Quinone reductase induction as a biomarker for cancer chemoprevention.
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Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Strategies for protecting cells from initiation events include decreasing metabolic enzymes responsible for generating reactive species (phase I enzymes) while increasing phase II enzymes that can deactivate radicals and electrophiles known to intercede in normal cellular processes. Reduction of electrophilic quinones by quinone reductase is an important detoxification pathway. Following evaluation of approximately 3000 plant and marine organism extracts, the number characterized as "active" was established in the range of 12% of the total, and over 60 active compounds have been isolated as quinone reductase inducers. One of them, isoliquiritigenin (1), isolated from tonka bean, was shown to be a monofunctional inducer by having similar quinone reductase inducing ability in wild-type Hepa 1c1c7 cells and two mutant cell lines. To further investigate the mechanism of induction, HepG2 human hepatoma cells stably transfected with ARE-luciferase plasmid were used. Isoliquiritigenin (1) significantly induced the luciferase activity in a dose-dependent manner. On the basis of these results, a full-term cancer chemoprevention study was conducted with 7,12-dimethylbenz[a]anthracene (DMBA)-treated female Sprague-Dawley rats. Dietary administration of 1 increased tumor latency. Based on these promising preliminary results, additional mechanistic studies are underway, as well as full-term carcinogenesis studies with chronic administration schedules. (+info)
Simultaneous determination of components in preparation Naodesheng injection by high performance liquid chromatograph-atmospheric pressure chemical ionization mass spectrometry (HPLC-MS/APCI).
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A high-performance liquid chromatograph with mass spectrum detection (HPLC-MS/APCI) method has been established for simultaneous determination of ten major bioactive components of Naodesheng injection including safflor yellow A, puerarin, daidzein, ginsenosides (Rg1, Rg2, Rb1, Rd, Re, Rh1), and notoginsenoside R1. The separations were carried out with a Luna C18 column (5 microm, 150x4.6 mm, Phenomenex, U.S.A.) with a stepwise gradient elution of the mobile phase consisting of water (0.1% of formic acid, v/v)-methanol (0 min, 70:30; 8 min, 30:70; 20 min, 10:90) at a flow-rate of 0.8 ml/min. The proposed method was applied to analyze five various Naodesheng injections and produced data with acceptable linearity, repeatability, precision and accuracy having lower limits of quantitation (LLOQs) of 0.02-0.2 microg. The calibration curves were linear in respective range for all compounds, all of them with coefficients of determination above 0.9900. The intraday precessions were less than 5.0%. The proposed method is accurate, sensitive and simple, a useful alternative for routine analysis in the quality control of Traditional Chinese Medicine. (+info)
Anti-angiogenic and anti-tumor activities of 2'-hydroxy-4'-methoxychalcone.
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In the present study, we evaluated the in vitro and in vivo anti-angiogenic and anti-tumor activities of 2'-hydroxy-4'-methoxychalcone (HMC). HMC decreased angiogenesis in both chick embryos in the chorioallantoic membrane assay and basic fibroblast growth factor (bFGF)-induced vessel formation in the mouse Matrigel plug assay. This compound also reduced the proliferation of calf pulmonary arterial endothelial cells and was found to possess relatively weak gelatinase/collagenase inhibitory activity in vitro. HMC, when administered subcutaneously at the dose of 30 mg/kg for 20 d to mice implanted with murine Lewis lung carcinoma, caused a significant inhibition of tumor volume by 27.2%. Intraperitoneal (i.p.) treatment at the same dosage for 10 d to ICR mice bearing sarcoma 180 caused a significant suppression in tumor weight by 33.7%. Taken together, out data demonstrate that the anti-angiogenic activities of HMC might be due to anti-proliferative activity under inhibition of the induction of COX-2 enzyme. Furthermore, the results suggest that the potent anti-angiogenic activity of HMC seems to be the possible mechanism of action in these animal models of solid tumors. (+info)
Isoliquiritigenin selectively inhibits H(2) histamine receptor signaling.
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Isoliquiritigenin, one of the major constituents of Glycyrrhiza uralensis (licorice), is a natural pigment with a simple chalcone structure 4,2',4'-trihydroxychalcone. In this study, isoliquiritigenin showed selective H(2) histamine receptor (H(2)R) antagonistic effect and remarkably reduced several H(2)R-mediated physiological responses. Preincubation of U937 and HL60 hematopoietic cells with isoliquiritigenin significantly inhibited H(2)R agonist-induced cAMP response in a concentration-dependent manner without affecting the viability of cells. Isoliquiritigenin also blocked the binding affinity of [(3)H]tiotidine to membrane receptors in HL-60 cells. Isoliquiritigenin did not affect the elevation of cAMP levels induced by cholera toxin, forskolin, or isoproterenol, indicating that the action site of isoliquiritigenin is not G(s) protein, effector enzyme, adenylyl cyclase, or beta(2)-adrenoceptor. Isoliquiritigenin affected neither H(1)R-nor H(3)R-mediated signaling. In molecular docking studies, isoliquiritigenin exhibited more favorable interactions with H(2)R than histamine. Isoliquiritigenin prominently inhibited H(2)R selective agonist dimaprit-induced cAMP generation in MKN-45 gastric cancer cell. Moreover, isoliquiritigenin reduced gastric acid secretion and protected gastric mucosal lesion formation in pylorus-ligated rat model. Taken together, the results demonstrate that isoliquiritigenin is an effective H(2)R antagonist and provides the basis for designing novel H(2)R antagonist. (+info)
Determination of safflor yellow A, puerarin, ferulic acid, ginsenoside Rg1, and Rb1 in the Traditional Chinese Medicinal preparation Naodesheng injection by high-performance liquid chromatography.
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High-performance liquid chromatography is employed to determine the contents of five mark components, safflor yellow A, puerarin, ferulic acid, ginsenoside Rg1, and Rb1, in the Traditional Chinese Medicinal preparation Naodesheng injection. The separation is performed on a C18 column by stepwise gradient elution with water (0.1%, v/v, phosphoric acid)-acetonitrile (0 min, 86:14; 48 min, 75:25; and 68 min, 50:50) as the mobile phase at a flow rate of 1.0 mL/min, with UV detection at 203 nm. Five regression equations show a good linear relationship between the peak area of each marker and concentration. The recoveries of the markers listed are 99.6%, 100.2%, 99.7%, 100.0%, and 99.7%, respectively. The repeatability and reproducibility (relative standard deviation) of the method are less than 1.4% and 1.8%, respectively. (+info)
Yellow flowers generated by expression of the aurone biosynthetic pathway.
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Flower color is most often conferred by colored flavonoid pigments. Aurone flavonoids confer a bright yellow color on flowers such as snapdragon (Antirrhinum majus) and dahlia (Dahlia variabilis). A. majus aureusidin synthase (AmAS1) was identified as the key enzyme that catalyzes aurone biosynthesis from chalcones, but transgenic flowers overexpressing AmAS1 gene failed to produce aurones. Here, we report that chalcone 4'-O-glucosyltransferase (4'CGT) is essential for aurone biosynthesis and yellow coloration in vivo. Coexpression of the Am4'CGT and AmAS1 genes was sufficient for the accumulation of aureusidin 6-O-glucoside in transgenic flowers (Torenia hybrida). Furthermore, their coexpression combined with down-regulation of anthocyanin biosynthesis by RNA interference (RNAi) resulted in yellow flowers. An Am4'CGT-GFP chimeric protein localized in the cytoplasm, whereas the AmAS1(N1-60)-RFP chimeric protein was localized to the vacuole. We therefore conclude that chalcones are 4'-O-glucosylated in the cytoplasm, their 4'-O-glucosides transported to the vacuole, and therein enzymatically converted to aurone 6-O-glucosides. This metabolic pathway is unique among the known examples of flavonoid, including anthocyanin biosynthesis because, for all other compounds, the carbon backbone is completed before transport to the vacuole. Our findings herein not only demonstrate the biochemical basis of aurone biosynthesis but also open the way to engineering yellow flowers for major ornamental species lacking this color variant. (+info)
Revised structures of gambiriins A1, A2, B1, and B2, chalcane-flavan dimers from gambir (Uncaria gambir extract).
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Gambir, the aqueous extract from Uncaria gambir (Rubiaceae), has been used as an astringent medicine in Asian countries. Investigation of the constituents in the extract led to the isolation of four chalcane-flavan dimers, gambiriin A1 (6), A2 (7), B1 (8), and B2 (9), in addition to (+)-catechin (1), (+)-epicatechin (2), and dimeric proanthocyanidins, procyanidin B1 (3), procyanidin B3 (4), and gambiriin C (5). The spectroscopic and chemical data obtained in the present study indicated that their previously proposed structures 6a, 7a, 8a, and 9a should be revised to 6, 7, 8, and 9, respectively. (+info)
Synthesis of alpha,beta-unsaturated ketones as chalcone analogues via a S(RN)1 mechanism.
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An electron-transfer chain reaction between 2-nitropropane anion and alpha-bromoketones derived from nitrobenzene and nitrothiophene was demonstrated by mechanistic study and a specific convenient synthetic protocol. Thus, 2-bromo-1-(5-nitrothiophen-2-yl)ethanone or 2-bromo-1-(4-nitrophenyl)ethanone were reacted with several cyclic nitronate anions to form alpha,beta-unsaturated ketones via a S(RN)1 mechanism. This new method can be used to synthesize a wide variety of chalcone analogues. (+info)