Kiyofumi Ninomiya

Protective effects of amide constituents from the fruit of Piper chaba on d-galactosamine/TNF-α-induced cell death in mouse hepatocytes

The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Bioactive constituents from chinese natural medicines. XXV.1 New flavonol bisdesmosides, sarmenosides I, II, III, and IV, with hepatoprotective activity from sedum sarmentosum (crassulaceae)

-Four new flavonol bisdesmosides, sarmenosides I, II, III, and IV, were isolated from the whole plant of Sedum sarmentosum (Crassulaceae). Their structures were elucidated on the basis of chemical and physicochemical evidence. Among them, sarmenoside III was found to show potent hepatoprotective effect (IC 50 = 4.4 μM) on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.

Quantitative determination of potent α-glucosidase inhibitors, salacinol and kotalanol, in Salacia species using liquid chromatography–mass spectrometry

A practical HPLC-MS method for the quantitative determination of salacinol (1) and kotalanol (2), potent alpha-glucosidase inhibitors from Salacia species (Hippocrateaceae) as a specific remedy for diabetes in Ayurvedic system, was developed. The optimum conditions of separation and detection of these two constituents were achieved on a Asahipak NH2P-50 column (5 mcirom particle size, 2.0 mm i.d. x 150 mm) with a CH(3)CN-H(2)O mobile phase, associated with MS using electrospray ionization source. The overall recoveries of 1 (85.8-112.6%) and 2 (99.7-106.1%), and relative standard deviation values of intra- and inter-day precision were lower than 6.8 and 8.5%, respectively. The detection (S/N=3) and quantitation limits (S/N=10) were established to be 0.015 and 0.050 ng for 1, and 0.030 and 0.10 ng for 2, respectively. The correlation coefficients of all the calibration curves showed good linearity within test ranges. The extraction process was also optimized as 2 h immersion in water under reflux. The method was applied to evaluate extracts of three kinds of Salacia species, i.e. S. reticulata, S. oblonga, and S. chinensis, and those of four different parts, i.e. roots, stems, leaves and fruits of the same material, revealing that the extract from the roots of S. reticulata had the highest contents of these compounds. The results indicated that the assay was reproducible and precise and could be readily utilized for the evaluation of Salacia species.

Docking and SAR studies of salacinol derivatives as α-glucosidase inhibitors

Salacinol is a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to alpha-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure-activity relationships of salacinol derivatives.

Hepatoprotective triterpenes from traditional Tibetan medicine Potentilla anserina

A methanol extract from the tuberous roots of Potentilla anserina (Rosaceae) exhibited hepatoprotective effects against d-galactosamine (d-GalN)/lipopolysaccharide-induced liver injuries in mice. Six triterpene 28-O-monoglucopyranosyl esters, potentillanosides A-F, were isolated from the extract along with 32 known compounds, including 15 triterpenes. The structures of potentillanosides A-F were determined on the basis of spectroscopic properties and chemical evidence. Four ursane-type triterpene 28-O-monoglycosyl esters, potentillanoside A (IC50=46.7μM), 28-O-β-d-glucopyranosyl pomolic acid (IC50=9.5μM), rosamutin (IC50=35.5μM), and kaji-ichigoside F1 (IC50=14.1μM), inhibited d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes. Among these four triterpenes, potentillanoside A, rosamutin, and kaji-ichigoside F1 exhibited in vivo hepatoprotective effects at doses of 50-100mg/kg, p.o. The mode of action was ascribable to the reduction in cytotoxicity caused by d-GalN.

New Flavanone Oligoglycosides, Theaflavanosides I, II, III, and IV, with Hepatoprotective Activity from the Seeds of Tea Plant (Camellia sinensis)

Four new flavanone oligoglycosides, theaflavanosides I, II, III, and IV, were isolated from the seeds of Camellia sinensis. The structures of theaflavanosides were elucidated on the basis of chemical and physicochemical evidence. Among them, theaflavanoside III was found to show hepatoprotective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes.

Suppressive effects of coumarins from Mammea siamensis on inducible nitric oxide synthase expression in RAW264.7 cells

A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells. From the extract, two new geranylated coumarins, mammeasins A (1) and B (2), were isolated together with 17 known compounds including 15 coumarins. The structures of 1 and 2 were determined on the basis of their spectroscopic properties as well as of their chemical evidence. Among the isolates, 1 (IC(50) = 1.8 μM), 2 (6.4 μM), surangins B (3, 5.0 μM), C (4, 6.8 μM), and D (5, 6.2 μM), kayeassamins E (7, 6.1 μM), F (8, 6.0 μM), and G (9, 0.8 μM), mammea A/AD (11, 1.3 μM), and mammea E/BB (16, 7.9 μM) showed NO production inhibitory activity. Compounds 1, 9, and 11 were found to inhibit induction of inducible nitric oxide synthase (iNOS). With regard to mechanism of action of these active constituents (1, 9, and 11), suppression of STAT1 activation is suggested to be mainly involved in their suppression of iNOS induction.

MEDICINAL FLOWERS. XXVIII.1 STRUCTURES OF FIVE NEW GLYCOSIDES, EVERLASTOSIDES A, B, C, D, AND E, FROM THE FLOWERS OF HELICHRYSUM ARENARIUM

Five new glycosides, everlastosides A (1), B (2), C (3), D (4), and E (5), were isolated from the methanolic extract of the flowers of Helichrysum arenarium. Their structures were elucidated on the basis of chemical and physicochemical evidence.

Andirolides W-Y from the flower oil of andiroba (Carapa guianensis, Meliaceae).

Three new limonoids, andirolides W-Y (1-3), were isolated from the flower oil of Carapa guianasis AUBLET (Meliaceae). Their structures were elucidated on the basis of spectroscopic analyses using 1D and 2D NMR spectra and FABMS. Seven known limonoids: 7-deacetoxy-7-oxogedunin (4), 6α-acetoxygedunin (5), methylangolensate (6), 6α-hydroxygedunin (7), 6α-acetoxy-7α-deacetoxy-7α-hydroxygedunin (8), gedunin (9), and 7-deacetoxy-7-hydroxygedunin (10) from this flower oil were evaluated for the effects on the production of NO in LPS-activated mouse peritoneal macrophages.

Salacinol and Related Analogs: New Leads for Type 2 Diabetes Therapeutic Candidates from the Thai Traditional Natural Medicine Salacia chinensis

The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-Ay mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-Ay mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-Ay mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, α-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the α-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human α-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9–4.9 μM for maltase) as they inhibited rat small intestinal α-glucosidase. The principal sulfonium constituents (1–4) were highly stable in an artificial gastric juice. In addition, 1–4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents.