Total saponins of Panax notoginseng protected rabbit iliac artery against balloon endothelial denudation injury.
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AIM: To investigate whether total Panax notoginseng saponins (PNS) could protect endothelium of rabbit iliac artery against balloon endothelial denudation (BED) injury. METHODS: The morphology changes of the endothelium were observed with scanning electron microscope (SEM) and hematoxylin and eosin stain after BED of rabbit iliac artery at 0, 4, 6, and 8 week respectively. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) was also determined by immunohistochemistry. PNS 10, 30, and 50 mg/kg were administered iv per day from 2 d before to 4 weeks after operation. RESULTS: The endothelium was denudated completely after BED. At the 4th week the endothelium was repaired in some degree, then recovered gradually at 6 and 8 week. The degree of intimal thickening at 4 week was significantly greater than that at 0, 6, or 8 week. The sequence of VEGF or MMP-2 staining from strong to weak was 4, 6, 0, 8 week, and normal control. However at 4 week, endothelial regeneration in PNS 30 and 50 mg/kg groups was significantly faster than that in saline group. The intimal thickness was significantly decreased and expressions of VEGF and MMP-2 were both down-regulated in PNS 30 or 50 mg/kg groups compared with saline control group. CONCLUSION: PNS promoted the endothelial regeneration and reduced ECM thickening, which was related to regulation of the expression of VEGF and MMP-2. PNS may have sustained antirestenotic effect after BED. (+info)
Ginsenosides regulate ligand-gated ion channels from the outside.
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Treatment with ginsenosides, the major active ingredients of Panax ginseng, produces a variety of physiological effects on the central and peripheral nervous systems. Ginsenosides inhibit various types of ligand-gated ion channel but it is not clear whether they act from within or outside the cell since they are somewhat membrane-permeable. In the present study, we used the Xenopus oocyte gene expression system to determine from which side of the cell membrane the ginsenoside Rg3 (Rg3), and M4, a ginsenoside metabolite, act to regulate ligand-gated ion channel activity. Ligand-gated ion currents were measured using the two-electrode voltage clamp technique. Rg3 and M4 inhibited 5-HT3A and a3b4 nACh receptor-mediated ion currents when present outside of the cell but not when injected intracellularly. We also examined the effect of these agents on oocytes expressing the gustatory cGMP-gated ion channel, which is known to have a cGMP binding site on the intracellular side of the plasma membrane and is only activated by cytosolic cGMP. Rg3 inhibited cGMP-gated ion currents when applied extracellularly or to an outside-out patch clamp, but not when injected into the cytosol or when using an excised inside-out patch clamp. These results indicate that Rg3 and M4 regulate ligand-gated ion channel activity from the extracellular side. (+info)
The inhibitory effect of intestinal bacterial metabolite of ginsenosides on CYP3A activity.
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The intestinal bacterial metabolites of ginsenosides are responsible for the main pharmacological activities of ginseng. The purpose of this study was to find whether these metabolites influence hepatic metabolic enzymes and to predict the potential for ginseng-prescription drug interactions. Utilizing the probe reaction of CYP3A activity, testosterone 6beta-hydroxylation, the effects of derivatives of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol families on CYP3A activity in rat liver microsomes were assayed. Our results showed that ginsenosides from the 20(S)-protopanaxadiol and 20(S)-protopanaxatriol family including Rb1, Rb2, Rc, Compound-K, Re, and Rg1 had no inhibitory effect, whereas Rg2, 20(S)-panaxatriol and 20(S)-protopanaxatriol exhibited competitive inhibitory activity against CYP3A activity in these microsomes with the inhibition constants (Ki) of 86.4+/-0.8 microM, 1.7+/-0.1 microM, and 3.2+/-0.2 microM, respectively. This finding demonstrates that differences in their chemical structure might influence the effects of ginsenosides on CYP3A activity and that ginseng-derived products might have potential for significant ginseng-drug interactions. (+info)
Metabolic activities of ginsenoside Rb1, baicalin, glycyrrhizin and geniposide to their bioactive compounds by human intestinal microflora.
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To evaluate the pharmacological actions of herbal medicines, metabolic activities of herbal medicine components, ginsenoside Rb1, glycyrrhizin, geniposide and baicalin to their bioactive compounds compound K, 18beta-glycyrrhetic acid, genipin and baicalein by fecal specimens were measured. Their metabolic activities were 646.1+/-591.4, 29.4+/-51.7, 926.3+/-569.6 and 3884.6+/-1400.1 micromol/h/g, respectively. The profiles of these metabolic activities of baicalin and ginsenoside Rb1 were not significantly different to those of water extracts of Scutellariae Radix and Ginseng Radix. None of the metabolic activities tested were different between males and females, or between ages. However, the difference in these metabolic activities in individuals was significant. These results suggest that the human intestinal microflora enzymes that convert herbal components to their bioactive compounds may be used as selection markers of responders to traditional medicines. (+info)
Antitumor promotional effects of a novel intestinal bacterial metabolite (IH-901) derived from the protopanaxadiol-type ginsenosides in mouse skin.
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Epidemiological studies have demonstrated that ginseng intake decreases the risk of cancer. Ginseng saponins (ginsenosides) have been regarded as principal components responsible for the majority of pharmacological activities exerted by ginseng. IH-901 [20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol], an intestinal bacterial metabolite derived from protopanaxadiol-type saponins of Panax ginseng C.A. Meyer, has been reported to possess antitumor effects, including inhibition of invasion, metastasis and angiogenesis and induction of tumor cell apoptosis. Tumor promotion often accompanies an elevated ornithine decarboxylase (ODC) activity, acute inflammation and induction of cyclooxygenase-2 (COX-2) activity. Here we examined the effects of IH-901 on tumor promotion and related molecular events in mouse skin in vivo. Mouse ear edema induced by the prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was repressed by IH-901 pre-treatment in a dose-dependent manner. Topical application of IH-901 onto shaven backs of female ICR mice led to the inhibition of TPA-induced expression of COX-2 and production of prostaglandin E(2). The eukaryotic transcription factor NF-kappaB has been involved in intracellular signaling pathways associated with inflammation and carcinogenesis. IH-901 pre-treatment inhibited TPA-induced epidermal NF-kappaB DNA binding in mouse skin, which appeared to be mediated by blocking phosphorylation and subsequent degradation of IkappaBalpha. In an attempt to elucidate the molecular mechanisms by which IH-901 inactivates NF-kappaB, its effects on activation of upstream signaling kinases were explored. IH-901 also inhibited the activation of ERK1/2 and Akt signaling. When IH-901 was treated topically prior to TPA, expression and activity of ODC were inhibited dose-dependently. In addition, IH-901 given prior to each topical dose of TPA markedly lowered the number of papillomas in mouse skin induced by 7,12-dimethylbenz[a]anthracene. Taken together, these findings suggest that IH-901 exerts anti-inflammatory effects by inhibiting TPA-induced COX-2 expression, which may contribute to its antitumor-promoting effects on mouse skin carcinogenesis. (+info)
Immunoenhancing activity of protopanaxatriol-type ginsenoside-F3 in murine spleen cells.
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AIM: To investigate the immunoenhancing activity of ginsenoside-F3 in murine spleen cells and explore its mechanism. METHODS: The enhancing effect of ginsenoside-F3 on murine spleen cell proliferation was studied using [3H]thymidine incorporation assay. Effects of ginsenoside-F3 on the production of type 1 cytokines IL-2, IFN-gamma, and type 2 cytokines IL-4 and IL-10 from murine spleen cells were detected by ELISA method. Effects of ginsenoside-F3 on mRNA level of cytokines IL-4, IFN-gamma, and transcription factors T-bet and GATA-3 were evaluated by RT-PCR analysis. Effect of ginsenoside-F3 on NF-kappaB DNA binding activity in murine spleen cells was investigated by electrophoretic mobility shift assays (EMSA). RESULTS: Ginsenoside-F3 at 0.1-100 micromol/L not only promoted the murine spleen cell proliferation, but also increased the production of IL-2 and IFN-gamma, while decreased the production of IL-4 and IL-10 from murine spleen cells with the maximal effect at 10 micromol/L. RT-PCR analysis displayed that ginsenoside-F3 enhanced the IFN-gamma and T-bet gene expression and decreased IL-4 and GATA-3 gene expression. EMSA experiment showed that ginsenoside-F3 10 micromol/L enhanced the NF-kappaB DNA binding activity induced by ConA in murine spleen cells. CONCLUSION: Ginsenoside-F3 has immunoenhancing activity by regulating production and gene expression of type 1 cytokines and type 2 cytokines in murine spleen cells. (+info)
Stereospecificity of ginsenoside Rg3 action on ion channels.
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Ginsenosides, active ingredients of Panax ginseng, exist as stereoisomers depending on the position of the hydroxyl group on carbon-20; i.e. 20(R)-ginsenoside and 20(S)-ginsenoside are epimers. We have shown previously that the mixture of 20(R)- and 20(S)-ginsenosides regulates ion channel activity. However, it was not clear which epimer was responsible. We investigated the structure-activity relationship of the ginsenoside Rg3 stereoisomers, 20-R-protopanaxatriol-3-[O-beta-D-glucopyranosyl (1-->2)-beta-glucopyranoside], (20(R)-Rg3) and 20-S-proto-panaxatriol-3-[O-beta-D-glucopyranosyl (1-->2)-beta-glucopyr-anoside], (20(S)-Rg3) in regulating voltage-dependent Ca2+, K+ or Na+ channel currents and 5-HT3A and a3b4 nicotinic acetylcholine (nACh) receptor channel currents expressed in Xenopus oocytes. 20(S)-Rg3 but not 20(R)-Rg3 inhibited the Ca2+, K+ and Na+ channel currents in a dose- and voltage-dependent manner. The fact that only 20(S)-Rg3 is active indicates that its hydroxyl group may be geometrically better aligned with the hydroxyl acceptor group in the ion channels than that of 20(R)-Rg3. However, both Rg3 stereoisomers inhibited 5-HT3A and a3beta4 nACh receptor channel currents. These results indicate that the selectivity of action of the Rg3 stereoisomers differs between voltage-dependent and ligand-gated ion channels. (+info)
Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress.
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AIM: To investigate the effect of ginsenoside Rg1, an effective ingredient from ginsenoside, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra neuron lesion. METHODS: C57-BL mice were given MPTP to prepare Parkinson disease mice model. Different doses of Rg1 (5, 10, and 20 mg.kg(-1).d(-1)) or N-acetylcystein (NAC) (300 mg.kg(-1).d(-1)) were given 3 d prior to MPTP in the pretreatment groups. Glutathione (GSH) level and total superoxide dismutase (T-SOD) activity in substantia nigra were determined by spectrophotometry. Nissl staining, tyrosine hydroxylase immunostaining, and TUNEL labeling were used to observe the damage and apoptosis of nigral neurons. Western blot analysis was used to detect the phospho-JNK and phospho-c-Jun levels in midbrain homogenates. RESULTS: Pretreatments of C57-BL mice with different doses of Rg1 or NAC were found to protect against MPTP-induced substantia nigra neurons loss. Rg1 or NAC prevented GSH reduction and T-SOD activation in substantia nigra, and attenuated the phosphorylations of JNK and c-Jun following MPTP treatment. CONCLUSION: The antioxidant property of Rg1 along with the blocking of JNK signaling cascade might contribute to the neuroprotective effect of ginsenoside Rg1 against MPTP. (+info)