Bioactive solanidane steroidal alkaloids from Solanum lyratum.

Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A-F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.

New steroidal glycosides from the fibrous roots of Ophiopogon japonicus.

Two new steroidal glycosides (named fibrophiopogonins A, B), along with one known glycoside, were isolated from the fibrous roots of Ophiopogon japonicus (Liliaceae). Comprehensive spectroscopic analysis, including 2D NMR spectroscopy, and the results of acid hydrolysis allowed the chemical structure of the compounds to be assigned as 26-[(O-ß-D-glucopyranosyl-(1 → 6)-D-glucopyranosyl)]-barogenin- 3-O-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside and (25R)-26-[(O- ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl)]- 3ß,22α,26- trihydroxyfurost- 5-ene-3-O-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside. This is the first isolation of a cholestane glycoside with disaccharide moiety from a Ophiopogon species. The cytotoxic activities of 1~3 against A375 and MCF-7 cells are described.

Two new homoisoflavonoids from the fibrous roots of Ophiopogon japonicus (Thunb.) Ker-Gawl.

Two new homoisoflavonoids ophiopogonone D (1) and ophiopogonanone G (2) were isolated from the fibrous roots of Ophiopogon japonicus. The structures of these two compounds were determined on the basis of spectroscopic means including HR-ESI-MS, 1D, and 2D NMR experiments. The cytotoxic activities of 1 and 2 against Hela and Hep2 cells are described.

Magnesium lithospermate B is excreted rapidly into rat bile mostly as methylated metabolites, which are potent antioxidants.

To elucidate the in vivo pharmacological activities of magnesium lithospermate B (MLB), an active constituent of Radix Salviae Miltiorrhizae, in the rat, its metabolic fate both in vivo and in vitro was investigated. High-performance liquid chromatography revealed that four major metabolites with lower polarity were excreted into bile after intravenous and oral administration of MLB. The metabolites present in combined samples of bile from rats after intravenous injection were isolated and purified by column chromatography and identified as four meta-O-methylated products, namely 3-monomethyl- (M1), 3,3"'-dimethyl- (M2), 3,3"-dimethyl-, and 3,3",3"'-trimethyl-lithospermic acid B according to their spectroscopic characteristics ((1)H, (13)C NMR, (1)H-(1)H correlation spectroscopy, (1)H-detected multiple quantum coherence, and heteronuclear multiple bond coherence combined with positive ion fast atom bombardment-mass spectroscopy). After administration of MLB at an intravenous dose of 4 mg/kg or an oral dose of 100 mg/kg, the total biliary recovery of the four metabolites after 30 h reached 95.5 +/- 2.4% (with approximately 90% recovered within 2 h) or 5.5 +/- 0.7%, respectively. The metabolic pathway was proposed to involve sequential formation of the four methylated metabolites. Incubation of MLB, M1, M2, or M4 in rat hepatic cytosol in the presence of S-adenosyl-l-methionine demonstrated the formation of all four metabolites, which indicated that the enzyme responsible for the biotransformation is catechol O-methyltransferase. MLB and its main metabolites M1 and M2 showed potent 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activities, the activity of M1 being stronger than those of caffeic acid (the monomer form of MLB) and alpha-tocopherol (a representative antioxidant) but weaker than that of MLB. The rapid and high biliary excretion levels of these metabolites suggested that they could undergo enterohepatic circulation in rats and that they might thereby be largely responsible for the pharmacological effects of MLB.

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat.

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.