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Jan F Stevens - One of the best experts on this subject based on the ideXlab platform.
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human pharmacokinetics of Xanthohumol an antihyperglycemic flavonoid from hops
Molecular Nutrition & Food Research, 2014Co-Authors: Leecole L Legette, Jaewoo Choi, Ralph L Reed, Gerd Bobe, Chanida Karnpracha, Mark J Christensen, Rosita Rodriguezproteau, Jonathan Q Purnell, Jan F StevensAbstract:Scope Xanthohumol (XN) is a bioactive prenylflavonoid from hops. A single-dose pharmacokinetic (PK) study was conducted in men (n = 24) and women (n = 24) to determine dose–concentration relationships. Methods and results Subjects received a single oral dose of 20, 60, or 180 mg XN. Blood was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 h. Plasma levels of XN and its metabolites, isoXanthohumol (IX), 8-prenylnaringenin (8PN), and 6-prenylnaringenin (6PN) were measured by LC-MS/MS. Xanthohumol (XN) and IX conjugates were dominant circulating flavonoids among all subjects. Levels of 8PN and 6PN were undetectable in most subjects. The XN PK profile showed peak concentrations around 1 h and between 4–5 h after ingestion. The maximum XN concentrations (Cmax) were 33 ± 7 mg/L, 48 ± 11 mg/L, and 120 ± 24 mg/L for the 20, 60, and 180 mg dose, respectively. Using noncompartmental modeling, the area under the curves (AUC0∞) for XN were 92 ± 68 h × μg/L, 323 ± 160 h × μg/L, and 863 ± 388 h × μg/L for the 20, 60, and 180 mg dose, respectively. The mean half-life of XN was 20 h for the 60 and 18 h for the 180 mg dose. Conclusion XN has a distinct biphasic absorption pattern with XN and IX conjugates being the major circulating metabolites.
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Xanthohumol lowers body weight and fasting plasma glucose in obese male zucker fa fa rats
The FASEB Journal, 2012Co-Authors: Leecole L Legette, Cristobal L Miranda, Arlyn Moreno Y Luna, Ralph L Reed, Gerd Bobe, Rosita R Proteau, Jan F StevensAbstract:Obesity contributes to increased risk for several chronic diseases including cardiovascular disease and type 2 diabetes. Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), was tested for efficacy on biomarkers of metabolic syndrome in 4 week old Zucker fa/fa rats, a rodent model of obesity. Rats received daily oral doses of Xanthohumol at 0, 1.86, 5.64, and 16.9 mg/kg BW for 6 weeks. All rats were maintained on a high fat (60% kcal) AIN-93G diet for 3 weeks to induce severe obesity followed by a normal AIN-93G (15% kcal fat) diet for the last 3 weeks of the study. Weekly food intake and body weight were recorded. Plasma cholesterol, glucose, insulin, triglyceride, and monocyte chemoattractant protein-1 (MCP-1) levels were assessed using commercial assay kits. Plasma and liver tissue levels of XN and its metabolites were determined by liquid-chromatography tandem mass spectrometry. Plasma and liver tissue levels of Xanthohumol were similar between low and medium dose groups and significantly (p<0.05) elevated in the highest dose group. There was a dose-dependent effect on body weight and plasma glucose levels. The highest dose group (n=6) had significantly lower plasma glucose levels compared to the control group (n=6) in male but not female rats. There was also a significant decrease in body weight for male rats in the highest dose group (16.9 mg/kg BW) compared to rats that received no Xanthohumol, which was also not seen for female rats. Plasma cholesterol, insulin, triglycerides, and MCP-1 as well as food intake were not affected by treatment. The findings suggest that Xanthohumol has beneficial effects on markers of metabolic syndrome.
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est analysis of hop glandular trichomes identifies an o methyltransferase that catalyzes the biosynthesis of Xanthohumol
The Plant Cell, 2008Co-Authors: Jan F Stevens, Jana Nagel, Lana K Culley, Yuping Lu, P Matthews, Jonathan E PageAbstract:The glandular trichomes (lupulin glands) of hop (Humulus lupulus) synthesize essential oils and terpenophenolic resins, including the bioactive prenylflavonoid Xanthohumol. To dissect the biosynthetic processes occurring in lupulin glands, we sequenced 10,581 ESTs from four trichome-derived cDNA libraries. ESTs representing enzymes of terpenoid biosynthesis, including all of the steps of the methyl 4-erythritol phosphate pathway, were abundant in the EST data set, as were ESTs for the known type III polyketide synthases of bitter acid and Xanthohumol biosynthesis. The Xanthohumol biosynthetic pathway involves a key O-methylation step. Four S-adenosyl-l-methionine–dependent O-methyltransferases (OMTs) with similarity to known flavonoid-methylating enzymes were present in the EST data set. OMT1, which was the most highly expressed OMT based on EST abundance and RT-PCR analysis, performs the final reaction in Xanthohumol biosynthesis by methylating desmethylXanthohumol to form Xanthohumol. OMT2 accepted a broad range of substrates, including desmethylXanthohumol, but did not form Xanthohumol. Mass spectrometry and proton nuclear magnetic resonance analysis showed it methylated Xanthohumol to 4-O-methylXanthohumol, which is not known from hop. OMT3 was inactive with all substrates tested. The lupulin gland-specific EST data set expands the genomic resources for H. lupulus and provides further insight into the metabolic specialization of glandular trichomes.
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Xanthohumol and related prenylflavonoids from hops and beer to your good health
Phytochemistry, 2004Co-Authors: Jan F Stevens, Jonathan E PageAbstract:Abstract Xanthohumol (3 ′ -[3,3-dimethyl allyl]-2 ′ ,4 ′ ,4-trihydroxy-6 ′ -methoxychalcone) is the principal prenylated flavonoid of the female inflorescences of the hop plant (`hops'), an ingredient of beer. Human exposure to Xanthohumol and related prenylflavonoids, such as 8-prenylnaringenin and isoXanthohumol, is primarily through beer consumption. Xanthohumol has been characterized a `broad-spectrum' cancer chemopreventive agent in in vitro studies, while 8-prenylnaringenin enjoys fame as the most potent phytoestrogen known to date. These biological activities suggest that prenylflavonoids from hops have potential for application in cancer prevention programs and in prevention or treatment of (post-)menopausal `hot flashes' and osteoporosis. Xanthohumol and 8-prenylnaringenin are metabolized into many flavonoid derivatives with modified 3,3-dimethyl allyl (prenyl) moieties. Xanthohumol is formed in lupulin glands by a specialized branch of flavonoid biosynthesis that involves prenylation and O-methylation of the polyketide intermediate chalconaringenin. Although a lupulin gland-specific chalcone synthase is known, the aromatic prenyltransferase and O -methyltransferase participating in Xanthohumol have not been identified. The prenylflavonoid pathway is a possible target for breeding or biotechnological modification of hops with the aim of increasing Xanthohumol levels for beer brewing and 8-prenylnaringenin levels for pharmaceutical production.
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prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2 amino 3 methylimidazo 4 5 f quinoline mediated by cdna expressed human cyp1a2
Drug Metabolism and Disposition, 2000Co-Authors: Cristobal L Miranda, Max L Deinzer, Jan F Stevens, Yeahuey Yang, Marilyn C Henderson, Gilberto Santanarios, Donald R BuhlerAbstract:The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potential human carcinogen found in cooked food that requires initial metabolic activation by cytochrome P450s, primarily CYP1A2. The present study was conducted to examine whether recombinant human CYP1A2 expressed in insect cells mediates the metabolic activation of IQ and whether prenylflavonoids found in hops and beer would modulate the CYP1A2-mediated activation of IQ. The cDNA-expressed human CYP1A2 was found to strongly activate IQ as measured by the Ames Salmonella assay and by the covalent binding of IQ metabolites to calf thymus DNA and protein. Inhibition studies showed that the prenylchalcone Xanthohumol and the prenylflavanones 8-prenylnaringenin and isoXanthohumol strongly inhibited the mutagenic activation of IQ mediated by cDNA-expressed human CYP1A2 in the Ames Salmonella assay. The three prenylflavonoids also markedly inhibited the human CYP1A2-mediated binding of IQ to metabolites that bind to DNA. The inhibition of the metabolic activation of IQ was paralleled by the inhibition of acetanilide 4-hydroxylase activity of human CYP1A2. Thus, Xanthohumol, isoXanthohumol, and prenylflavanones 8-prenylnaringenin are potent inhibitors of the metabolic activation of IQ and may have the potential to act as chemopreventive agents against cancer induced by heterocyclic amines activated by CYP1A2.
Max L Deinzer - One of the best experts on this subject based on the ideXlab platform.
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prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2 amino 3 methylimidazo 4 5 f quinoline mediated by cdna expressed human cyp1a2
Drug Metabolism and Disposition, 2000Co-Authors: Cristobal L Miranda, Max L Deinzer, Jan F Stevens, Yeahuey Yang, Marilyn C Henderson, Gilberto Santanarios, Donald R BuhlerAbstract:The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potential human carcinogen found in cooked food that requires initial metabolic activation by cytochrome P450s, primarily CYP1A2. The present study was conducted to examine whether recombinant human CYP1A2 expressed in insect cells mediates the metabolic activation of IQ and whether prenylflavonoids found in hops and beer would modulate the CYP1A2-mediated activation of IQ. The cDNA-expressed human CYP1A2 was found to strongly activate IQ as measured by the Ames Salmonella assay and by the covalent binding of IQ metabolites to calf thymus DNA and protein. Inhibition studies showed that the prenylchalcone Xanthohumol and the prenylflavanones 8-prenylnaringenin and isoXanthohumol strongly inhibited the mutagenic activation of IQ mediated by cDNA-expressed human CYP1A2 in the Ames Salmonella assay. The three prenylflavonoids also markedly inhibited the human CYP1A2-mediated binding of IQ to metabolites that bind to DNA. The inhibition of the metabolic activation of IQ was paralleled by the inhibition of acetanilide 4-hydroxylase activity of human CYP1A2. Thus, Xanthohumol, isoXanthohumol, and prenylflavanones 8-prenylnaringenin are potent inhibitors of the metabolic activation of IQ and may have the potential to act as chemopreventive agents against cancer induced by heterocyclic amines activated by CYP1A2.
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fate of Xanthohumol and related prenylflavonoids from hops to beer
Journal of Agricultural and Food Chemistry, 1999Co-Authors: Jan F Stevens, Alan W Taylor, Jeff E Clawson, Max L DeinzerAbstract:The fate of three prenylated flavonoids of the chalcone type, Xanthohumol, desmethylXanthohumol, and 3'-geranylchalconaringenin, was monitored with LC/MS-MS from hops (Humulus lupulus L.) to beer in two brewing trials. The three prenylchalcones were largely converted into their isomeric flavanones, isoXanthohumol, prenylnaringenins, and geranylnaringenins, respectively, in the boiling wort. Losses of prenylflavonoids were due to incomplete extraction from the hops into the wort (13-25%), adsorption to insoluble malt proteins (18-26%), and adsorption to yeast cells (11-32%) during fermentation. The overall yield of Xanthohumol, after lagering of the beer and largely in the form of isoXanthohumol, amounted to 22-30% of the hops' Xanthohumol. About 10% of the hops' desmethylXanthohumol, completely converted into prenylnaringenins, remained in the beers. 3'-Geranylchalconaringenin behaved similarly to desmethylXanthohumol. Solubility experiments indicated that (1) malt carbohydrates form soluble complexes with Xanthohumol and isoXanthohumol and (2) solubility does not dictate the isoXanthohumol levels of finished beers.
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quantitative analysis of Xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography tandem mass spectrometry
Journal of Chromatography A, 1999Co-Authors: Jan F Stevens, Alan W Taylor, Max L DeinzerAbstract:A method for quantitation of six prenylflavonoids (Xanthohumol, isoXanthohumol, desmethylXanthohumol, 6- and 8-prenylnaringenins and 6-geranylnaringenin) in hops and beer by HPLC-tandem mass spectrometry has been developed. The method allows direct analysis of beer and crude methanolic extracts of hops. After HPLC separation, prenylflavonoids were detected by positive ion multiple-reaction monitoring using a triple-quadrupole mass spectrometer equipped with a heated nebulizer--atmospheric pressure chemical ionization interface. The accuracy and precision were evaluated by replicate analyses of (spiked) samples. Thirteen commercial beers were analysed with the method. IsoXanthohumol, formed by isomerization of Xanthohumol during the brewing process, was the most abundant flavonoid in hopped beers, ranging from 0.04 to 3.44 mg/l.
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prenylflavonoids from humulus lupulus
Phytochemistry, 1997Co-Authors: Jan F Stevens, Monika Ivancic, Max L DeinzerAbstract:Abstract Five flavonoids were isolated from the resin part of the female inflorescences of Humulus lupulus , together with four known hop flavonoids, i.e. Xanthohumol, 2′,4′,6′,4-tetrahydroxy-3′- C -prenylchalcone, iso-Xanthohumol and 6-prenylnaringenin. The new hop compounds were identified as 2′,4′,6′,4-tetrahydroxy-3′- C -geranylchalcone, 5′-prenylXanthohumol, 6″,6″-dimethylpyrano (2″,3″: 3′,4′)-2′,4-dihydroxy-6′-methoxychalcone, its hydrate and 8-prenylnaringenin; apart from 8-prenylnaringenin, these are new flavonoids. Their mass fragmentation patterns were studied by mass spectrometry using atmospheric pressure chemical ionization in combination with collision-activated decomposition. Loss of the isoprenoid substituent in the positive ion mode and retro Diels-Alder fission in both the positive and negative ion modes provided useful information on the substitution patterns of the A and B rings. Nine hop varieties were qualitatively and quantatively characterized by HPLC-mass spectrometry. The flavonoid profiles of the samples examined were uniform and proved to be of little value in hop variety identification. Xanthohumol was the principal flavonoid in all samples (80–90% of the total of flavonoids) and was accompanied by minor amounts of the other eight flavonoids in virtually all samples.
Metka Filipic - One of the best experts on this subject based on the ideXlab platform.
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protective effects of Xanthohumol against the genotoxicity of benzo a pyrene bap 2 amino 3 methylimidazo 4 5 f quinoline iq and tert butyl hydroperoxide t booh in hepg2 human hepatoma cells
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2007Co-Authors: Janja Plazar, Bojana Zegura, Tamara T Lah, Metka FilipicAbstract:Abstract Xanthohumol is the major prenylated flavonoid present in the hop plant Humulus lupulus L. (Cannabinaceae) and a common ingredient of beer. Recently, Xanthohumol has gained considerable interest due to its potential cancer chemo-preventive effect. The aim of this study was to reveal the possible anti-genotoxic activity of Xanthohumol in metabolically competent human hepatoma HepG2 cells, by use of the comet assay. Xanthohumol by itself was neither cytotoxic nor genotoxic to the cells at concentrations below 10 μM. However, a significant protective effect against the pro-carcinogens benzo(a)pyrene (BaP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was observed at concentrations as low as 0.01 μM. In cells treated with Xanthohumol in combination with tert -butyl hydroperoxide ( t -BOOH) – an inducer of reactive oxygen species (ROS) – no protective effect was observed and Xanthohumol also showed no significant scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. On the other hand, HepG2 cells pre-treated with Xanthohumol showed significantly reduced levels of t -BOOH-induced DNA strand breaks, indicating that its protective effect is mediated by induction of cellular defence mechanisms against oxidative stress. As Xanthohumol is known to be an effective inhibitor of cytochrome P450 enzymes and an inducer of NAD(P)H: quinone reductase (QR), our findings can be explained by an inhibition of metabolic activation of pro-carcinogens and/or by induction of carcinogen-detoxifying and anti-oxidative enzymes by Xanthohumol. These results provide evidence that Xanthohumol displays anti-genotoxic activity in metabolically competent human cells.
Raquel Soares - One of the best experts on this subject based on the ideXlab platform.
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Xanthohumol and 8 prenylnaringenin reduce type 2 diabetes associated oxidative stress by downregulating galectin 3
Porto Biomedical Journal, 2019Co-Authors: Carla Luis, Raquel Costa, Ilda Rodrigues, ângela Castela, Pedro Coelho, Susana G Guerreiro, Joana Gomes, Celso A Reis, Raquel SoaresAbstract:Background Galectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the literature to play either a protective role or exacerbating disease. Methods Herein, we examined the interplay between Gal3 and oxidative stress in a high-fat diet -induced type 2 DMC57Bl/6 mice model. Because natural polyphenols are known to play antioxidant and anti-inflammatory roles and to modulate metabolic activity, we further evaluated the effect of Xanthohumol and 8-prenylnaringenin polyphenols in this crosstalk. Results Gal3 expression was accompanied by 3-nitrotyrosine and AGE production in liver and kidney of diabetic mice compared to healthy animals (fed with standard diet). Oral supplementation with polyphenols decreased the levels of these oxidative biomarkers as evaluated by immunohistochemistry and western blotting. Interestingly, blocking Gal3 by incubating human microvascular endothelial cells with modified citrus pectin increased 3-nitrotyrosine protein expression. Conclusions These findings imply that Gal3 overexpression is probably controlling oxidative stress in endothelial cells. In conclusion, our results indicate that supplementation with 8-prenylnaringenin or Xanthohumol reverses diabetes-associated oxidation in liver and kidney, and consequently decreases this diabetic biomarker that predispose to cardiovascular complications.
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Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts
Journal of Cellular Biochemistry, 2008Co-Authors: Rosario Monteiro, Isabel Azevedo, Conceicao Calhau, Susana G Guerreiro, Artur Oliveira E Silva, Sandra Pinheirosilva, Fatima Gartner, Raquel SoaresAbstract:Xanthohumol, a natural polyphenol present in beer, is known to exert anti-cancer effects. However, its precise mechanisms are not yet clearly defined. The aim of this study was to investigate the effect of oral administration of Xanthohumol (XN) in breast cancer xenografts in nude mice. Proliferation and apoptosis were first examined in MCF7 cell cultures after incubation with XN by trypan blue exclusion assay, ( 3 H)-thymidine incorporation, KI67 immunostaining and TUNEL. Morphological and histological characteristics of tumours from XN-treated or control (vehicle-treated) mice were compared. Immunohistochemistry for proliferative, inflammatory and endothelial cell markers was performed and activation of nuclear factor kappa B (NFkB) pathway was assessed by ELISA. In vitro MCF7 cell proliferation decreased in a dose-dependent manner. Oral administration of XN to nude mice inoculated with MCF7 cells resulted in central necrosis within tumours, reduced inflammatory cell number, focal proliferation areas, increased percentage of apoptotic cells and decreased microvessel density. Anti-angiogenic effects of XN were further confirmed by immunoblotting for factor VIII expression in XN-treated tumours as compared to controls. Decreased immunostaining for NFkB, phosphorylated- inhibitor of kappa B and interleukin-1b were also observed as well as a significant decrease in NFkB activity to 60% of control values. These novel findings indicate that XN is able to target both breast cancer and host cells, namely inflammatory and endothelial cells, suggesting its potential use as a double-edge anti-cancer agent. J. Cell. Biochem.
Thomas Hofmann - One of the best experts on this subject based on the ideXlab platform.
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sensomics analysis of key bitter compounds in the hard resin of hops humulus lupulus l and their contribution to the bitter profile of pilsner type beer
Journal of Agricultural and Food Chemistry, 2015Co-Authors: Michael Dresel, Andreas Dunkel, Thomas HofmannAbstract:Recent brewing trials indicated the occurrence of valuable bitter compounds in the hard resin fraction of hop. Aiming at the discovery of these compounds, hop’s e-resin was separated by means of a sensory guided fractionation approach and the key taste molecules were identified by means of UV/vis, LC-TOF-MS, and 1D/2D-NMR studies as well as synthetic experiments. Besides a series of literature known Xanthohumol derivatives, multifidol glucosides, flavon-3-on glycosides, and p-coumaric acid esters, a total of 11 bitter tastants are reported for the first time, namely, 1″,2″-dihydroXanthohumol F, 4′-hydroxytunicatachalcone, isoxantholupon, 1-methoxy-4-prenylphloroglucinol, dihydrocyclohumulohydrochinone, Xanthohumols M, N, and P, and isoXanthohumols M, N, and P, respectively. Human sensory analysis revealed low bitter recognition threshold concentrations ranging from 5 (co-multifidol glucopyranoside) to 198 μmol/L (trans-p-coumaric acid ethyl ester) depending on their chemical structure. For the first time,...
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sensomics analysis of key bitter compounds in the hard resin of hops humulus lupulus l and their contribution to the bitter profile of pilsner type beer
Journal of Agricultural and Food Chemistry, 2015Co-Authors: Michael Dresel, Andreas Dunkel, Thomas HofmannAbstract:Recent brewing trials indicated the occurrence of valuable bitter compounds in the hard resin fraction of hop. Aiming at the discovery of these compounds, hop's e-resin was separated by means of a sensory guided fractionation approach and the key taste molecules were identified by means of UV/vis, LC-TOF-MS, and 1D/2D-NMR studies as well as synthetic experiments. Besides a series of literature known Xanthohumol derivatives, multifidol glucosides, flavon-3-on glycosides, and p-coumaric acid esters, a total of 11 bitter tastants are reported for the first time, namely, 1",2"-dihydroXanthohumol F, 4'-hydroxytunicatachalcone, isoxantholupon, 1-methoxy-4-prenylphloroglucinol, dihydrocyclohumulohydrochinone, Xanthohumols M, N, and P, and isoXanthohumols M, N, and P, respectively. Human sensory analysis revealed low bitter recognition threshold concentrations ranging from 5 (co-multifidol glucopyranoside) to 198 μmol/L (trans-p-coumaric acid ethyl ester) depending on their chemical structure. For the first time, LC-MS/MS quantitation of these taste compounds in Pilsner-type beer, followed by taste re-engineering experiments, revealed the additive contribution of iso-α-acids and the identified hard resin components to be truly necessary and sufficient for constructing the authentic bitter percept of beer. Finally, brewing trails using the e-resin as the only hop source impressively demonstrated the possibility to produce beverages strongly enriched with prenylated hop flavonoids.
