Publications by authors named "Jan F Stevens"

91 Publications

Xanthohumol Requires the Intestinal Microbiota to Improve Glucose Metabolism in Diet-Induced Obese Mice.

Mol Nutr Food Res 2021 Sep 8:e2100389. Epub 2021 Sep 8.

Linus Pauling Institute, Department of Biochemistry and Biophysics, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR, 97331, USA.

Scope: The polyphenol xanthohumol (XN) improves dysfunctional glucose and lipid metabolism in diet-induced obesity animal models. Because XN changes intestinal microbiota composition, we hypothesized that XN requires the microbiota to mediate its benefits.

Methods And Results: To test our hypothesis, we fed conventional and germ-free male Swiss Webster mice either a low-fat diet (10% fat derived calories), a high-fat diet (60% fat derived calories), or a high-fat diet supplemented with XN at 60 mg/kg body weight per day for 10 weeks, and measured parameters of glucose and lipid metabolism. In conventional mice, we discovered XN supplementation decreased plasma insulin concentrations and improved Homeostatic Model Assessment of Insulin Resistance. In germ-free mice, XN supplementation failed to improve these outcomes. Fecal sample 16S rRNA gene sequencing analysis suggested 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, 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. Our results warrant future metagenomic studies, which will provide insight into complex microbe-microbe interactions, and diet-host-microbiota interactions. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mnfr.202100389DOI Listing
September 2021

Caffeoylquinic acids: chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity.

Plant J 2021 Sep 23;107(5):1299-1319. Epub 2021 Jul 23.

Department of Chemistry, Oregon State University, Corvallis, OR, USA.

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.
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http://dx.doi.org/10.1111/tpj.15390DOI Listing
September 2021

Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ.

Elife 2021 06 15;10. Epub 2021 Jun 15.

Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States.

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.
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http://dx.doi.org/10.7554/eLife.66398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205491PMC
June 2021

Nitrate-induced improvements in exercise performance are coincident with exuberant changes in metabolic genes and the metabolome in zebrafish () skeletal muscle.

J Appl Physiol (1985) 2021 07 27;131(1):142-157. Epub 2021 May 27.

OU Health, Harold Hamm Diabetes Center, Department of Nutritional Sciences, College of Allied Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Dietary nitrate supplementation improves exercise performance by reducing the oxygen cost of exercise and enhancing skeletal muscle function. However, the mechanisms underlying these effects are not well understood. The purpose of this study was to assess changes in skeletal muscle energy metabolism associated with exercise performance in a zebrafish model. Fish were exposed to sodium nitrate (60.7 mg/L, 303.5 mg/L, 606.9 mg/L), or control water, for 21 days and analyzed at intervals (5, 10, 20, 30, 40 cm/s) during a 2-h strenuous exercise test. We measured oxygen consumption during an exercise test and assessed muscle nitrate concentrations, gene expression, and the muscle metabolome before, during, and after exercise. Nitrate exposure reduced the oxygen cost of exercise and increased muscle nitrate concentrations at rest, which were reduced with increasing exercise duration. In skeletal muscle, nitrate treatment upregulated expression of genes central to nutrient sensing (), redox signaling (), and muscle differentiation (). In rested muscle, nitrate treatment increased phosphocreatine ( = 0.002), creatine ( = 0.0005), ATP ( = 0.0008), ADP ( = 0.002), and AMP ( = 0.004) compared with rested-control muscle. Following the highest swimming speed, concentration of phosphocreatine ( = 8.0 × 10), creatine ( = 6.0 × 10), ATP ( = 2.0 × 10), ADP ( = 0.0002), and AMP ( = 0.004) decreased compared with rested nitrate muscle. Our data suggest nitrate exposure in zebrafish lowers the oxygen cost of exercise by changing the metabolic programming of muscle prior to exercise and increasing availability of energy-rich metabolites required for exercise. We show that skeletal muscle nitrate concentration is higher with supplementation at rest and was lower in groups with increasing exercise duration in a zebrafish model. The higher availability of nitrate at rest is associated with upregulation of key nutrient-sensing genes and greater availability of energy-producing metabolites (i.e., ATP, phosphocreatine, glycolytic intermediates). Overall, nitrate supplementation may lower oxygen cost of exercise through improved fuel availability resulting from metabolic programming of muscle prior to exercise.
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http://dx.doi.org/10.1152/japplphysiol.00185.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325611PMC
July 2021

Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling.

Front Pharmacol 2021 20;12:643857. Epub 2021 Apr 20.

Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.

The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXR) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis and decreased BA concentrations in FXR mice, the effect being stronger in male mice. XN induced the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) gene expression in the liver of FXR mice. These findings suggest that activation of BA detoxification pathways represents the predominant mechanism for controlling hydrophobic BA concentrations in FXR mice. Collectively, these data indicated sex-dependent relationship between FXR, lipids and BAs, and suggest that XN ameliorates HFD-induced liver dysfunction via FXR-dependent and independent signaling.
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http://dx.doi.org/10.3389/fphar.2021.643857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093804PMC
April 2021

Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish.

PLoS One 2020 31;15(12):e0240070. Epub 2020 Dec 31.

School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, United States of America.

Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18-19%), and its precursor, glutamine (17-22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774831PMC
January 2021

Caffeoylquinic Acids in Reverse Cognitive Deficits in Male 5XFAD Alzheimer's Disease Model Mice.

Nutrients 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.

(CA) is an edible plant and a popular botanical dietary supplement. It is reputed, in Ayurveda, to mitigate age-related cognitive decline. There is a considerable body of preclinical literature supporting CA's ability to improve learning and memory. This study evaluated the contribution of CA's triterpenes (TT), widely considered its active compounds, and caffeoylquinic acids (CQA) to the cognitive effects of CA water extract (CAW) in 5XFAD mice, a model of Alzheimer's disease. 5XFAD mice were fed a control diet alone, or one containing 1% CAW or compound groups (TT, CQA, or TT + CQA) equivalent to their content in 1% CAW. Wild-type (WT) littermates received the control diet. Conditioned fear response (CFR) was evaluated after 4.5 weeks. Female 5XFAD controls showed no deficit in CFR compared to WT females, nor any effects from treatment. In males, CFR of 5XFAD controls was attenuated compared to WT littermates ( = 0.005). 5XFAD males receiving CQA or TT + CQA had significantly improved CFR ( < 0.05) compared to 5XFAD male controls. CFR did not differ between 5XFAD males receiving treatment diets and WT males. These data confirm a role for CQA in CAW's cognitive effects.
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http://dx.doi.org/10.3390/nu12113488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698091PMC
November 2020

Plasma metabolomics supports the use of long-duration cardiac arrest rodent model to study human disease by demonstrating similar metabolic alterations.

Sci Rep 2020 11 12;10(1):19707. Epub 2020 Nov 12.

Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.

Cardiac arrest (CA) is a leading cause of death and there is a necessity for animal models that accurately represent human injury severity. We evaluated a rat model of severe CA injury by comparing plasma metabolic alterations to human patients. Plasma was obtained from adult human control and CA patients post-resuscitation, and from male Sprague-Dawley rats at baseline and after 20 min CA followed by 30 min cardiopulmonary bypass resuscitation. An untargeted metabolomics evaluation using UPLC-QTOF-MS/MS was performed for plasma metabolome comparison. Here we show the metabolic commonality between humans and our severe injury rat model, highlighting significant metabolic dysfunction as seen by similar alterations in (1) TCA cycle metabolites, (2) tryptophan and kynurenic acid metabolites, and (3) acylcarnitine, fatty acid, and phospholipid metabolites. With substantial interspecies metabolic similarity in post-resuscitation plasma, our long duration CA rat model metabolically replicates human disease and is a suitable model for translational CA research.
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http://dx.doi.org/10.1038/s41598-020-76401-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665036PMC
November 2020

Potential use of polyphenols in the battle against COVID-19.

Curr Opin Food Sci 2020 Apr 9;32:149-155. Epub 2020 Sep 9.

Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA.

The coronavirus disease 2019 (COVID-19) is a public health emergency of international concern. The rising number of cases of this highly transmissible infection has stressed the urgent need to find a potent drug. Although repurposing of known drugs currently provides an accelerated route to approval, there is no satisfactory treatment. Polyphenols, a major class of bioactive compounds in nature, are known for their antiviral activity and pleiotropic effects. The aim of this review is to assess the effects of polyphenols on COVID-19 drug targets as well as to provide a perspective on the possibility to use polyphenols in the development of natural approaches against this viral disease.
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http://dx.doi.org/10.1016/j.cofs.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480644PMC
April 2020

Targeting the Liver-Brain Axis with Hop-Derived Flavonoids Improves Lipid Metabolism and Cognitive Performance in Mice.

Mol Nutr Food Res 2020 08 6;64(15):e2000341. Epub 2020 Jul 6.

Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA.

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 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.
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http://dx.doi.org/10.1002/mnfr.202000341DOI Listing
August 2020

Water Extract Shows Low Potential for Cytochrome P450-Mediated Drug Interactions.

Drug Metab Dispos 2020 10 24;48(10):1053-1063. Epub 2020 Jun 24.

Department of Neurology, Oregon Health and Science University, Portland, Oregon (K.M.W., J.F.Q., A.S.); Departments of Chemistry (A.A.M., C.S.M.) and Pharmaceutical Sciences (J.F.S.) and Linus Pauling Institute (A.A.M., J.F.S.), Oregon State University, Corvallis, Oregon; BioIVT, Durham, North Carolina (R.M.L., C.L.M., T.T.B.); and Department of Neurology, Veterans Affairs Portland Health Care System Center, Portland, Oregon (J.F.Q.)

(CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the extract, suggesting a low potential for drug interactions modulated by P450 metabolism.
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http://dx.doi.org/10.1124/dmd.120.090860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543484PMC
October 2020

Integration of mass spectral fingerprinting analysis with precursor ion (MS1) quantification for the characterisation of botanical extracts: application to extracts of Centella asiatica (L.) Urban.

Phytochem Anal 2020 Nov 12;31(6):722-738. Epub 2020 Apr 12.

Department of Chemistry, Oregon State University, Corvallis, OR, USA.

Introduction: The phytochemical composition of plant material governs the bioactivity and potential health benefits as well as the outcomes and reproducibility of laboratory studies and clinical trials.

Objective: The objective of this work was to develop an efficient method for the in-depth characterisation of plant extracts and quantification of marker compounds that can be potentially used for subsequent product integrity studies. Centella asiatica (L.) Urb., an Ayurvedic herb with potential applications in enhancing mental health and cognitive function, was used as a case study.

Methods: A quadrupole time-of-flight analyser in conjunction with an optimised high-performance liquid chromatography (HPLC) separation was used for in-depth untargeted fingerprinting and post-acquisition precursor ion quantification to determine levels of distinct phytochemicals in various C. asiatica extracts.

Results: We demonstrate the utility of this workflow for the characterisation of extracts of C. asiatica. This integrated workflow allowed the identification or tentative identification of 117 compounds, chemically interconnected based on Tanimoto chemical similarity, and the accurate quantification of 24 phytochemicals commonly found in C. asiatica extracts.

Conclusion: We report a phytochemical analysis method combining liquid chromatography, high resolution mass spectral data acquisition, and post-acquisition interrogation that allows chemical fingerprints of botanicals to be obtained in conjunction with accurate quantification of distinct phytochemicals. The variability in the composition of specialised metabolites across different C. asiatica accessions was substantial, demonstrating that detailed characterisation of plant extracts is a prerequisite for reproducible use in laboratory studies, clinical trials and safe consumption. The methodological approach is generally applicable to other botanical products.
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http://dx.doi.org/10.1002/pca.2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587007PMC
November 2020

Germ-Free Swiss Webster Mice on a High-Fat Diet Develop Obesity, Hyperglycemia, and Dyslipidemia.

Microorganisms 2020 Apr 5;8(4). Epub 2020 Apr 5.

Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.

A calorie-dense diet is a well-established risk factor for obesity and metabolic syndrome (MetS), whereas the role of the intestinal microbiota (IMB) in the development of diet-induced obesity (DIO) is not completely understood. To test the hypothesis that Swiss Webster (Tac:SW) mice can develop characteristics of DIO and MetS in the absence of the IMB, we fed conventional (CV) and germ-free (GF) male Tac:SW mice either a low-fat diet (LFD; 10% fat derived calories) or a high-fat diet (HFD; 60% fat derived calories) for 10 weeks. The HFD increased feed conversion and body weight in GF mice independent of the increase associated with the microbiota in CV mice. In contrast to CV mice, GF mice did not decrease feed intake on the HFD and possessed heavier fat pads. The HFD caused hyperglycemia, hyperinsulinemia, and impaired glucose absorption in GF mice independent of the increase associated with the microbiota in CV mice. A HFD also elevated plasma LDL-cholesterol and increased hepatic triacylglycerol, free fatty acids, and ceramides in all mice, whereas hypertriglyceridemia and increased hepatic medium and long-chain acylcarnitines were only observed in CV mice. Therefore, GF male Tac:SW mice developed several detrimental effects of obesity and MetS from a high-fat, calorie dense diet.
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http://dx.doi.org/10.3390/microorganisms8040520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232377PMC
April 2020

Vitamin C Activates the Folate-Mediated One-Carbon Cycle in C2C12 Myoblasts.

Antioxidants (Basel) 2020 Mar 5;9(3). Epub 2020 Mar 5.

Linus Pauling Institute, Oregon State University, 2900 SW Campus way, Corvallis, OR 97331, USA.

Vitamin C (L-ascorbic acid, AA) is an essential cellular antioxidant and cofactor for several α-ketoglutarate-dependent dioxygenases. As an antioxidant, AA interacts with vitamin E to control oxidative stress. While several reports suggest an interaction of AA with folate (vitamin B9) in animals and humans, little is known about the nature of the interaction and the underlying molecular mechanisms at the cellular level. We used an untargeted metabolomics approach to study the impact of AA on the metabolome of C2C12 myoblast cells. Compared to untreated cells, treatment of C2C12 cells with AA at 100 µM resulted in enhanced concentrations of folic acid (2.5-fold) and 5-methyl-tetrahydrofolate (5-methyl-THF, 10-fold increase) whereas the relative concentrations of 10-formyl-tetrahydrofolate decreased by >90% upon AA pretreatment, indicative of increased utilization for the biosynthesis of active THF metabolites. The impact of AA on the folate-mediated one-carbon cycle further manifested itself as an increase in the levels of methionine, whose formation from homocysteine is 5-methyl-THF dependent, and an increase in thymidine, whose formation from deoxyuridine monophosphate (dUMP) is dependent on 5,10-methylene-THF. These findings shed new light on the interaction of AA with the folate-mediated one-carbon cycle and partially explain clinical findings that AA supplementation enhances erythrocyte folate status and that it may decrease serum levels of homocysteine, which is considered as a biomarker of cardiovascular disease risk.
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http://dx.doi.org/10.3390/antiox9030217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139526PMC
March 2020

Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism.

Mol Nutr Food Res 2020 01 15;64(1):e1900789. Epub 2019 Dec 15.

Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA.

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.
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http://dx.doi.org/10.1002/mnfr.201900789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029812PMC
January 2020

Integrated Metabolomics-DNA Methylation Analysis Reveals Significant Long-Term Tissue-Dependent Directional Alterations in Aminoacyl-tRNA Biosynthesis in the Left Ventricle of the Heart and Hippocampus Following Proton Irradiation.

Front Mol Biosci 2019 10;6:77. Epub 2019 Sep 10.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States.

In this study, an untargeted metabolomics approach was used to assess the effects of proton irradiation (1 Gy of 150 MeV) on the metabolome and DNA methylation pattern in the murine hippocampus and left ventricle of the heart 22 weeks following exposure using an integrated metabolomics-DNA methylation analysis. The integrated metabolomics-DNA methylation analysis in both tissues revealed significant alterations in aminoacyl-tRNA biosynthesis, but the direction of change was tissue-dependent. Individual and total amino acid synthesis were downregulated in the left ventricle of proton-irradiated mice but were upregulated in the hippocampus of proton-irradiated mice. Amino acid tRNA synthetase methylation was mostly downregulated in the hippocampus of proton-irradiated mice, whereas no consistent methylation pattern was observed for amino acid tRNA synthetases in the left ventricle of proton-irradiated mice. Thus, proton irradiation causes long-term changes in the left ventricle and hippocampus in part through methylation-based epigenetic modifications. Integrated analysis of metabolomics and DNA methylation is a powerful approach to obtain converging evidence of pathways significantly affected. This in turn might identify biomarkers of the radiation response, help identify therapeutic targets, and assess the efficacy of mitigators directed at those targets to minimize, or even prevent detrimental long-term effects of proton irradiation on the heart and the brain.
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http://dx.doi.org/10.3389/fmolb.2019.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746933PMC
September 2019

Treatment with Nitrate, but Not Nitrite, Lowers the Oxygen Cost of Exercise and Decreases Glycolytic Intermediates While Increasing Fatty Acid Metabolites in Exercised Zebrafish.

J Nutr 2019 12;149(12):2120-2132

School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA.

Background: Dietary nitrate improves exercise performance by reducing the oxygen cost of exercise, although the mechanisms responsible are not fully understood.

Objectives: We tested the hypothesis that nitrate and nitrite treatment would lower the oxygen cost of exercise by improving mitochondrial function and stimulating changes in the availability of metabolic fuels for energy production.

Methods: We treated 9-mo-old zebrafish with nitrate (sodium nitrate, 606.9 mg/L), nitrite (sodium nitrite, 19.5 mg/L), or control (no treatment) water for 21 d. We measured oxygen consumption during a 2-h, strenuous exercise test; assessed the respiration of skeletal muscle mitochondria; and performed untargeted metabolomics on treated fish, with and without exercise.

Results: Nitrate and nitrite treatment increased blood nitrate and nitrite levels. Nitrate treatment significantly lowered the oxygen cost of exercise, as compared with pretreatment values. In contrast, nitrite treatment significantly increased oxygen consumption with exercise. Nitrate and nitrite treatments did not change mitochondrial function measured ex vivo, but significantly increased the abundances of ATP, ADP, lactate, glycolytic intermediates (e.g., fructose 1,6-bisphosphate), tricarboxylic acid (TCA) cycle intermediates (e.g., succinate), and ketone bodies (e.g., β-hydroxybutyrate) by 1.8- to 3.8-fold, relative to controls. Exercise significantly depleted glycolytic and TCA intermediates in nitrate- and nitrite-treated fish, as compared with their rested counterparts, while exercise did not change, or increased, these metabolites in control fish. There was a significant net depletion of fatty acids, acyl carnitines, and ketone bodies in exercised, nitrite-treated fish (2- to 4-fold), while exercise increased net fatty acids and acyl carnitines in nitrate-treated fish (1.5- to 12-fold), relative to their treated and rested counterparts.

Conclusions: Nitrate and nitrite treatment increased the availability of metabolic fuels (ATP, glycolytic and TCA intermediates, lactate, and ketone bodies) in rested zebrafish. Nitrate treatment may improve exercise performance, in part, by stimulating the preferential use of fuels that require less oxygen for energy production.
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http://dx.doi.org/10.1093/jn/nxz202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887948PMC
December 2019

Tissue-Specific Metabolic Profiles After Prolonged Cardiac Arrest Reveal Brain Metabolome Dysfunction Predominantly After Resuscitation.

J Am Heart Assoc 2019 09 31;8(17):e012809. Epub 2019 Aug 31.

Laboratory for Critical Care Physiology Feinstein Institute for Medical Research Manhasset NY.

Background Cardiac arrest (CA) has been a leading cause of death for many decades. Despite years of research, we still do not understand how each organ responds to the reintroduction of blood flow after prolonged CA. Following changes in metabolites of individual organs after CA and resuscitation gives context to the efficiency and limitations of current resuscitation protocols. Methods and Results Adult male Sprague-Dawley rats were arbitrarily assigned into 3 groups: control, 20 minutes of CA, or 20 minutes of CA followed by 30 minutes of cardiopulmonary bypass resuscitation. The rats were euthanized by decapitation to harvest brain, heart, kidney, and liver tissues. The obtained tissue samples were analyzed by ultra-high-performance liquid chromatography-high-accuracy mass spectrometry for comprehensive metabolomics evaluation. After resuscitation, the brain showed decreased glycolysis metabolites and fatty acids and increased amino acids compared with control. Similarly, the heart displayed alterations mostly in amino acids. The kidney showed decreased amino acid and fatty acid pools with severely increased tricarboxylic acid cycle metabolites following resuscitation, while the liver showed minimal alterations with slight changes in the lipid pool. Each tissue has a distinct pattern of metabolite changes after ischemia/reperfusion. Furthermore, resuscitation worsens the metabolic dysregulation in the brain and kidney, while it normalizes metabolism in the heart. Conclusions Developing metabolic profiles using a global metabolome analysis identifies the variable nature of metabolites in individual organs after CA and reperfusion, establishing a stark contrast between the normalized heart and liver and the exacerbated brain and kidney, only after the reestablishment of blood circulation.
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http://dx.doi.org/10.1161/JAHA.119.012809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755859PMC
September 2019

Antiproliferative and Cytotoxic Activity of Xanthohumol and Its Non-Estrogenic Derivatives in Colon and Hepatocellular Carcinoma Cell Lines.

Int J Mol Sci 2019 Mar 9;20(5). Epub 2019 Mar 9.

Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.

Xanthohumol (XN), a prenylated flavonoid found in hops, inhibits growth in a variety of cancer cell lines; however, its use raises concerns as gut microbiota and the host's hepatic cytochrome P450 enzymes metabolize it into the most potent phytoestrogen known, 8-prenylnaringenin (8-PN). The XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN) are not metabolized into 8-PN and they show higher tissue concentrations in vivo compared with XN when orally administered to mice at the same dose. Here we show that DXN and TXN possess improved anti-proliferative activity compared with XN in two colon (HCT116, HT29) and two hepatocellular (HepG2, Huh7) carcinoma cell lines, as indicated by their respective IC values. Furthermore, XN, DXN, and TXN induce extensive apoptosis in all these carcinoma cell lines. Finally, TXN induces G₀/G₁ cell cycle arrest in the colon carcinoma cell line HT29. Our findings suggest that DXN and TXN could show promise as therapeutic agents against colorectal and liver cancer in preclinical studies without the drawback of metabolism into a phytoestrogen.
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http://dx.doi.org/10.3390/ijms20051203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429097PMC
March 2019

Phytochemical characterization of root bark and its effects on dysfunctional metabolism and cognitive performance in high-fat-fed C57BL/6J mice.

J Food Bioact 2018 Sep 30;3:111-123. Epub 2018 Sep 30.

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.

Preparations of the root bark of have long been used in Central and West African traditional medicine to combat fatigue, as a neuro-stimulant in rituals, and for treatment of diabetes. The principal alkaloid of ibogaine, has attracted attention in many countries around the world for providing relief for opioid craving in drug addicts. Using a plant metabolomics approach, we detected five phenolic compounds, including 3--caffeoylquinic acid, and 30 alkaloids, seven of which were previously reported from root bark. Following a report that iboga extracts contain insulinotropic agents, we aimed to determine the potential alleviating effects of the water extract of iboga root bark on high-fat diet (HFD)-induced hyperglycemia as well as its effects on cognitive function in male C57BL/6J mice. Feeding a HFD to mice for 10 weeks produced manifestations of metabolic syndrome such as increased body weight and increased plasma levels of glucose, triacylglycerols, total cholesterol, LDL-cholesterol, insulin, leptin, and pro-inflammatory mediators (IL-6, MCP-1, ICAM-1), as compared to mice fed a low-fat diet (LFD). Supplementation of HFD with iboga extract at ibogaine doses of 0.83 (low) and 2.07 (high) mg/kg/day did not improve these HFD-induced metabolic effects except for a reduction of plasma MCP-1 in the low dose group, indicative of an anti-inflammatory effect. When the HFD mice were tested in the water maze, the high-dose iboga extract caused hippocampus-dependent impairments in spatial learning and memory, as compared to mice receiving only a HFD.
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http://dx.doi.org/10.31665/JFB.2018.3154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301038PMC
September 2018

Reductive Metabolism of Xanthohumol and 8-Prenylnaringenin by the Intestinal Bacterium Eubacterium ramulus.

Mol Nutr Food Res 2019 01 3;63(2):e1800923. Epub 2018 Dec 3.

Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA.

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.
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http://dx.doi.org/10.1002/mnfr.201800923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561348PMC
January 2019

Sulforaphane absorption and histone deacetylase activity following single dosing of broccoli sprout supplement in normal dogs.

Vet Med Sci 2018 11 17;4(4):357-363. Epub 2018 Aug 17.

School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA.

The role of epigenetic alterations during cancer has gained increasing attention and has resulted in a paradigm shift in our understanding of mechanisms leading to cancer susceptibility. Sulforaphane (SFN) is a naturally occurring isothiocyanate derived from the precursor glucosinolate, glucoraphanin (GFN), which is found in cruciferous vegetables such as broccoli. Sulforaphane has been shown to suppress tumour growth by several mechanisms including inhibiting histone deacetylases. The objective of this study was to provide a detailed analysis of sulforaphane absorption following a single oral dose of a broccoli sprout supplement in normal dogs. A single dose of broccoli sprout supplement (with active myrosinase) was orally administered to 10 healthy adult dogs. Blood and urine samples were collected prior to dosing, and at various time points post-dosing. Plasma total SFN metabolite levels peaked at 4 h post-consumption and were cleared by 24 h post-consumption. Urinary SFN metabolites peaked at 4 h post-consumption, and remained detectable at 24 and 48 h post-supplement consumption. A trend for decrease in histone deacetylase activity was observed at 1 h post-consumption and a significant decrease was observed at 24 h post-consumption. The data presented herein indicate that oral SFN is absorbed in dogs, SFN metabolites are detectable in plasma and urine post-dosing, and SFN and its metabolites have some effect on histone deacetylase activity following a single dose.
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http://dx.doi.org/10.1002/vms3.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236138PMC
November 2018

Isolation and Identification of Tyrosinase-Inhibitory and Copper-Chelating Peptides from Hydrolyzed Rice-Bran-Derived Albumin.

J Agric Food Chem 2018 Aug 31;66(31):8346-8354. Epub 2018 Jul 31.

Department of Pharmaceutical Sciences, College of Pharmacy and the Linus Pauling Institute , Oregon State University , Corvallis , Oregon 97331 , United States.

Rice-bran albumin (RBAlb), which shows higher tyrosinase-inhibitory activity than other protein fractions, was hydrolyzed with papain to improve the bioactivity. The obtained RBAlb hydrolysate (RBAlbH) was separated into 11 peptide fractions by RP-HPLC. Tyrosinase inhibition and copper chelation activities decreased with increasing retention times of the peptide fractions. RBAlbH fraction 1, which exhibited the greatest activity, contained 13 peptides whose sequences were determined by using LC-MS/MS. Most of the peptide sequences contained features of previously reported tyrosinase-inhibitory and metal-chelating peptides, especially peptide SSEYYGGEGSSSEQGYYGEG. RBAlbH fraction 1 showed more effective tyrosinase inhibition (IC = 1.31 mg/mL) than citric acid (IC = 9.38 mg/mL), but it was less effective than ascorbic acid (IC = 0.03 mg/mL, P ≤ 0.05). It showed copper-chelating activity (IC = 0.62 mg/mL) stronger than that of EDTA (IC = 1.06 mg/mL, P ≤ 0.05). These results suggest that RBAlbH has potential as a natural tyrosinase inhibitor and copper chelator for application in the food and cosmetic industries.
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http://dx.doi.org/10.1021/acs.jafc.8b01849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431294PMC
August 2018

Photoprotective Properties of Isothiocyanate and Nitrile Glucosinolate Derivatives From Meadowfoam () Against UVB Irradiation in Human Skin Equivalent.

Front Pharmacol 2018 15;9:477. Epub 2018 May 15.

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, United States.

Exposure to ultraviolet B (UVB) irradiation of the skin leads to numerous dermatological concerns including skin cancer and accelerated aging. Natural product glucosinolate derivatives, like sulforaphane, have been shown to exhibit chemopreventive and photoprotective properties. In this study, we examined meadowfoam () glucosinolate derivatives, 3-methoxybenzyl isothiocyanate (MBITC) and 3-methoxyphenyl acetonitrile (MPACN), for their activity in protecting against the consequences of UV exposure. To that end, we have exposed human primary epidermal keratinocytes (HPEKs) and 3D human skin reconstructed (EpiDerm FT-400) to UVB insult and investigated whether MBITC and MPACN treatment ameliorated the harmful effects of UVB damage. Activity was determined by the compounds' efficacy in counteracting UVB-induced DNA damage, matrix-metalloproteinase (MMP) expression, and proliferation. We found that in monolayer cultures of HPEK, MBITC and MPACN did not protect against a UVB-induced loss in proliferation and MBITC itself inhibited cell proliferation. However, in human reconstructed skin-equivalents, MBITC and MPACN decrease epidermal cyclobutane pyrimidine dimers (CPDs) and significantly reduce total phosphorylated γH2A.X levels. Both MBITC and MPACN inhibit UVB-induced MMP-1 and MMP-3 expression indicating their role to prevent photoaging. Both compounds, and MPACN in particular, showed activity against UVB-induced proliferation as indicated by fewer epidermal PCNA+ cells and prevented UVB-induced hyperplasia as determined by a reduction in reconstructed skin epidermal thickness (ET). These data demonstrate that MBITC and MPACN exhibit promising anti-photocarcinogenic and anti-photoaging properties in the skin microenvironment and could be used for therapeutic interventions.
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http://dx.doi.org/10.3389/fphar.2018.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962701PMC
May 2018

- Phytochemistry and mechanisms of neuroprotection and cognitive enhancement.

Phytochem Rev 2018 Feb 20;17(1):161-194. Epub 2017 Sep 20.

Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239.

This review describes in detail the phytochemistry and neurological effects of the medicinal herb (L.) Urban. is a small perennial plant that grows in moist, tropical and sub-tropical regions throughout the world. Phytochemicals identified from to date include isoprenoids (sesquiterpenes, plant sterols, pentacyclic triterpenoids and saponins) and phenylpropanoid derivatives (eugenol derivatives, caffeoylquinic acids, and flavonoids). Contemporary methods for fingerprinting and characterization of compounds in extracts include liquid chromatography and/or ion mobility spectrometry in conjunction with high-resolution mass spectrometry. Multiple studies in rodent models, and a limited number of human studies support 's traditional reputation as a cognitive enhancer, as well as its anxiolytic and anticonvulsant effects. Neuroprotective effects of are seen in several models, for example against beta amyloid toxicity, and appear to be associated with increased mitochondrial activity, improved antioxidant status, and/or inhibition of the pro-inflammatory enzyme, phospholipase A2. Neurotropic effects of include increased dendritic arborization and synaptogenesis, and may be due to modulations of signal transduction pathways such as ERK1/2 and Akt. Many of these neurotropic and neuroprotective properties of have been associated with the triterpene compounds asiatic acid, asiaticoside and madecassoside. More recently, caffeoylquinic acids are emerging as a second important group of active compounds in , with the potential of enhancing the Nrf2-antioxidant response pathway. The absorption, distribution, metabolism and excretion of the triterpenes, caffeoylquinic acids and flavonoids found in have been studied in humans and animal models, and the compounds or their metabolites found in the brain. This review highlights the remarkable potential for extracts and derivatives to be used in the treatment of neurological conditions, and considers the further research needed to actualize this possibility.
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http://dx.doi.org/10.1007/s11101-017-9528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857646PMC
February 2018

Untargeted Metabolomic Screen Reveals Changes in Human Plasma Metabolite Profiles Following Consumption of Fresh Broccoli Sprouts.

Mol Nutr Food Res 2018 10 23;62(19):e1700665. Epub 2018 Feb 23.

School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA.

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.
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http://dx.doi.org/10.1002/mnfr.201700665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310001PMC
October 2018

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice.

Sci Rep 2018 01 12;8(1):613. Epub 2018 Jan 12.

Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA.

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.
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http://dx.doi.org/10.1038/s41598-017-18992-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766630PMC
January 2018

Rice Protein Matrix Enhances Circulating Levels of Xanthohumol Following Acute Oral Intake of Spent Hops in Humans.

Mol Nutr Food Res 2018 03 26;62(6):e1700692. Epub 2018 Feb 26.

Metagenics Inc, Gig Harbor, WA, USA.

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 , T , 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.
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http://dx.doi.org/10.1002/mnfr.201700692DOI Listing
March 2018

Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models.

Antioxid Redox Signal 2018 12 11;29(16):1589-1611. Epub 2017 Dec 11.

2 Linus Pauling Institute, Oregon State University , Corvallis, Oregon.

Significance: Humans are exposed daily to polyphenols in milligram-to-gram amounts through dietary consumption of fruits and vegetables. Polyphenols are also available as components of dietary supplements for improving general health. Although polyphenols are often advertised as antioxidants to explain health benefits, experimental evidence shows that their beneficial cancer preventing and controlling properties are more likely due to stimulation of pro-oxidant and proapoptotic pathways. Recent Advances: The understanding of the biological differences between cancer and normal cell, and especially the role that mitochondria play in carcinogenesis, has greatly advanced in recent years. These advances have resulted in a wealth of new information on polyphenol bioactivity in cell culture and animal models of cancer. Polyphenols appear to target oxidative phosphorylation and regulation of the mitochondrial membrane potential (MMP), glycolysis, pro-oxidant pathways, and antioxidant (adaptive) stress responses with greater selectivity in tumorigenic cells.

Critical Issues: The ability of polyphenols to dissipate the MMP (Δψ) by a protonophore mechanism has been known for more than 50 years. However, researchers focus primarily on the downstream molecular effects of Δψ dissipation and mitochondrial uncoupling. We argue that the physicochemical properties of polyphenols are responsible for their anticancer properties by virtue of their protonophoric and pro-oxidant properties rather than their specific effects on downstream molecular targets.

Future Directions: Polyphenol-induced dissipation of Δψ is a physicochemical process that cancer cells cannot develop resistance against by gene mutation. Therefore, polyphenols should receive more attention as agents for cotherapy with cancer drugs to gain synergistic activity. Antioxid. Redox Signal.
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http://dx.doi.org/10.1089/ars.2017.7404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207154PMC
December 2018

Comprehensive analysis of phospholipids in the brain, heart, kidney, and liver: brain phospholipids are least enriched with polyunsaturated fatty acids.

Mol Cell Biochem 2018 May 9;442(1-2):187-201. Epub 2017 Oct 9.

Department of Emergency Medicine, Feinstein Institute for Medical Research, Northwell Health System, 350 Community Dr, Manhasset, NY, 11030, USA.

It is commonly accepted that brain phospholipids are highly enriched with long-chain polyunsaturated fatty acids (PUFAs). However, the evidence for this remains unclear. We used HPLC-MS to analyze the content and composition of phospholipids in rat brain and compared it to the heart, kidney, and liver. Phospholipids typically contain one PUFA, such as 18:2, 20:4, or 22:6, and one saturated fatty acid, such as 16:0 or 18:0. However, we found that brain phospholipids containing monounsaturated fatty acids in the place of PUFAs are highly elevated compared to phospholipids in the heart, kidney, and liver. The relative content of phospholipid containing PUFAs is ~ 60% in the brain, whereas it is over 90% in other tissues. The most abundant species of phosphatidylcholine (PC) is PC(16:0/18:1) in the brain, whereas PC(18:0/20:4) and PC(16:0/20:4) are predominated in other tissues. Moreover, several major species of plasmanyl and plasmenyl phosphatidylethanolamine are found to contain monounsaturated fatty acid in the brain only. Overall, our data clearly show that brain phospholipids are the least enriched with PUFAs of the four major organs, challenging the common belief that the brain is highly enriched with PUFAs.
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http://dx.doi.org/10.1007/s11010-017-3203-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882520PMC
May 2018
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