ginsenoside-m1 and Disease-Models--Animal

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disease affecting women of reproductive age. Due to its complex aetiology, there is no currently effective cure for PCOS. Brown adipose tissue (BAT) activity is significantly decreased in PCOS patients, and BAT activation has beneficial effects in animal models of PCOS. Here, we investigated the effect of ginsenoside compound K (CK) in an animal model of PCOS and its mechanism of BAT activation.. Primary brown adipocytes, Db/Db mice and dehydroepiandrosterone (DHEA)-induced PCOS rats were used. The core body temperature, oxygen consumption, energy metabolism related gene and protein expression were assessed to identify the effect of CK on overall energy metabolism. Oestrous cycle, serum sex hormone, ovarian steroidogenic enzyme gene expression and ovarian morphology were also evaluated following CK treatment.. Our results indicated that CK treatment could significantly protect against body weight gain in Db/Db mice via BAT activation. Furthermore, we found that CK treatment could normalize hyperandrogenism, oestrous cyclicity, normalize steroidogenic enzyme expression and decrease the number of cystic follicles in PCOS rats. Interestingly, as a potential endocrine intermediate, C-X-C motif chemokine ligand-14 protein (CXCL14) was significantly up-regulated following CK administration. In addition, exogenous CXC14 supplementation was found to reverse DHEA-induced PCOS in a phenotypically similar manner to CK treatment.. In summary, CK treatment significantly activates BAT, increases CXCL14 expression and ameliorates PCOS. These findings suggest that CK might be a potential drug candidate for PCOS treatment.

Topics: Adipose Tissue, Brown; Animals; Dehydroepiandrosterone; Disease Models, Animal; Female; Ginsenosides; Humans; Mice; Polycystic Ovary Syndrome; Rats

IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice. The potential mechanism for CK includes 1) inhibiting the activation of NLRP3 inflammasome in renal tissues, macrophages and bone marrow-derived dendritic cells, 2) enhancing the induction of autophagy through increased SIRT1 expression, and 3) eliciting autophagy-mediated NLRP3 inflammasome inhibition. The results support CK as a drug candidate for IgAN.

Topics: Animals; Autophagy; Cell Line; Dendritic Cells; Disease Models, Animal; Ginsenosides; Glomerulonephritis, IGA; Humans; Inflammasomes; Kidney Glomerulus; Macrophages; Mice; Mice, Inbred Strains; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Primary Cell Culture; Signal Transduction; Sirtuin 1

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 ± 106.28, 975.82 ± 160.32, 1136.96 ± 121.85, 1191.08 ± 107.59 and 1258.27 ± 148.70 ng/mL, respectively) in comparison with CK (1501.85 ± 184.66 ng/mL). These potent compounds could serve as leads for further development.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Disease Models, Animal; Dose-Response Relationship, Drug; Ginsenosides; Immunoglobulin E; Mice; Molecular Conformation; Ovalbumin; Structure-Activity Relationship

Chemoresistance is a major clinical problem compromising the successful treatment of cancer. One exciting approach is the eradication of cancer stem/tumor-initiating cells (jointly CSCs), which account for tumor initiation, progression, and drug resistance. Here we show for the first time, with mechanism-based evidence, that ginsenoside-Rb1, a natural saponin isolated from the rhizome of Panax quinquefolius and notoginseng, exhibits potent cytotoxicity on CSCs. Rb1 and its metabolite compound K could effectively suppress CSC self-renewal without regrowth. Rb1 and compound K treatment also sensitized the CSCs to clinically relevant doses of cisplatin and paclitaxel. These effects were associated with the Wnt/β-catenin signaling pathway by downregulating β-catenin/T-cell factor-dependent transcription and expression of its target genes ATP-binding cassette G2 and P-glycoprotein. We also identified reversal of epithelial-to-mesenchymal transition as a new player in the Rb1 and compound K-mediated inhibition of CSCs. Rb1 and compound K treatment also inhibited the self-renewal of CSCs derived from ovarian carcinoma patients as well as in xenograft tumor model. Moreover, we did not observe toxicity in response to doses of Rb1 and compound K that produced an anti-CSC effect. Therefore, Rb1 should be explored further as a promising nutraceutical prototype of treating refractory tumors.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Ginsenosides; Humans; Mice; Mitogen-Activated Protein Kinases; Neoplastic Stem Cells; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease, which has no standard treatment available. Panax notoginseng saponines (PNS) have recently been reported to protect liver against hepatocyte injury induced by ethanol or high fat diet (HFD) in rats. Compound K and ginsenoside Rh1 are the main metabolites of PNS. In this study, we evaluated the effects of CK and Rh1 on NAFLD. Rats fed HFD showed significant elevations in liver function markers, lipids, glucose tolerance, and insulin resistance. Treatment with CK or Rh1 either alone or in combination dramatically ameliorated the liver function impairment induced by HFD. Histologically, CK and Rh1 significantly reversed HFD-induced hepatocyte injury and liver fibrosis. In vitro experiments demonstrated that treatment with CK or Rh1 alone or in combination markedly induced cell apoptosis, and inhibited cell proliferation and activation in HSC-T6 cells. Additionally, CK and Rh1, either alone or in combination, also repressed the expression of fibrotic factors TIMP-1, PC-I, and PC-III. Taken together, our results demonstrate that CK and Rh1 have positive effects on NAFLD via the anti-fibrotic and hepatoprotective activity.

Topics: Animals; Apoptosis; Cell Line; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Ginsenosides; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Phosphatidylcholines; Rats; Tissue Inhibitor of Metalloproteinase-1

Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K.. We treated the atherosclerotic model animals (apoE(-/-) mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments.. Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K.. These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Caspase 1; Cholesterol; Cytokines; Disease Models, Animal; Fatty Liver; Foam Cells; Ginsenosides; Liver X Receptors; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Transcription Factor RelA; Triglycerides

This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)).. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K.. Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells.. FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Fermentation; Ginsenosides; Hep G2 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Liver; Male; Panax; Phosphorylation; Phytotherapy; Plant Extracts; Rats, Wistar

To investigate the effect of ginseng-derived compound K (C-K) on apoptosis, immunosuppressive activity, and pro-inflammatory cytokine production of myeloid-derived suppressor cells (MDSCs) from mice bearing colorectal cancer xenograft.. Flow-sorted bone marrow MDSCs from Balb/c mice bearing CT26 tumor xenograft were treated with either C-K or PBS for 96 h and examined for apoptosis with Annexin V/7-AAD, Cox-2 and Arg-1 expressions using qRT-PCR, and supernatant IL-1β, IL-6, and IL-17 levels with ELISA. C-K- or PBS-treated MDSCs were subcutaneously implanted along with CT26 tumor cells in WT Balb/c mice, and the tumor size and morphology were evaluated 21 days later.. C-K treatment significantly increased the percentages of early and late apoptotic MDSCs in vitro (P<0.01 and P<0.05, respectively), decreased the expressions of immunosuppression-related genes Cox-2 (P<0.05) and Arg-1 (P<0.01), and suppressed the production of IL-1β (P<0.05), IL-6 (P<0.01), and IL-17 (P<0.05) by the MDSCs . Compared with PBS-pre-treated cells, C-K-pretreated MDSCs showed significantly attenuated activity in promoting CT26 tumor growth in mice (P<0.01).. C-K can suppress the immunosuppresive effect of MDSCs to inhibit tumor cell proliferation in mice, which suggests a new strategy of tumor therapy by targeting MDSCs.

Topics: Animals; Apoptosis; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Ginsenosides; Humans; Immunosuppression Therapy; Interleukin-17; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred BALB C; Myeloid Cells; Neoplasm Transplantation

Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L.. Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models.. Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC).. Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic.

Topics: Animals; Body Composition; Body Weight; Chromatography, Liquid; Diacylglycerol O-Acyltransferase; Disease Models, Animal; Dogs; Enteroendocrine Cells; Feces; Gastrointestinal Tract; Ginsenosides; Hormones; HT29 Cells; Humans; Immunohistochemistry; Lactones; Male; Mice; Mice, Inbred C57BL; Orlistat; Postprandial Period; Tandem Mass Spectrometry; Triglycerides

Chemotherapy frequently results in neurocognitive deficits that include impaired learning and memory. Thus, it is important to prevent or ameliorate the persistence of cognitive impairment. Compound K was employed to examine the ameliorating effect on chronic treatment with cyclophosphamide. Eight week-old ICR mice were given 80 mg/kg cyclophosphamide, cyclophosphamide combined with compound K (2.5, 5 and 10 mg/kg) or saline injections once per week for 4 weeks. Passive avoidance test and Y maze were used to evaluate memory and learning ability. Immunohistochemical staining for progenitor cell and immature neurons was used to assess changes in neurogenesis. Compound K (10 mg/kg) is able to ameliorate the decrease of neurogenesis in the hippocampus caused by cyclophosphamide. These results suggest that compound K might be a potential strategy to ameliorate or repair the disrupted hippocampal neurogenesis induced by the side effect of chemotherapy agent.

Topics: Animals; Antineoplastic Agents; Cognition Disorders; Cyclophosphamide; Disease Models, Animal; Ginsenosides; Hippocampus; Male; Maze Learning; Memory; Mice; Mice, Inbred ICR; Neurons; Stem Cells; Time Factors

The antipruritic and vascular permeability-inhibitory effects of ginsenoside Rb1, a main component of ginseng frequently used as a traditional medicine in Asian countries, and its metabolite compound K by intestinal microflora were investigated in scratching behavior animal models induced by compound 48/80, substance P, and histamine. Ginsenoside Rb1 and compound K orally administered 1 and 6 h before the treatment of compound 48/80 showed antipruritic effect. These ginsenosides administered at a dose of 50 mg/kg 6 h before the treatment of compound 48/80 inhibited scratching behaviors by 51% and 64%, respectively, compared with that of the control. These ginsenosides also inhibited the vascular permeability of skin. Compound K intraperitoneally administered 1 h before the treatment of compound 48/80 potently inhibited the scratching behaviors induced by compound 48/80. However, intraperitoneally administered ginsenoside Rb1 did not inhibit scratching behaviors. Compound K inhibited compound 48/80-, substance P-, and histamine-induced scratching behaviors, with 50% inhibitory doses of 4.2, 5.9, and 3.8 mg/kg, respectively, and vascular permeability, with 50% inhibitory doses of 5.8, 6.8, and 4.1 mg/kg, respectively. These results suggest that ginsenoside Rb1 and its metabolite compound K by intestinal microflora can improve scratching behaviors.

Topics: Animals; Antipruritics; Behavior, Animal; Capillary Permeability; Disease Models, Animal; Ginsenosides; Histamine; Inhibitory Concentration 50; Male; Mice; p-Methoxy-N-methylphenethylamine; Phthalazines; Pruritus; Substance P; Time Factors