Phytochemicals induce breast cancer resistance protein in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate.
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We have previously reported that breast cancer resistance protein (BCRP) is involved in the transport of phase II metabolites of the food carcinogen benzo[a]pyrene (BP) in the human intestinal cell line Caco-2. Furthermore, the expression of BCRP seemed most likely to be aryl hydrocarbon receptor (AhR) dependent. Since numerous plant-derived anticarcinogens with AhR-agonistic activity have been identified to date, in the present study we investigated the effects of naturally occurring dietary compounds and tert-butyl hydroquinone (TBHQ) for their effects on BCRP expression. In Caco-2 cells, the most pronounced induction of BCRP expression could be observed after treatment with TBHQ (100 microM), dibenzoylmethane (DBM, 50 microM), and quercetin (25 microM), while green tea component (-)-epicatechin (50 microM) decreased BCRP expression. On mRNA level, quercetin, chrysin, flavone, and indole-3-carbinol showed a strong inducing effect, while genistein had no effect on BCRP mRNA expression. Curcumin and resveratrol showed a strong effect on BCRP induction in MCF-7 wild-type cells but no response in AhR-deficient MCF-7AHR(200) cells, supporting our hypothesis that BCRP is regulated via AhR-dependent signaling pathways. Inhibition of proteasome-mediated degradation of ligand-activated AhR caused a "superinduction" of BCRP mRNA. Antioxidant responsive element activators sulforaphane and diethylmaleate (DEM) had no inducing effect on BCRP mRNA expression. Caco-2 cells pretreated with quercetin or DBM showed an enhancement of apically transported benzo[a]pyrene-3-sulfate, indicating that induced BCRP was functionally active. In conclusion, apart from the modulation of detoxifying enzymes in the intestine, induction of BCRP by dietary constituents may contribute to the detoxification of food-derived procarcinogens such as BP. (+info)
Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine.
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Glycyrrhizae radix is used to treat abdominal pain as a component of shakuyakukanzoto (shaoyao-gancao-tang), a traditional Chinese medicine formulation. Previously, we have reported the isolation of glycycoumarin as a potent antispasmodic with an IC50 value of 2.93+/-0.94 microM for carbamylcholine (CCh)-induced contraction of mouse jejunum from an aqueous extract of Glycyrrhizae radix (licorice), and clarified that its mechanism of action involves inhibition of phosphodiesterase 3. The purpose of the present study was to examine an antispasmodic principle of licorice other than glycycoumarin. Isoliquiritigenin was isolated from an aqueous extract of licorice as a potent relaxant, which inhibited the contraction induced by various types of stimulants, such as CCh, KCl, and BaCl2 with IC50 values of 4.96+/-1.97 microM, 4.03+/-1.34 microM and 3.70+/-0.58 microM, respectively, which are close to those of papaverine. However, the amount of isoliquiritigenin in the aqueous extract of licorice was very small. When the aqueous licorice extract was treated with naringinase, the amounts of glycosides such as isoliquiritin, which were abundant but had much less potent relaxant activity, were decreased while isoliquiritigenin was increased. At the time, the relaxant activity of the treated sample was increased significantly, shifting the IC50 from 358+/-104 to 150+/-38 microg/ml for CCh-induced contraction. Isoliquiritigenin also showed the most potent inhibition of mouse rectal contraction induced by CCh with an IC50 value of 1.70+/-0.07 microM. These results suggest that isoliquiritigenin acts as a potent relaxant in the lower part of the intestine by transformation from its glycosides. (+info)
In vitro study for inhibition of NO production about constituents of Sappan Lignum.
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In the course of our screening, we found that the methanolic extract of Sappan Lignum showed strong activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production by macrophages in vitro. As it was reported that Brazilin inhibited inducible NO gene, we conducted to similar tests for six known compounds isolated from Sappan Lignum, namely, brazilein, sappanchalcone, protosappanin A, protosappanin B, protosappanin C besides brazilin. And six compounds were also subjected to six tests to speculate their properties: (1) inhibition of NO production by cultured J774.1 (macrophage-like) cell line, (2) suppression of inducible NO synthase (iNOS) gene expression, (3) inhibition of NO production by murine peritoneal macrophages, (4) DPPH radical scavenging activity, (5) reduction of ferric ion and (6) antioxidant activity. Brazilein and sappanchalcone showed significant inhibition of lipopolysaccharide (LPS)-induced NO production by J774.1 cell line like Brazilin; 100% inhibition at 30 microM in test (1) and at 10 microM in test (3). The mechanisms underlying the inhibition of NO production by the compounds were investigated in test (2). As a result, brazilin was found to almost completely suppress iNOS gene expression at 100 microM as reported, and brazilein and sappanchalcone also suppressed iNOS gene expression. But strong activities were not observed for protosappanins A, B and C. So, we conducted tests (4), (5) and (6) to investigate other properties about six compounds. Protosappanin A and Brazilin demonstrated high antioxidant activity compared with Vitamin E in tests (4) and (5). Protosappanin A and B inhibited the oxidation of linoleic acid in test (6). Among the dibenzoxocin derivatives, only protosappanin C did not show significant activity in all the tests. We found that sappanchalcone showed same activity as brazilin, and six compounds isolated from Sappan Lignum showed various properties. (+info)
QSAR studies on chalcones and flavonoids as anti-tuberculosis agents using genetic function approximation (GFA) method.
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Design of compounds having good anti-tubercular activity is gaining much importance in the field of tuberculosis research due to reemergence of antibiotic resistance strains. In this paper quantitative structure activity relationships (QSAR) were developed on chalcones, chalcone-like compounds, flavones and flavanones to understand the relationship between biological activity and structural features. Genetic function approximation (GFA) method was used to identify the descriptors that would lead to good regression equations. The best molecular descriptors identified were Jurs descriptors (Jurs charged partial surface area), hydrogen bond donor, principal moment of inertia, molecular energy, dipole magnetic, molecular area, absorption, distribution, metabolism and excretion (ADME) properties and Chi indices (Kier & Hall chi connectivity indices). Excellent statistically significant models were developed by this approach (r(2)=0.8-0.97) for the four groups of compounds. The cross validated r(2) (XV r(2)) which is an indication of the predictive capability of the model for all the cases was also very good (=0.79-0.94). (+info)
Antioxidant properties of neohesperidin dihydrochalcone: inhibition of hypochlorous acid-induced DNA strand breakage, protein degradation, and cell death.
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Neohesperidin dihydrochalcone (NHDC), a non-nutritive sweetening agent, is simply produced by hydrogenation of neohesperidin. The aim of this study is to evaluate the antioxidant and radical scavenging properties of neohesperidin dihydrochalcone and other structurally related compounds (phloridzin, neohesperidin) toward different reactive radical and oxygen species including .ABTS+, .O2-, .OH, H2O2, and HOCl in vitro. NHDC showed remarkable radical scavenging activity against stable radical and reactive oxygen species (ROS) in concentration dependent manner. Especially, NHDC was the most potent inhibitor of H2O2 and HOCl. NHDC showed HOCl scavenging activity of 93.5% and H2O2 scavenging property of 73.5% which was more than those of all the tested compounds including ascorbic acid and BHT. Moreover, NHDC could inhibit protein degradation, plasmid DNA strand cleavage and HIT-T15, HUVEC cell death from HOCl attack while mannitol, BHT, and ascorbic acid could not protect them effectively. These results suggest that NHDC is a potent antioxidant, especially it is evaluated as a novel HOCl scavenger. This study implies the possibility of therapeutic effect of NHDC on ROS-related inflammatory diseases. (+info)
The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation.
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Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans. (+info)
Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue.
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Although butein (3,4,2',4'-tetrahydroxychalcone) is known to exhibit anti-inflammatory, anti-cancer, and anti-fibrogenic activities, very little is known about its mechanism of action. Because numerous effects modulated by butein can be linked to interference with the NF-kappaB pathway, we investigated in detail the effect of this chalcone on NF-kappaB activity. As examined by DNA binding, we found that butein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation in a dose- and time-dependent manner; suppressed the NF-kappaB activation induced by various inflammatory agents and carcinogens; and inhibited the NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKK-beta. We also found that butein blocked the phosphorylation and degradation of IkappaBalpha by inhibiting IkappaBalpha kinase (IKK) activation. We found the inactivation of IKK by butein was direct and involved cysteine residue 179. This correlated with the suppression of phosphorylation and the nuclear translocation of p65. In this study, butein also inhibited the expression of the NF-kappaB-regulated gene products involved in anti-apoptosis (IAP2, Bcl-2, and Bcl-xL), proliferation (cyclin D1 and c-Myc), and invasion (COX-2 and MMP-9). Suppression of these gene products correlated with enhancement of the apoptosis induced by TNF and chemotherapeutic agents; and inhibition of cytokine-induced cellular invasion. Overall, our results indicated that antitumor and anti-inflammatory activities previously assigned to butein may be mediated in part through the direct inhibition of IKK, leading to the suppression of the NF-kappaB activation pathway. (+info)
Rapid identification of antibacterial agents effective against Staphylococcus aureus using small-molecule macroarrays.
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There is an urgent, global need for the development of new antibacterial agents. We have applied the small-molecule macroarray approach to the synthesis and screening of antibacterial compounds active against the Gram-positive pathogen Staphylococcus aureus. Several macroarrays of 1,3-diphenyl-2-propen-1-ones (chalcones), cyanopyridines, and pyrimidines were synthesized on a planar cellulose support system on the order of days. This support system was found to be highly compatible with antibacterial assay formats, including disk-diffusion and agar-overlay visualization methods. Further, sufficient compound was isolated from each spot of the macroarray for both compound characterization and minimum inhibitory concentration (MIC) estimation. Analysis of the small-molecule macroarrays in these assays uncovered a set of antibacterial agents with in vitro MIC values against methicillin-resistant S. aureus comparable to certain antibacterial drugs in use today. (+info)