in the study. They were induced with platelet-derived growth factor-BB (PDGF-BB) and then treated with CK. The cells were randomly assigned to the control group (receiving no treatment), the model group (PDGF-BB, 20 ng/mL), and the intervention group (20 ng/mL PDGF-BB+5 µmol/L CK). The cell proliferation was measured by CCK-8 assay (on the basis of the above group assignment, concentrations of CK was set at 1, 3, and 5 µmol/L in the intervention group, and the drug group was added, receiving 1, 3, and 5 µmol/L CK, respectively). Cell cycle and apoptosis were examined by flow cytometry. The levels of mRNA and proteins of α-smooth muscle actin ( α-SMA) and smooth muscle 22α ( SM22 α), markers of phenotypic conversion, were detected by quantitative real-time PCR and Western blot. The levels of protein expression related to Wnt/ß-catenin signaling pathway were examined by Western blot. RESULTS: Compared with the model group, CK significantly inhibited PDGF-BB-induced proliferation of PASMCs in a dose-dependent way. The results of 5 µmol/L CK intervention were not significantly different from that of the control group ( P>0.05). Hence, 5 µmol/L CK was chosen for subsequent experiments. Separate treatment of PASMCs with CK at doses of 1, 3, and 5 µmol/L did not reveal any cytotoxicity to PASMCs ( P>0.05). CK also arrested the cell cycle of PASMCs at the G 0/G 1 phase, promoted the apoptosis of PASMCs, and reversed the mRNA and protein expression of α-SMA and SM22 α ( P<0.01). In addition, CK down-regulated the expressions of cyclin D1 and ß-catenin, while it up-regulated the protein expressions of phosphorylated glycogen synthase kinase-3ß (pGSK-3ß)/glycogen synthase kinase-3ß (GSK-3ß) ( P<0.01). CONCLUSION: CK was capable of inhibiting the abnormal proliferation of PASMCs and reversing the phenotypic conversion, and its acting mechanism may be related to the Wnt/ß-catenin signaling pathway, suggesting the therapeutic potential of CK in controlling pulmonary arterial hypertension.

Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis.

Sodium valproate (SVP) is a first-line treatment for various forms of epilepsy; however, it can cause severe liver injury. Ginsenoside compound K (G-CK) is the main active ingredient of the traditional herbal medicine ginseng. According to our previous research, SVP-induced elevation of ALT and AST levels, as well as pathological changes of liver tissue, was believed to be significantly reversed by G-CK in LiCl-pilocarpine induced epileptic rats. Thus, we aimed to evaluate the protective effect of G-CK on hepatotoxicity caused by SVP. The rats treated with SVP showed liver injury with evident increases in hepatic index, transaminases activity, alkaline phosphatase level, hepatic triglyceride and lipid peroxidation; significant decreases in plasma albumin level and antioxidant capacity; and obvious changes in histopathological and subcellular structures. All of these changes could be mitigated by co-administration with G-CK. Proteomic analysis indicated that hepcidin, soluble epoxide hydrolase (sEH, UniProt ID P80299), and the peroxisome pathway were involved in the hepatoprotective effect of G-CK. Changes in protein expression of hepcidin and sEH were verified by ELISA and Western blot analysis, respectively. In addition, we observed that the hepatic iron rose in SVP group and decreased in the combination group. In summary, our findings demonstrate the clear hepatoprotective effect of G-CK against SVP-induced hepatotoxicity through the antioxidant effect, regulation of peroxisome pathway relying on sEH (P80299) downregulation, as well as regulation of iron homeostasis dependent on hepcidin upregulation.

Ginsenoside compound K ameliorates imiquimod-induced psoriasis-like dermatitis through inhibiting REG3A/RegIIIγ expression in keratinocytes.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation. Ginsenoside compound K (CK), a bioactive metabolite of ginseng, modulates various skin disorders with an impact on keratinocyte biology. However, the effect of Ginsenoside CK in psoriasis has not been explored. OBJECTIVE: Our aim was to investigate whether ginsenoside CK could affect the homeostasis of keratinocytes and their expression of psoriasis-associated antimicrobial protein regenerating islet-derived protein 3-alpha (REG3A) and its murine ortholog RegIIIγ. We further explored the therapeutic potential of ginsenoside CK in imiquimod (IMQ)-induced psoriasis-like dermatitis. METHODS: The effects of ginsenoside CK in cell growth and apoptosis of human keratinocytes were measured by MTT assay and flow cytometry, respectively. Bax levels were evaluated by Western blot in HaCaT cells following ginsenoside CK stimulation. REG3A levels were assessed by RT-PCR and Western blot in human keratinocytes following interleukin (IL)-36γ and ginsenoside CK co-simulation. Utilizing IMQ-induced psoriasis mouse model, the therapeutic effects of 0.1% and 1% ginsenoside CK cream were assessed by skin thicknesses and histological examinations, and RegIIIγ level in the lesional skin was detected by Western blot and immunofluorescence. RESULTS: Ginsenoside CK prohibited human keratinocyte proliferation but did not affect their apoptosis. Moreover, it inhibited IL-36γ-induced REG3A expression in HaCaT cells. Ginsenoside CK alleviated imiquimod-induced psoriasis-like hyperkeratosis and reduced RegIIIγ expression in the keratinocytes from lesional skin. CONCLUSION: Ginsenoside CK ameliorated IMQ-induced psoriasis-like dermatitis possibly through inhibiting REG3A/RegIIIγ expression in keratinocytes, which highlighted a therapeutic potential of ginsenoside CK in psoriasis.

Synthesis and biological evaluation of Ginsenoside Compound K analogues as a novel class of anti-asthmatic agents.

Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value = 1237.11 ±â€¯106.28, 975.82 ±â€¯160.32, 1136.96 ±â€¯121.85, 1191.08 ±â€¯107.59 and 1258.27 ±â€¯148.70 ng/mL, respectively) in comparison with CK (1501.85 ±â€¯184.66 ng/mL). These potent compounds could serve as leads for further development.

Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aß deposition.

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-ß1-42 peptides (Aß1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aß1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3ß (pSer9-GSK3ß) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aß1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3ß and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aß1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3ß and IDE.

Characterization of ginsenoside compound K metabolites in rat urine and feces by ultra-performance liquid chromatography with electrospray ionization quadrupole time-of-flight tandem mass spectrometry.

Ginsenoside compound K (CK) is an active metabolite of ginsenoside and has been shown to have ameliorative property in various diseases. However, the detailed in vivo metabolism of this compound has rarely been reported. In the present study, a method using liquid chromatography quadrupole time-of-flight tandem mass spectrometry together with multiple data processing techniques, including extracted ion chromatogram, multiple mass defect filter and MS/MS scanning, was developed to detect and characterize the metabolites of CK in rat urine and feces. After oral administration of CK at a dose of 50 mg/kg, urine and feces were collected for a period of time and subjected to a series of pretreatment. A total of 12 metabolites were tentatively or conclusively identified, comprising 11 phase I metabolites and a phase II metabolite. Metabolic pathways of CK has been proposed, including oxidation, deglycosylation, deglycosylation with sequential oxidation and dehydrogenation and deglycosylation with sequential glucuronidation. Relative quantitative analyses suggested that deglycosylation was the main metabolic pathway. The result could offer insights for better understanding of the mechanism of its pharmacological activities.

Ginsenoside metabolite compound K exerts anti-inflammatory and analgesic effects via downregulating COX2.

OBJECTIVE: The present study aimed to evaluate the anti-inflammatory and analgesic activities of the ginsenoside metabolite compound K (CK) and its mechanisms. METHODS: Mice model of xylene-induced ear swelling and rat model of carrageenan-induced paw swelling were used to evaluate the effect of CK on acute inflammation. The analgesic effect of CK was evaluated on heat-, acetic acid-, and carrageenan-induced hyperalgesia. The levels of prostaglandin E2 (PGE2), cyclooxygenase-1 (COX-1), and COX-2 in carrageenan-induced rat paw swelling and gastric mucosa were detected by enzyme-linked immunosorbent assay (ELISA). COX-1 and COX-2 expressions in carrageenan-induced rat paw swelling and gastric mucosa were detected by western blotting. In vitro effect of CK (10-9, 10-8, 10-7, 10-6, 10-5 M) on COX-1 and COX-2 activities was evaluated by measuring the production of 6-keto-PGF1α and PGE2 in rat peritoneal macrophages. RESULTS: CK at doses of 7, 14, 28, 56, 112, and 224 mg/kg alleviated xylene-induced ear oedema, whereas CK at 40, 80, and 160 mg/kg alleviated carrageenan-induced paw oedema. CK at 224 mg/kg showed an analgesic effect against acetic acid-induced pain. CK at 40, 80, and 160 mg/kg significantly increased rat inflammatory pain threshold, but had no effect on heat-induced pain threshold. CK at 10, 20, 40, 80, and 160 mg/kg reduced PGE2 level in the paw tissue, but showed no effect on that in the gastric mucosa. CK at 20, 40, 80, and 160 mg/kg decreased COX-2 expression in the paw tissue and gastric mucosa, but exhibited no effect on COX-1 expression or on COX-1 and COX-2 activities. CONCLUSION: CK exerted anti-inflammatory and analgesic effects, possibly by reducing the catalytic synthesis of PGE2 via downregulation of COX-2 expression.

Ginsenoside compound-K inhibits the activity of B cells through inducing IgD-B cell receptor endocytosis in mice with collagen-induced arthritis.

Previously, ginsenoside metabolite compound K (C-K) was able to reduce B cell proliferation and serum anti-type II collagen (anti-CII) antibody to normal levels in mice with collagen-induced arthritis (CIA); however, the mechanism by which C-K restores B cell balance is unclear. In the present work, C-K treatment not only alleviated the polyarthritis index, swollen joint count, pathological scores of spleen and joints, spleen index, B cell proliferation and the level of serum antibodies (IgG1, IgG2a and anti-collagen II), but C-K treatment also restored B cell subsets including regulatory B cells, plasma cells, memory B cells, mature B cells, and follicular B cells in CIA mice. Interestingly, C-K did not change the expression level of immunoglobulin D-type B-cell receptor (IgD-BCR) but promoted IgD-BCR endocytosis. C-K treatment enhanced ß-arrestin1 expression, facilitating the colocalization between IgD and ß-arrestin1, as well as colocalization between IgD and adaptor protein 2 (AP2). Inhibition of the ß-arrestin1-AP2 interaction with barbadin significantly reduced the ability of C-K to attenuate IgD-BCR plasma membrane localization. These results taken together depict that C-K ameliorates CIA in part by inhibiting B cell activation through the triggering of IgD-BCR internalization in a ß-arrestin1-AP2 dependent manner.

Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator.

Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity.