Uptake and metabolism of ginsenoside Rh2 and its aglycon protopanaxadiol by Caco-2 cells. (17/92)

The uptake and metabolism profiles of ginsenoside Rh2 and its aglycon protopanaxadiol (ppd) were studied in the human epithelial Caco-2 cell line. High-performance liquid chromatography-mass spectrometry was applied to determine Rh2 and its aglycon ppd concentration in the cells at different pH, temperature, concentration levels and in the presence or absence of inhibitors. Rh2 uptake was time and concentration dependent, and its uptake rates were reduced by metabolic inhibitors and influenced by low temperature, thus indicating that the absorption process was energy-dependent. Drug uptake was maximal when the extracellular pH was 7.0 for Rh2 and 8.0 for ppd. Rh2 kinetic analysis showed that a non-saturable component (Kd 0.17 nmol x h(-1) x mg(-1) protein) and an active transport system with a Km of 3.95 micromol x l(-1) and a Vmax of 4.78 nmol x h(-1) x mg(-1)protein were responsible for the drug uptake. Kinetic analysis of ppd showed a non-saturable component (Kd 0.78 nmol x h(-1) x mg(-1) protein). It was suggested that active extrusion of P-glycoprotein and drug degradation in the intestine may influence Rh2 bioavailability.  (+info)

A role for the carbohydrate portion of ginsenoside Rg3 in Na+ channel inhibition. (18/92)

We showed recently that ginsenosides inhibit the activity of various types of ion channel. Here we have investigated the role of the carbohydrate component of ginsenoside Rg3 in the inhibition of Na+ channels. The channels were expressed in Xenopus oocytes by injecting cRNAs encoding rat brain Nav1.2 alpha and beta1 subunits, and analyzed by the two-electrode voltage clamp technique. Treatment with Rg3 reversibly inhibited the inward Na+ peak current (INa) with an IC50 of 32.2 +/- 4.5 microM, and the inhibition was voltage-dependent. To examine the role of the sugar moiety, we prepared a straight chain form of the second glucose and a conjugate of this glucose with 3-(4-hydroxyphenyl) propionic acid hydrazide (HPPH). Neither derivative inhibited INa. Treatment with the carbohydrate portion of ginsenoside Rg3, sophorose [beta-D-glucopyranosyl (1-->2)- beta-glucopyranoside], or the aglycone (protopanaxadiol), on their own or in combination had no effect on INa. These observations indicate that the carbohydrate portion of ginsenoside Rg3 plays an important role in its effect on the Na+ channel.  (+info)

Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis. (19/92)

Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 mumol/L led to both apoptotic cell death and G1 arrest in Hep3B cells, but only resulted in G1 arrest in MDA-MB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E2. In MDA-MB-231 cells, IH-901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked IH-901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G1 arrest resulted from an increase in p27Kip1 mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G1 arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.  (+info)

Radioprotective potential of ginseng. (20/92)

A majority of potential radioprotective synthetic compounds have demonstrated limited clinical application owing to their inherent toxicity, and thus, the seeking of naturally occurring herbal products, such as ginseng, for their radioprotective capability has become an attractive alternative. In general, ginseng refers to the roots of the species of the genus Panax. As a medicinal herb, ginseng has been widely used in traditional Chinese medicine for its wide spectrum of medicinal effects, such as tonic, immunomodulatory, antimutagenic, adaptogenic and antiaging activities. Many of its medicinal effects are attributed to the triterpene glycosides known as ginsenosides (saponins). This review addresses the issue of the radioprotective effects of ginseng on mammalian cells both in vitro and in vivo. Results indicate that the water-soluble extract of whole ginseng appears to give a better protection against radiation-induced DNA damage than does the isolated ginsenoside fractions. Since free radicals play an important role in radiation-induced damage, the underlying radioprotective mechanism of ginseng could be linked, either directly or indirectly, to its antioxidative capability by the scavenging free radicals responsible for DNA damage. In addition, ginseng's radioprotective potential may also be related to its immunomodulating capabilities. Ginseng is a natural product with worldwide distribution, and in addition to its antitumor properties, ginseng appears to be a promising radioprotector for therapeutic or preventive protocols capable of attenuating the deleterious effects of radiation on human normal tissue, especially for cancer patients undergoing radiotherapy.  (+info)

Tomato new sapogenols, isoesculeogenin A and esculeogenin B. (21/92)

Two novel sapogenols, isoesculeogenin A (1) and esculeogenin B (2) of steroidal alkaloid glycosides, lycoperoside F and esculeoside B, respectively, isolated from the ripe tomato have been characterized as (5alpha,22R,23R,25S)-3beta,23,27-trihydroxyspirosolane and (5alpha,22S,23R,25S)-22,26-epimino-16beta,23-epoxy-3beta,23,27-trihydroxycholesta ne, respectively.  (+info)

Isolation of saponins with the inhibitory effect on nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha production from Pleurospermum kamtschaticum. (22/92)

As an attempt to search for bioactive natural products exerting antiinflammatory activity, we have isolated two saponins were isolated from the aerial portion of Pleurospermum kamtschaticum (Umbelliferae) by nitrite assay activity-directed chromatographic fractionation. They were identified as saikogenin F 3-O-{beta-D-glucopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->3)]-beta-D-fucopyr anoside} (buddlejasaponin IV, 1) and 3beta,16beta,23,28-tetrahydroxy-11alpha-methoxyolean-12-ene 3-O-{beta-D-glucopyranosyl(1-->2)-[beta-D-glucopyranosyl(1-->3)]-beta-D-fucopyran oside} (buddlejasaponin IVa, 2). Compound 1 significantly inhibited nitric oxide (NO) production, and it also significantly decreased prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) release in the lipopolysaccharide (LPS)-activated macrophage Raw 264.7 cells whereas compound 2 was much less active. Saikogenin A (3) and -H (4) were obtained by hydrolyzing 1 and 2. Although these sapogenin showed strong NO inhibition, these effects were caused by the cytotoxic effect on Raw 264.7 cells. These results supported the notion that buddlejasaponin IV is a major inhibitors of NO, PGE2 and TNF-alpha production in P. kamtschaticum.  (+info)

Metabolite 1 of protopanaxadiol-type saponins, an axonal regenerative factor, stimulates teneurin-2 linked by PI3-kinase cascade. (23/92)

We previously showed that 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (M1), a metabolite of protopanaxadiol-type ginseng saponins by intestinal bacteria had axonal extension activity in degenerated neurons, and improved memory disorder and synaptic loss induced by an active fragment of amyloid beta, Abeta(25-35). It is unknown how M1 shows these effects in neurons. To clarify the signal transduction mechanism of M1-induced axonal extension, phosphorylated proteins by M1 stimulation were identified because most cellular signal pathways are regulated by phosphorylation/dephosphorylation. The combination of immunoprecipitation and MALDI-TOF-MS revealed that teneurin-2 and mPar3 were specifically phosphorylated by M1 stimulation. Because mPar3 is known as an axonal specifying molecule and to be regulated by phosphatidylinositol 3-kinase (PI3-kinase), the involvement of teneurin-2 and PI3-kinase in the M1 signal was studied. In teneurin-2-deficient cortical neurons, M1-induced axonal extension and PI3-kinase activation were significantly inhibited. In addition, treatment with PI3-kinase inhibitor also reduced M1-induced axonal extension. These results suggest that M1 induces axonal outgrowth through the teneurin-2-PI3-kinase cascade.  (+info)

Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes. (24/92)

There is still an argument about ginseng-prescription drug interactions. To evaluate the influence on cytochrome P450 (P450) activities of ginseng in the present study, the influence on P450 activities of naturally occurring ginsenosides and their degradation products in human gut lumen was assayed by using human liver microsomes and cDNA-expressed CYP3A4. The results showed that the naturally occurring ginsenosides exhibited no inhibition or weak inhibition against human CYP3A4, CYP2D6, CYP2C9, CYP2A6, or CYP1A2 activities; however, their main intestinal metabolites demonstrated a wide range of inhibition of the P450-mediated metabolism. There was no mechanism-based inhibition found on these P450 isoforms. It is noteworthy that Compound K, protopanaxadiol (Ppd), and protopanaxatriol (Ppt) all exhibited moderate inhibition against CYP2C9 activity, and Ppd and Ppt also exhibited potent competitive inhibition against CYP3A4 activity. We suggest that after oral administration, naturally occurring ginsenosides might influence hepatic P450 activity in vivo via their intestinal metabolites.  (+info)