Selective effect of 2',6'-dihydroxy-4'-methoxychalcone isolated from Piper aduncum on Leishmania amazonensis.
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2',6'-Dihydroxy-4'-methoxychalcone (DMC) was purified from the dichloromethane extract of Piper aduncum inflorescences. DMC showed significant activity in vitro against promastigotes and intracellular amastigotes of Leishmania amazonensis, with 50% effective doses of 0.5 and 24 micrograms/ml, respectively. Its inhibitory effect on amastigotes is apparently a direct effect on the parasites and is not due to activation of the nitrogen oxidative metabolism of macrophages, since the production of nitric oxide by both unstimulated and recombinant gamma interferon-stimulated macrophages was decreased rather than increased with DMC. The phagocytic activity of macrophages was functioning normally even with DMC concentrations as high as 80 micrograms/ml, as seen by electron microscopy and by the uptake of fluorescein isothiocyanate-labeled beads. Ultrastructural studies also showed that in the presence of DMC the mitochondria of promastigotes were enlarged and disorganized. Despite destruction of intracellular amastigotes, no disarrangement of macrophage organelles were observed, even at 80 micrograms of DMC/ml. These observations suggest that DMC is selectively toxic to the parasites. Its simple structure may well enable it to serve as a new lead compound for the synthesis of novel antileishmanial drugs. (+info)
Improvement of in vitro and in vivo antileishmanial activities of 2', 6'-dihydroxy-4'-methoxychalcone by entrapment in poly(D,L-lactide) nanoparticles.
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The inhibition of intracellular Leishmania amazonensis growth by 2', 6'-dihydroxy-4'-methoxychalcone (DMC) isolated from Piper aduncum was further enhanced after encapsulation of DMC in polymeric nanoparticles. Encapsulated DMC also showed increased antileishmanial activity in infected BALB/c mice, as evidenced by significantly smaller lesions and fewer parasites in the lesions. (+info)
Cytochrome P-450-derived epoxyeicosatrienoic acids (EETs) are avidly incorporated into and released from endothelial phospholipids, a process that results in potentiation of endothelium-dependent relaxation. EETs are also rapidly converted by epoxide hydrolases to dihydroxyeicosatrienoic acid (DHETs), which are incorporated into phospholipids to a lesser extent than EETs. We hypothesized that epoxide hydrolases functionally regulate EET incorporation into endothelial phospholipids. Porcine coronary artery endothelial cells were treated with an epoxide hydrolase inhibitor, 4-phenylchalcone oxide (4-PCO, 20 micromol/l), before being incubated with (3)H-labeled 14,15-EET (14,15-[(3)H]EET). 4-PCO blocked conversion of 14,15-[(3)H]EET to 14,15-[(3)H]DHET and doubled the amount of radiolabeled products incorporated into cell lipids, with >80% contained in phospholipids. Moreover, pretreatment with 4-PCO before incubation with 14,15-[(3)H]EET enhanced A-23187-induced release of radiolabeled products into the medium. In contrast, 4-PCO did not alter uptake, distribution, or release of [(3)H]arachidonic acid. In porcine coronary arteries, 4-PCO augmented 14,15-EET-induced potentiation of endothelium-dependent relaxation to bradykinin. These data suggest that epoxide hydrolases may play a role in regulating EET incorporation into phospholipids, thereby modulating endothelial function in the coronary vasculature. (+info)
2'-hydroxychalcone inhibits nuclear factor-kappaB and blocks tumor necrosis factor-alpha- and lipopolysaccharide-induced adhesion of neutrophils to human umbilical vein endothelial cells.
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Inhibition of expression of cell adhesion molecules (CAM), including intercellular CAM-1 (ICAM-1), vascular CAM-1 (VCAM-1), and E-selectin, has been shown to be important in controlling various inflammatory diseases. The cell adhesion proteins are induced by various inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1, and bacterial lipopolysaccharide. The induction process primarily takes place at the level of transcription, where nuclear factor-kappaB (NF-kappaB) plays a major role. We demonstrate here that 2'-hydroxychalcone inhibits the adhesion of peripheral neutrophils to the endothelial cell monolayers by inhibiting the expression of ICAM-1, VCAM-1, and E-selectin in a concentration-dependent manner. The inhibition by 2'-hydroxychalcone is reversible. 2'-hydroxychalcone inhibits the induction of steady-state transcript levels of ICAM-1, VCAM-1, and E-selectin by tumor necrosis factor-alpha as determined by reverse transcription-polymerase chain reaction, and therefore it may interfere with the transcription of their genes. Because NF-kappaB is a major transcription factor involved in CAM expression, we studied its status in the 2'-hydroxychalcone treated cells. We demonstrate that 2'-hydroxychalcone inhibits the activation of NF-kappaB. These results have implications for using NF-kappaB inhibitors for the treatment of various inflammatory diseases. (+info)
Neohesperidin dihydrochalcone is not a taste enhancer in aqueous sucrose solutions.
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Neohesperidin dihydrochalcone (NHDC) is an intensive sweetener, obtained by alkaline hydrogenation of neohesperidin. In this investigation a supposed taste enhancing effect of this substance was tested. A three-step procedure was used. In the first experiment, using a pool of 31 subjects, NHDC and sucrose detection thresholds were measured. In the second experiment, psychophysical functions for both tastants were determined. Then, 15 participants closest to the group threshold who, in addition, had produced monotonic psychophysical taste functions were selected to participate in the next two experiments. In the third experiment, taste enhancement was tested. Three psychophysical sucrose functions were constructed, one with a near-threshold amount of NHDC added to each of seven sucrose concentrations, one with a near-threshold amount of sucrose added (control 1) and one without any addition (control 2). No difference was found between the NHDC-enriched sucrose function and the sucrose-enriched sucrose function. Finally, in experiment 4, differential threshold functions were constructed with either NHDC or sucrose added. Neither the overall shape of the functions nor a comparison of the points of subjective equality showed enhancement. It was concluded that weak NHDC does not enhance the taste of aqueous sucrose solutions. (+info)
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)
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)
Dibenzoylmethane modulates aryl hydrocarbon receptor function and expression of cytochromes P50 1A1, 1A2, and 1B1.
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The phytochemical dibenzoylmethane (DBM) has been shown to prevent polycyclic aromatic hydrocarbon (PAH)-induced tumorigenesis in rodents. However, the biochemical basis of this activity is unclear. We have therefore investigated the effects of DBM on the activity and expression of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2, and 1B1. Oral administration of DBM to female Sprague Dawley rats inhibited the increase in hepatic enzyme activity and mRNA levels of CYP1A1, 1A2, and 1B1 caused by the PAH 7,12-dimethylbenz[a]anthracene (DMBA). However, DBM administration alone caused an increase in both activity and expression in the liver, albeit to levels much lower than that induced by DMBA. To characterize the molecular mechanisms involved in this dual action of DBM, we examined the effects of DBM in vitro. In HepG2 human hepatoma cells, DBM inhibited DMBA- and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced enzyme activity and CYP1A1, 1A2, and 1B1 mRNA levels, whereas DBM itself induced activity and mRNA expression. Modulation of CYP1A1 expression by DBM occurred at the transcriptional level, as transient transfection assays demonstrated. Because the transcription of CYP1A1 is regulated by the aryl hydrocarbon receptor (AhR), we investigated the effect of DBM on AhR activation. DBM inhibited TCCD-induced DNA-binding of the AhR to the xenobiotic-responsive element (XRE) of CYP1A1 as measured by electrophoretic mobility shift assay. These data suggest that the chemopreventive activity of DBM results from its ability to affect Phase 1 enzyme expression by modulation of AhR function. (+info)