Agrimonia eupatoria protects against chronic ethanol-induced liver injury in rats.

This study examined the hepatoprotective effects of Agrimonia eupatoria water extract (AE) against chronic ethanol-induced liver injury. Rats were fed a Lieber-DeCarli liquid diet for 8 weeks. Animals were treated orally with AE at 10, 30, 100, and 300 mg/kg/day. After chronic consumption of ethanol, serum aminotransferase activities and pro-inflammatory cytokines markedly increased, and those increases were attenuated by AE. The cytochrome P450 2E1 activity and lipid peroxidation increased after chronic ethanol consumption, while reduced glutathione concentration decreased. Those changes were attenuated by AE. Chronic ethanol consumption increased the levels of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expression, inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expression, and nuclear translocation of nuclear factor-kappa B, which was attenuated by AE. Our results suggest that AE ameliorates chronic ethanol-induced liver injury, and that protection is likely due to the suppression of oxidative stress and TLR-mediated inflammatory signaling.

Cytotoxic effects of triterpenoid saponins from Androsace umbellata against multidrug resistance (MDR) and non-MDR cells.

Cytotoxicity-guided fractionation and separation of MeOH extract from Androsace umbellata (Lour.) Merr. led to the isolation of four triterpenoid saponins. Compounds isolated from the n-BuOH soluble fraction were identified as saxifragifolin C (1), A (2), B (3), and D (4) by spectroscopic analysis. Antiproliferative effect of isolated compounds were evaluated by the sulforhodamin B assay against multidrug resistance (MDR; MES-SA/DX5 and HCT15/CLO2) and non-MDR (A549, SK-OV-3, SK-MEL-2, MES-SA, and HCT15) human tumor cell lines. All compounds exhibited strong cytotoxicity against non-MDR human tumor cell lines with IC(50) values of 0.19-2.37 muM. MDR cells and non-MDR cells had similar sensitivity to these compounds, however, MDR cells were highly resistant to doxorubicin. Compounds 1-4 induced an increase in the percentage of Annexin V-binding cells, indicating that 1-4 induced apoptosis in RAW 264.7 cells. Also, the condensation of nuclei, a characteristic morphological change of apoptosis, was observed in RAW 264.7 cells by the treatment with n-BuOH fraction, compounds 3 and 4, respectively.

Antioxidative iridoid glycosides and phenolic compounds from Veronica peregrina.

Eight iridoid glycosides and four phenolic compounds were isolated from the EtOAc soluble fraction of Veronica peregrina MeOH extract as the radical scavengers for antioxidant activity. The compounds were identified as protocatechuic acid (1), luteolin (2), veronicoside (3), minecoside (4), specioside (5), amphicoside (6), catalposide (7), 6-O-cis-p-coumaroyl catalpol (8), p-hydroxy benzoic acid methyl ester (9), verproside (10), verminoside (11), and chrysoeriol 7-glucuronide (12) by spectroscopic analysis. All compounds except for 1 and 2 were isolated for the first time from this plant. The antioxidant activity was evaluated by the ORAC(Oxygen Radical Absorbance Capacity) assay, which measures scavenging activity against peroxy radicals induced by 2,2'-azobis (2-methoxypropion-amidine) dihydrochloride, and the ORAC value is expressed as relative trolox equivalent. Compounds 2, 4, 5, 6, 8, and 12 exhibited potent antioxidant activity, and compounds 1, 11 had similar activity with trolox, whereas the other compounds showed weaker activity than trolox.

Cytotoxic phenolic compounds from Chionanthus retusus.

Cytotoxicity-guided fractionation and purification of MeOH extract from Chionanthus retusus Lindl. et Paxton resulted in the isolation of compounds. Fourteen phenolic compounds were isolated from the EtOAc soluble fraction, and their structures were determined by spectroscopic analysis. Isolated compounds were identified as phillygenin (1), scopoletin (2), pinoresinol (3), kaempferol (4), aromadendrin (5), 2-(4-hydroxyphenyl)ethanol (6), 3,3',5,5',7-pentahydroxyflavanone (7), luteolin (8), quercetin (9), apigenin (10), chrysoeriol (11), phillyrin (12), oleuropein (13), (7R,8R)-guaiacylglycerol (14). All compounds except for 12 and 13 were isolated for the first time from this plant and genus Chionanthus. Anti-proliferative effect of isolated compounds were evaluated by the sulforhodamin B assay against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15). Compounds 4 and 8-10 were significantly active with ED50 values of 1.84-6.35 microg/mL. Also, compounds 1, 3, 5 and 7 revealed cytotoxic effects at concentrations below 30 microg/mL.

Anti-proliferative effects of estrogen receptor-modulating compounds isolated from Rheum palmatum.

The Rheum palmatum L., a traditional medicine in Korea, was screened for their estrogenic activity in a recombinant yeast system with a human estrogen receptor (ER) expression plasmid and a reporter plasmid used in a previous study. The EC50 values of the n-hexane, dichloromethane, ethyl acetate, n-butanol, and water fractions of the methanolic extract of R. palmatum in the yeast-based estrogenicity assay system were 0.145, 0.093, 0.125, 1.459, 2.853 microg/mL, respectively, with marked estrogenic activity in the dichloromethane fraction. Using an activity-guided fractionation approach, five known anthraquinones, chrysophanol (1), physcion (2), emodin (3), aloe-emodin (4) and rhein (5), were isolated from the dichloromethane fraction. Compound 3 had the highest estrogenic relative potency (RP, 17bestradiol = 1.00) (6.3 x 10(-2)), followed by compound 4 (3.8 x 10(-3)), compound 5 (2.6 x 10(-4)), a compound 1 (2.1 x 10(-4)). Also, compound 3 and fraction 3 (which contained compound 3) of the dichloromethane fraction of R. palmatum showed strong cytotoxicity in both ER-positive (MCF-7) and-negative (MDA-MB-231) breast cancer cell lines.

Soraphinol C, a new free-radical scavenger from Sorangium cellulosum.

A new compound named soraphinol C (1) was isolated from myxobacteria Sorangium cellulosum KM1001 a soil isolate, together with a structurally related known compound, 4-hydroxysattabacin (2). These compounds were isolated by silica gel column chromatography and recycling preparative HPLC, consecutively. The structures of the compounds were determined on the basis of combined spectroscopic analyses. Compounds 1 and 2 exhibited antioxidant activity as a radical scavenger in the experiment using a hydrophilic free-radical initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride with ORAC values of 0.956 and 0.617, respectively.

Screening of estrogenic and antiestrogenic activities from medicinal plants.

The medicinal plant extracts commercially used in Asia were screened for their estrogenic and antiestrogenic activities in a recombinant yeast system featuring both a human estrogen receptor (ER) expression plasmid and a reporter plasmid. Pueraria lobata (flower) had the highest estrogenic relative potency (RP, 7.75×10(-3); RP of 17ß-estradiol=1), followed by Amomum xanthioides (1.25×10(-3)). Next potent were a group consisting of Glycyrrhiza uralensis, Zingiber officinale, Rheum undulatum, Curcuma aromatica, Eriobotrya japonica, Sophora flavescens, Anemarrhena asphodeloides, Polygonum multiflorum, and Pueraria lobata (root) (ranging from 9.5×10(-4) to 1.0×10(-4)). Least potent were Prunus persica, Lycoppus lucidus, and Adenophora stricta (ranging from 9.0×10(-5) to 8.0×10(-5)). The extracts exerting antiestrogenic effects, Cinnamomum cassia and Prunus persica, had relative potencies of 1.14×10(-3) and 7.4×10(-4), respectively (RP of tamoxifen=1). The solvent fractions from selected estrogenic or antiestrogenic herbs had higher estrogenic relative potencies, with their RP ranging from 9.3×10(-1) to 2.7×10(-4) and from 8.2×10(-1) to 9.1×10(-3), respectively. These results support previous reports on the efficacy of Oriental medicinal plants used or not used as phytoestrogens for hormone replacement therapy.

Synthesis of psoralen derivatives and their blocking effect of hKv1.5 channel.

Previously, we found that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-7-one), blocked a human Kv1.5 potassium channel (hKv1.5) and has a potential antiarrhythmic effect. In the present study, to develop more potent hKv1.5 blockers or antiarrhythmic drugs, we synthesized ten psoralen derivatives and examined their blocking effects on hKv1.5 stably expressed in Ltk cells. Among the newly synthesized psoralen derivatives, three derivatives (Compounds 5, 9 and 10) showed the open channel-blocking effect. Compound 9 among them was the most potent in blocking hKv1.5. We found that compound 9, one of the psoralen derivatives, inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent manner with an IC50 value of 27.4 +/- 5.1 nM at +60 mV. Compound 9 accelerated the inactivation kinetics of the hKv1.5 channel, slowed the deactivation kinetics of hKv1.5 current resulting in a tail crossover phenomenon. Compound 9 inhibited hKv1.5 current in a use-dependent manner. These results indicate that compound 9, one of psoralen derivatives, acts on hKv1.5 channel as an open channel blocker and is much more potent than psoralen in blocking hKv1.5 channel. If further studies were done, compound 9 might be an ideal antiarrhythmic drug for atrial fibrillation.

Evaluation of oriental medicinal herbs for estrogenic and antiproliferative activities.

Herb extracts commercially used in Asia were screened for their estrogenic activity with a recombinant yeast system with both a human estrogen receptor (ER) expression plasmid and a reporter plasmid. Pueraria lobata (flower) had the highest estrogenic relative potency (RP, 17-estradiol = 1.00) (7.8e-3) (RP for + control), followed by Amomum xanthioides (1.3e-3), Glycyrrhiza uralensis, Zingiber officinale, Rheum palmatum, Curcuma aromatica, Eriobotrya japonica, Sophora flavescens, Anemarrhena asphodeloides, Polygonum multiflorum and Pueraria lobata (root) (9.5e-4-1.0e-4), and Prunus persica, Lycoppus lucidus and Adenophora stricta (9.0e-5-8.0e-5). In the antiproliferative assay, five human cancer cell lines representing different tissues (breast, lung and ovary) were used. Eriobotrya japonica showed strong cytotoxicity in ER-negative breast cancer (MDA-MB-231), cervix epitheloid (HeLa) and lung (A549) carcinoma cell lines.

Regioselective and diastereoselective amination of polybenzyl ethers using chlorosulfonyl isocyanate: total syntheses of 1,4-dideoxy-1,4-imino-D-arabinitol and (-)-lentiginosine.

The total syntheses of DAB1 (1) and (-)-lentiginosine (2) were concisely accomplished from D-lyxose via regioselective and diastereoselective NHCbz introduction using CSI, chemoselective removal of the Cbz protection, and ring-closing metathesis as key steps.

Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats.

This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8-1.1 h, 59.6-68.0 ml/min/kg and 2.4-2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%-0.020% and 0.049% +/- 0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9-1.1 h, 520.3-621.2 ml/min/kg and 67.6-84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats.

Regulation effect of 2',4',7-trihydroxyisoflavone on the expression of matrix metalloproteinase-1, 2 in ultraviolet-B irradiated primary cultured old aged human skin fibroblasts.

Long term and repeated exposure of UV light on the skin often induces chronic skin diseases such as skin cancer as well as photoaging, and the mechanisms of these skin damages are closely associated with up-regulation of matrix metalloproteinase's (MMPs) activities. We investigated the effect of 2',4',7-trihydroxyisoflavone purified from the whole plants of Viola hondoensis W. BECKER et H BOISSIEU (Violaceae) on the expression of MMPs in UV-B irradiated old aged human skin fibroblasts. 2',4',7-trihydroxyisoflavone markedly reduced UV-induced MMP-1 expression, but not MMP-2, at the both mRNA and protein levels in a dose-dependent manner. Our report is the first description for the ability of 2',4',7-trihydroxyisoflavone to regulate MMP-1 expression from ultraviolet-B irradiated primary cultured old aged human skin fibroblasts.

Regioselective and diastereoselective amination with use of chlorosulfonyl isocyanate: a short and efficient synthesis of (-)-cytoxazone.

The total synthesis of (-)-cytoxazone 1 was achieved in six linear steps (34% overall yield) from p-anisaldehyde. The key steps in this route are the regioselective and stereoselective introduction of a N-protected amine group, using the CSI reaction of the anti-1,2-dimethyl ether 3, and the subsequent regioselective cyclization of the N-protected amino diol 13 to give the 2-oxazolidinone unit of (-)-cytoxazone 1. [reaction: see text]

The effect of flavonol glycoside on the expressions of matrix metalloproteinase-1 in ultraviolet-irradiated cultured human skin fibroblasts.

Long-term and repeated exposure of ultraviolet (UV) light, a harmful environmental stress, on the skin often induces chronic skin diseases, such as skin cancer as well as photo-aging (premature skin aging), and the mechanisms of these skin damages are closely associated with up-regulation of matrix metalloproteinases (MMPs) activities. Here, we investigated the effect of quercetin-3-O-beta-d-(6''-feruloyl)-galactopyranoside isolated from the stems of Viola hondoensis (Violaceae) on the expression of MMPs in UV-irradiated human skin fibroblasts in vitro. Quercetin-3-O-beta-d-(6''-feruloyl)-galactopyranoside markedly reduced UV-induced MMP-1 expression at the protein levels in a dose-dependent manner. Our report is the first description for the ability of quercetin-3-O-beta-d-(6''-feruloyl)-galactopyranoside to regulate UV-induced MMP-1 expression.

A glycosidic isoflavonoid from Viola hondoensis W. BECKER et H. BOISSIEU (Violaceae), and its effect on the expression of matrix metalloproteinase-1 caused by ultraviolet irradiation in cultured human skin fibroblasts.

Isolation of the ethyl acetate soluble fraction from aerial parts of Viola hondoensis W. BECKER et H. BOISSIEU yielded one major isoflavonoid glycoside, tectoridin-4'-O-beta-D-glucoside. The structure of the compound was certainly determined by chemical analyses, as well as 1D- and 2D-NMR spectroscopy. The compound exhibited potent inhibitory activity against the expression of matrix metalloproteinase-1 caused by UV-irradiation in cultured human skin fibroblasts.

Isoflavonoid from Viola hondoensis, regulates the expression of matrix metalloproteinase-1 in human skin fibroblasts.

Long term and repeated exposure of ultraviolet (UV) light, a harmful environmental stress, on the skin often induces chronic skin diseases such as skin cancer as well as photoaging (premature skin aging), and the mechanisms of these skin damages are closely associated with up-regulation of matrix metalloproteinases (MMPs) activities. Here we investigated the effect of 2',4',7-trihydroxyisoflavone isolated from the whole plants of Viola hondoensis (Violaceae) on the expression of MMPs in UV-irradiated human skin fibroblasts in vitro. 2',4',7-Trihydroxyisoflavone markedly reduced UV-induced MMP-1 expression, but not MMP-2, at the both mRNA and protein levels in a dose-dependent manner. Our report is the first description for the ability of 2',4',7-trihydroxyisoflavone to regulate MMP-1 expression specifically.

Triterpenoid from Tiarella polyphylla, regulation of type 1 procollagen and MMP-1 in ultraviolet irradiation of cultured old age human dermal fibroblasts.

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of natural products. Ultraviolet irradiation is widely considered to be an environmental stress. Here we investigated the effect of 3,23-dihydroxy-20(29)-lupen-27-oic acid on the regulation of MMP-1 and type 1 procollagen in Ultraviolet irradiation of cultured old age human dermal fibroblasts. 3, 23-dihydroxy-20(29)-lupen-27-oic acid was isolated from Tiarella polyphylla D. Don (Saxifragaceae). Among them, 3, 23-dihydroxy-20(29)-lupen-27-oic acid induced the regulation of Type 1- procollagen and reduced the regulation of MMP-1 at the protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that 3, 23-dihydroxy-20(29)-lupen-27-oic acid plays an important role in the induction of Type 1-procollagen and reduction of MMP-1 by ultraviolet irradiation in old age human dermal fibroblasts.

Triterpenoid saponin from Viola hondoensis W. Becker et H Boss. and their effect on MMP-1 and type I procollagen expression.

Bioassay-guided fractionation has led to the isolation of triterpenoid saponins such as Acutoside A (3-omicron-[omicron-beta-D-glucopyranosyl-(1 --> 2)-omicron-beta-D-glucopyranosyl] oleanolic acid) from the whole plants of Viola hondoensis. Among them, Saponin 1 exhibited potent inhibitory activity against matrix metalloproteinase (MMP)-1, and prevented the UV-induced changes in the MMP-1 expression. In addition, compound was isolated from this plant for the first time.

Regioselective and diastereoselective allylic amination using chlorosulfonyl isocyanate. A novel asymmetric synthesis of unsaturated aromatic 1,2-amino alcohols.

The diastereoselective synthesis of unsaturated aromatic 1,2-amino alcohols can be achieved on an epimeric mixture of optically active allylic ethers having a hydroxyl group attached to an allylic chiral center to the pi-system using chlorosulfonyl isocyanate. These reactions produced the unsaturated anti-1,2-amino alcohols either exclusively or predominantly only for aromatic derivatives. The anti-selectivity may be explained by the Cieplak electronic model during the conversion from ethers to carbamates.