Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells.
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We investigated the growth inhibitory activity of several flavonoids, including apigenin, luteolin, kaempherol, quercetin, butein, isoliquiritigenin, naringenin, genistein, and daizein against B16 mouse melanoma 4A5 cells. Isoliquiritigenin and butein, belonging to the chalcone group, markedly suppressed the growth of B16 melanoma cells and induced cell death. The other flavonoids tested showed little growth inhibitory activity and scarcely caused cell death. In cells treated with isoliquiritigenin or butein, condensation of nuclei and fragmentation of nuclear DNA, which are typical phenomena of apoptosis, were observed by Hoechst 33258 staining and by agarose gel electrophoresis of DNA. Flowcytometric analysis showed that isoliquiritigenin and butein increased the proportion of hypodiploid cells in the population of B16 melanoma cells. These results demonstrate that isoliquiritigenin and butein inhibit cell proliferation and induce apoptosis in B16 melanoma cells. Extracellular glucose decreased the proportion of hypodiploid cells that appeared as a result of isoliquiritigenin treatment. p53 was not detected in cells treated with either of these chalcones, however, protein of the Bcl-2 family were detected. The level of expression of Bax in cells treated with either of these chalcones was markedly elevated and the level of Bcl-XL decreased slightly. Isoliquiritigenin did not affect Bcl-2 expression, but butein down-regulated Bcl-2 expression. From these results, it seems that the pathway by which the chalcones induce apoptosis may be independent of p53 and dependent on proteins of the Bcl-2 family. It was supposed that isoliquiritigenin induces apoptosis in B16 cells by a mechanism involving inhibition of glucose transmembrane transport and promotion of Bax expression. On the other hand, it was suggested that butein induces apoptosis via down-regulation of Bcl-2 expression and promotion of Bax expression. This mechanism differs from the isoliquiritigenin induction pathway. (+info)
Chalcone, acyl hydrazide, and related amides kill cultured Trypanosoma brucei brucei.
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BACKGROUND: Protozoan parasites of the genus Trypanosoma cause disease in a wide range of mammalian hosts. Trypanosoma brucei brucei, transmitted by tsetse fly to cattle, causes a disease (Nagana) of great economic importance in parts of Africa. T. b. brucei also serves as a model for related Trypanosoma species, which cause human sleeping sickness. MATERIALS AND METHODS: Chalcone and acyl hydrazide derivatives are known to retard the growth of Plasmodium falciparum in vitro and inhibit the malarial cysteine proteinase, falcipain. We tested the effects of these compounds on the growth of bloodstream forms of T. b. brucei in cell culture and in a murine trypanosomiasis model, and investigated their ability to inhibit trypanopain-Tb, the major cysteine proteinase of T. b. brucei. RESULTS: Several related chalcones, acyl hydrazides, and amides killed cultured bloodstream forms of T. b. brucei, with the most effective compound reducing parasite numbers by 50% relative to control populations at a concentration of 240 nM. The most effective inhibitors protected mice from an otherwise lethal T. b. brucei infection in an in vivo model of acute parasite infection. Many of the compounds also inhibited trypanopain-Tb, with the most effective inhibitor having a Ki value of 27 nM. Ki values for trypanopain-Tb inhibition were up to 50- to 100-fold lower than for inhibition of mammalian cathepsin L, suggesting the possibility of selective inhibition of the parasite enzyme. CONCLUSIONS: Chalcones, acyl hydrazides, and amides show promise as antitrypanosomal chemotherapeutic agents, with trypanopain-Tb possibly being one of their in vivo targets. (+info)
PROP (6-n-Propylthiouracil) tasting and sensory responses to caffeine,sucrose, neohesperidin dihydrochalcone and chocolate.
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The genetically determined ability to taste 6-n-propylthiouracil (PROP) has been linked with lowered acceptance of some bitter foods. Fifty-four women, aged 18-30 years, tasted and rated PROP-impregnated filter paper and seven solutions of PROP. Summed bitterness intensity ratings for PROP solutions determined PROP taster status. Respondents also tasted five sucrose and seven caffeine solutions, as well as seven solutions each of caffeine and PROP that had been sweetened with 0.3 mmol/l neohesperidin dihydrochalcone (NHDC). Respondents also rated three kinds of chocolate using 9-point category scales. PROP tasters rated caffeine solutions as more bitter than did non-tasters and liked them less. PROP tasters did not rate either sucrose or NHDC as more sweet. The addition of NHDC to PROP and caffeine solutions suppressed bitterness intensity more effectively for tasters than for non-tasters and improved hedonic ratings among both groups. PROP tasters and non-tasters showed the same hedonic response to sweetened caffeine solutions and did not differ in their sensory responses to chocolate. Genetic taste markers may have only a minor impact on the consumption of such foods as sweetened coffee or chocolate. (+info)
Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups.
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Induction of phase 2 enzymes and elevations of glutathione are major and sufficient strategies for protecting mammals and their cells against the toxic and carcinogenic effects of electrophiles and reactive forms of oxygen. Inducers belong to nine chemical classes and have few common properties except for their ability to modify sulfhydryl groups by oxidation, reduction, or alkylation. Much evidence suggests that the cellular "sensor" molecule that recognizes the inducers and signals the enhanced transcription of phase 2 genes does so by virtue of unique and highly reactive sulfhydryl functions that recognize and covalently react with the inducers. Benzylidene-alkanones and -cycloalkanones are Michael reaction acceptors whose inducer potency is profoundly increased by the presence of ortho- (but not other) hydroxyl substituent(s) on the aromatic ring(s). This enhancement correlates with more rapid reactivity of the ortho-hydroxylated derivatives with model sulfhydryl compounds. Proton NMR spectroscopy provides no evidence for increased electrophilicity of the beta-vinyl carbons (the presumed site of nucleophilic attack) on the hydroxylated inducers. Surprisingly, these ortho-hydroxyl groups display a propensity for extensive intermolecular hydrogen bond formation, which may raise the reactivity and facilitate addition of mercaptans, thereby raising inducer potencies. (+info)
Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones.
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Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4-dimethoxy-4'-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4'-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. major promastigotes. Although licochalcone A inhibited the activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate- and NADH-cytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC(50)) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC(50) of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmania parasite and does not exist in mammalian cells, it could be an excellent target for antiprotozoal drugs. (+info)
Specificity analysis and mechanism of aurone synthesis catalyzed by aureusidin synthase, a polyphenol oxidase homolog responsible for flower coloration.
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Aureusidin synthase, which plays a key role in the yellow coloration of snapdragon flowers, is a homolog of plant polyphenol oxidase (PPO). The enzyme specifically acted on chalcones with a 4-monohydroxy or 3,4-dihydroxy B-ring to produce aurones, for whose production the oxidative cyclization of chalcones must be preceded by 3-oxygenation. However, it exhibited virtually no PPO activity toward non-chalcone phenolics. The enzyme was competitively inhibited by phenylthiourea, a specific PPO inhibitor. These results led us to propose a mechanism of aurone synthesis by aureusidin synthase on the basis of known PPO-catalyzed reactions and conclude that the enzyme is a chalcone-specific PPO specialized for aurone biosynthesis. (+info)
In vitro inhibition of rat monoamine oxidase by liquiritigenin and isoliquiritigenin isolated from Sinofranchetia chinensis.
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AIM: To study the inhibition of liquiritigenin (1) and isoliquiritigenin (2) isolated from Sinofranchetia chinensis on rat monoamine oxidase A and B (MAO A and B). METHODS: Rat brain mitochondrial fraction, prepared by differential centrifugation, was utilized as a source of MAO activity. MAO activity was determined radiochemically with [14C]5-hydroxytryptamine (5-HT) and [14C]beta-phenylethylamine (beta-PEA) used as MAO A or B specific radiolabled substrates, respectively. The Ki and KI values were obtained from Lineweaver-Burk plot using linear regression analysis. RESULTS: Liquiritigenin and isoliquiritigenin were found to be inhibitory against both MAO A and B in a dose-dependent manner. IC50 (95% of confidence limits) of liquiritigenin and isoliquiritigenin were 32 (26-36) and 13.9 (12.8-15.6) mumol/L for the inhibition of MAO A, and 104.6 (89.0-118.9) and 47.2 (39.5-54.5) mumol/L for that of MAO B, respectively. Lineweaver-Burk transformation of the MAO A inhibition data indicated that the inhibition was non-competitive for both liquiritigenin and isoliquiritigenin whereas their inhibition of MAO B was of mixed type. Regarding MAO A inhibition, the Ki values of liquiritigenin and isoliquiritigenin were 31.5 mumol/L and 14.3 mumol/L, respectively. As to the inhibition of MAO B, the Ki and KI data for liquiritigenin were 164.7 and 15.2 mumol/L, and those for isoliquiritigenin were 62.2 and 9.3 mumol/L, respectively. CONCLUSION: Liquiritigenin and isoliquiritigen inhibited the activity of MAO A and B in rat brain mitochondria, and the latter was more active than the former. (+info)
Isolation and identification of two new flavanones and a chalcone from Citrus kinokuni.
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Two new flavanones and one chalcone were isolated from the peel of Citrus kinokuni Hort. ex Tanaka and identified as (2S)-5,6,7,8,4'-pentamethoxyflavanone (1), (2S)-5,6,7,3',4'-pentamethoxyflavanone (2) and 2'-hydroxy-3,4,3',4',6'-pentamethoxychalcone (3). The structures of new compounds were elucidated by spectroscopic analysis. (+info)