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Scope: Inflorescences of the female hop plant (Humulus lupulus L.) contain biologically active compounds, most of which have a bitter taste. Given the rising global obesity rates, there is much increasing interest in bitter taste receptors (TAS2Rs). Intestinal TAS2Rs can have beneficial effects on obesity when activated by bitter agonists. This study aims to investigate the mechanism of action of a hydroalcoholic hop extract in promoting hormone secretion that reduces the sense of hunger at the intestinal level through the interaction with TAS2Rs., Methods and Results: The results demonstrate that the hop extract is a rich source of bitter compounds (mainly α-, β-acids) that stimulate the secretion of anorexigenic peptides (glucagon-like peptide 1 [GLP-1], cholecystokinin [CCK]) in a calcium-dependent manner while reducing levels of hunger-related hormones like ghrelin. This effect is mediated through interaction with TAS2Rs, particularly Tas2r138 and Tas2r120, and through the activation of downstream signaling cascades. Knockdown of these receptors using siRNA transfection and inhibition of Trpm5, Plcβ-2, and other calcium channels significantly reduces the hop-induced calcium response as well as GLP-1 and CCK secretion., Conclusions: This study provides a potential application of H. lupulus extract for the formulation of food supplements with satiating activity capable of preventing or combating obesity., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Scope: The glucosinolate glucoraphanin from broccoli is converted to sulforaphane (SFN) or sulforaphane-nitrile (SFN-NIT) by plant enzymes or the gut microbiome. Human feeding studies typically observe high inter-individual variation in absorption and excretion of SFN, however, the source of this variation is not fully known. To address this, a human feeding trial to comprehensively evaluate inter-individual variation in the absorption and excretion of all known SFN metabolites in urine, plasma, and stool, and tested the hypothesis that gut microbiome composition influences inter-individual variation in total SFN excretion has been conducted., Methods and Results: Participants (n = 55) consumed a single serving of broccoli or alfalfa sprouts and plasma, stool, and total urine are collected over 72 h for quantification of SFN metabolites and gut microbiome profiling using 16S gene sequencing. SFN-NIT excretion is markedly slower than SFN excretion (72 h vs 24 h). Members of genus Bifidobacterium, Dorea, and Ruminococcus torques are positively associated with SFN metabolite excretion while members of genus Alistipes and Blautia has a negative association., Conclusion: This is the first report of SFN-NIT metabolite levels in human plasma, urine, and stool following consumption of broccoli sprouts. The results help explain factors driving inter-individual variation in SFN metabolism and are relevant for precision nutrition., (© 2023 Wiley-VCH GmbH.)

Polyphenols have attracted huge interest among researchers of various disciplines because of their numerous biological activities, such as antioxidative, antiinflammatory, antiapoptotic, cancer chemopreventive, anticarcinogenic, and antimicrobial properties, and their promising applications in many fields, mainly in the medical, cosmetics, dietary supplement and food industries. In this review, the latest scientific findings in the research on polyphenols interaction with the microbiome and mitochondria, their metabolism and health beneficial effects, their involvement in cognitive diseases and obesity development, as well as some innovations in their analysis, extraction methods, development of cosmetic formulations and functional food are summarized based on the papers presented at the 13th World Congress on Polyphenol Applications. Future implications of polyphenols in disease prevention and their strategic use as prophylactic measures are specifically addressed. Polyphenols may play a key role in our tomorrow´s food and nutrition to prevent many diseases., (© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Scope: The polyphenol xanthohumol (XN) improves dysfunctional glucose and lipid metabolism in diet-induced obesity animal models. Because XN changes intestinal microbiota composition, the study hypothesizes that XN requires the microbiota to mediate its benefits., Methods and Results: To test the hypothesis, the study feeds conventional and germ-free male Swiss Webster mice either a low-fat diet (LFD, 10% fat derived calories), a high-fat diet (HFD, 60% fat derived calories), or a high-fat diet supplemented with XN at 60 mg kg -1 body weight per day (HXN) for 10 weeks, and measure parameters of glucose and lipid metabolism. In conventional mice, the study discovers XN supplementation decreases plasma insulin concentrations and improves Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). In germ-free mice, XN supplementation fails to improve these outcomes. Fecal sample 16S rRNA gene sequencing analysis suggests XN supplementation changes microbial composition and dramatically alters the predicted functional capacity of the intestinal microbiota. Furthermore, the intestinal microbiota metabolizes XN into bioactive compounds, including dihydroxanthohumol (DXN), an anti-obesogenic compound with improved bioavailability., Conclusion: XN requires the intestinal microbiota to mediate its benefits, which involves complex diet-host-microbiota interactions with changes in both microbial composition and functional capacity. The study results warrant future metagenomic studies which will provide insight into complex microbe-microbe interactions and diet-host-microbiota interactions., (© 2021 Wiley-VCH GmbH.)

Scope: Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol., Methods and Results: Thirty healthy volunteers were randomized to 24 mg day -1 xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in the placebo and xanthohumol groups, respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs are documented in both the placebo (n = 42) and xanthohumol (n = 58) groups., Conclusion: Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults., (© 2021 Wiley-VCH GmbH.)

Scope: Sphingolipids including ceramides are implicated in the pathogenesis of obesity and insulin resistance. Correspondingly, inhibition of pro-inflammatory and neurotoxic ceramide accumulation prevents obesity-mediated insulin resistance and cognitive impairment. Increasing evidence suggests the farnesoid X receptor (FXR) is involved in ceramide metabolism, as bile acid-FXR crosstalk controls ceramide levels along the gut-liver axis. The authors previously reported that FXR agonist xanthohumol (XN), the principal prenylated flavonoid in hops (Humulus lupulus), and its hydrogenated derivatives, α,β-dihydroxanthohumol (DXN), and tetrahydroxanthohumol (TXN), ameliorated obesity-mediated insulin resistance, and cognitive impairment in mice fed a high-fat diet., Methods and Results: To better understand how the flavonoids improve both, lipid and bile acid profiles in the liver are analyzed, sphingolipid relative abundance in the hippocampus is measured, and linked them to metabolic and neurocognitive performance. XN, DXN, and TXN (30 mg kg -1 BW per day) decrease ceramide content in liver and hippocampus; the latter is linked to improvements in spatial learning and memory. In addition, XN, DXN, and TXN decrease hepatic cholesterol content by enhancing de novo synthesis of bile acids., Conclusion: These observations suggest that XN, DXN, and TXN may alleviate obesity-induced metabolic and neurocognitive impairments by targeting the liver-brain axis., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Two hydrogenated xanthohumol (XN) derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation., Methods and Results: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host., Conclusion: Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: The intestinal microbiota transforms a wide range of available substrates, including polyphenols. Microbial catabolites of polyphenols can contribute in significant ways to the health-promoting properties of their parent polyphenols. This work aims to identify intestinal metabolites of xanthohumol (XN), a prenylated flavonoid found in hops (Humulus lupulus) and beer, as well as to identify pathways of metabolism of XN in the gut., Methods and Results: To investigate intestinal metabolism, XN and related prenylated flavonoids, isoxanthohumol (IX), and 8-prenylnaringenin (8PN) were added to growing cultures of intestinal bacteria, Eubacterium ramulus and E. limosum. Liquid chromatography coupled with mass spectrometry was used to identify metabolites of the flavonoids from the cultures. The metabolic capacity of E. limosum appears to be limited to O-demethylation. Evidence from the study indicates that E. ramulus hydrogenates XN to form α,β-dihydroxanthohumol (DXN) and metabolizes the potent phytoestrogen 8PN into the chalcones, O-desmethylxanthohumol (DMX) and O-desmethyl-α,β-dihydroxanthohumol (DDXN)., Conclusion: Microbial metabolism is likely to affect both activity and toxicity of XN and derivatives. This study along with others highlights that attention should be focused on metabolites, in particular, products of intestinal microbial metabolism., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Several lines of evidence suggest that the consumption of cruciferous vegetables is beneficial to human health. Yet, underlying mechanisms and key molecular targets that are involved with achieving these benefits in humans are still not fully understood. To accelerate this research, we conduct a human study to identify potential molecular targets of crucifers for further study. This study aims to characterize plasma metabolite profiles in humans before and after consuming fresh broccoli sprouts (a rich dietary source of bioactive sulforaphane)., Methods and Results: Ten healthy adults consume fresh broccoli sprouts (containing 200 μmol sulforaphane equivalents) at time 0 and provide blood samples at 0, 3, 6, 12, 24, and 48 h. An untargeted metabolomics screen reveals that levels of several plasma metabolites are significantly different before and after sprout intake, including fatty acids (14:0, 14:1, 16:0, 16:1, 18:0, and 18:1), glutathione, glutamine, cysteine, dehydroepiandrosterone, and deoxyuridine monophosphate. Evaluation of all time points is conducted using paired t-test (R software) and repeated measures analysis of variance for a within-subject design (Progenesis QI)., Conclusion: This investigation identifies several potential molecular targets of crucifers that may aid in studying established and emerging health benefits of consuming cruciferous vegetables and related bioactive compounds., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Xanthohumol (XN), a prenylated flavonoid found in hops, exhibits anti-inflammatory and antioxidant properties. However, poor bioavailability may limit therapeutic applications. As food components are known to modulate polyphenol absorption, the objective is to determine whether a protein matrix could enhance the bioavailability of XN post oral consumption in humans., Methods and Results: This is a randomized, double-blind, crossover study in healthy participants (n = 6) evaluating XN and its major metabolites (isoxanthohumol [IX], 6- and 8-prenylnaringenin [6-PN, 8-PN]) for 6 h following consumption of 12.4 mg of XN delivered via a spent hops-rice protein matrix preparation or a control spent hops preparation. Plasma XN and metabolites are measured by LC-MS/MS. C max , T max , and area-under-the-curve (AUC) values were determined. Circulating XN and metabolite response to each treatment was not bioequivalent. Plasma concentrations of XN and XN + metabolites (AUC) are greater with consumption of the spent hops-rice protein matrix preparation., Conclusion: Compared to a standard spent hops powder, a protein-rich spent hops matrix demonstrates enhanced plasma levels of XN and metabolites following acute oral intake., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults., Methods and Results: Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 μmol SFN daily, as a single dose and as two 100-μmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ∼3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21)., Conclusion: We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: The influence of excess α-tocopherol (α-T) on tissue depletion of phylloquinone (PK) and menaquinone-4 (MK-4) was evaluated., Methods and Results: Rats (n = 5 per group) were fed deuterium-labeled PK (2 μmol/kg diet) for 17 days, thereby labeling the conversion from deuterium-labeled PK to d₄-MK-4. Then they were injected subcutaneously daily for the last 7 days with saline, vehicle, or α-T (100 mg/kg body weight). α-T injections (i) increased α-T concentrations by tenfold in liver, doubled them in plasma and most tissues, but they were unchanged in brain; (ii) increased the α-T metabolite, carboxyethyl hydroxychromanol (α-CEHC) concentrations: >25-fold in liver and kidney, tenfold in plasma and lung, and 50-fold in heart; brain contained detectable α-CEHC (0.26 ± 0.03 nmol/g) only in α-T-injected animals; and (iii) depleted most tissues' vitamin K. Compared with vehicle-injected rats, brains from α-T rats contained half the total vitamin K (10.3 ± 0.5 versus 21 ± 2 pmol/g, p = 0.0002) and one-third the d₄-MK-4 (5.8 ± 0.5 versus 14.6 ± 1.7 pmol/g, p = 0.0002). Tissues with high PK concentrations (liver, 21-30 pmol/g and heart, 28-50 pmol/g) were resistant to K depletion., Conclusion: We propose that α-T-dependent vitamin K depletion is likely mediated at an intermediate step in MK-4 production; thus, tissues with high PK are unaffected., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 (C(max)) 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 (AUC(0→∞)) 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., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Xanthohumol (XN), a dietary flavonoid found in hops, may have health-protective actions against cardiovascular disease and type 2 diabetes. Yet, there are limited data on the pharmacokinetics (PK) of XN. This study provides PK parameters for XN and its major metabolites in rats., Methods and Results: A PK study was conducted in male jugular vein-cannulated Sprague-Dawley rats. Rats (n = 12/group) received an intravenous (IV) injection (1.86 mg/kg BW) or an oral gavage of a low (1.86 mg/kg BW), medium (5.64 mg/kg BW), or high (16.9 mg/kg BW) dose of XN. Plasma samples were analyzed for XN and its metabolites using LC-MS/MS. The maximum concentration (C(max) ) and area under the curve (AUC(0-96 h) ) of total XN (free and conjugated) were 2.9±0.1 mg/L and 2.5±0.3 h*  mg/L in IV group, 0.019±0.002 mg/L and 0.84±0.17 h*  mg/L in the oral low group, 0.043±0.002 mg/L and 1.03±0.12 h*  mg/L in the oral medium group, and 0.15±0.01 mg/L and 2.49±0.10 h*  mg/L in the oral high group., Conclusion: The bioavailability of XN is dose-dependent and approximately 0.33, 0.13, and 0.11 in rats, for the low-, medium-, and high-dose groups, respectively., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Acrolein (ACR) exposure leads to the formation of protein-ACR adducts. Protein modification by ACR has been associated with various chronic diseases including cardiovascular and neurodegenerative diseases. Here, we report an analytical strategy that enables the quantification of Michael-type protein adducts of ACR in mitochondrial proteome samples using liquid chromatography in combination with tandem mass spectrometry and selected ion monitoring (LC-MS/MS SRM) analysis. Our approach combines site-specific identification and relative quantification at the peptide level of protein-ACR adducts in relation to the unmodified protein thiol pool. Treatment of 3-month-old rats with CCl(4) , an established in vivo model of acute oxidative stress, resulted in significant increases in the ratios of distinct ACR-adducted peptides to the corresponding unmodified thiol-peptides obtained from proteins that were isolated from cardiac mitochondria. The mitochondrial proteins that were found adducted by ACR were malate dehydrogenase, NADH dehydrogenase [ubiquinone] flavoprotein 1, cytochrome c oxidase subunit VIb isoform 1, ATP synthase d chain, and ADP/ATP translocase 1. The findings indicate that protein modification by ACR has potential value as an index of mitochondrial oxidative stress., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.