Publications by authors named "Claudia S Maier"

86 Publications

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

Elife 2021 Jun 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

Plasma Oxylipins: A Potential Risk Assessment Tool in Atherosclerotic Coronary Artery Disease.

Front Cardiovasc Med 2021 21;8:645786. Epub 2021 Apr 21.

Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, United States.

While oxylipins have been linked to coronary artery disease (CAD), little is known about their diagnostic and prognostic potential. We tested whether plasma concentration of specific oxylipins may discriminate among number of diseased coronary arteries and predict median 5-year outcomes in symptomatic adults. Using a combination of high-performance liquid chromatography (HPLC) and quantitative tandem mass spectrometry, we conducted a targeted analysis of 39 oxylipins in plasma samples of 23 asymptomatic adults with low CAD risk and 74 symptomatic adults (≥70% stenosis), aged 38-87 from the Greater Portland, Oregon area. Concentrations of 22 oxylipins were above the lower limit of quantification in >98% of adults and were compared, individually and in groups based on precursors and biosynthetic pathways, in symptomatic adults to number of diseased coronary arteries [(1) = 31; (2) = 23; (3) = 20], and outcomes during a median 5-year follow-up (no surgery: = 7; coronary stent placement: = 24; coronary artery bypass graft surgery: = 26; death: = 7). Plasma levels of six quantified oxylipins decreased with the number of diseased arteries; a panel of five oxylipins diagnosed three diseased arteries with 100% sensitivity and 70% specificity. Concentrations of five oxylipins were lower and one oxylipin was higher with survival; a panel of two oxylipins predicted survival during follow-up with 86% sensitivity and 91% specificity. Quantification of plasma oxylipins may assist in CAD diagnosis and prognosis in combination with standard risk assessment tools.
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http://dx.doi.org/10.3389/fcvm.2021.645786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097092PMC
April 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

Exosomal proteomic signatures correlate with drug resistance and carboplatin treatment outcome in a spontaneous model of canine osteosarcoma.

Cancer Cell Int 2021 May 1;21(1):245. Epub 2021 May 1.

Texas A&M University, College Station, USA.

Background: Osteosarcoma patients often experience poor outcomes despite chemotherapy treatment, likely due in part to various mechanisms of tumor cell innate and/or acquired drug resistance. Exosomes, microvesicles secreted by cells, have been shown to play a role in drug resistance, but a comprehensive protein signature relating to osteosarcoma carboplatin resistance has not been fully characterized.

Methods: In this study, cell lysates and exosomes from two derivatives (HMPOS-2.5R and HMPOS-10R) of the HMPOS osteosarcoma cell line generated by repeated carboplatin treatment and recovery, were characterized proteomically by mass spectrometry. Protein cargos of circulating serum exosomes from dogs with naturally occurring osteosarcoma, were also assessed by mass spectrometry, to identify biomarkers that discriminate between good and poor responders to carboplatin therapy.

Results: Both cell lysates and exosomes exhibited distinct protein signatures related to drug resistance. Furthermore, exosomes from the resistant HMPOS-2.5R cell line were found to transfer drug resistance to drug-sensitive HMPOS cells. The comparison of serum exosomes from dogs with a favorable disease-free interval [DFI] of > 300 days, and dogs with < 100 days DFI revealed a proteomic signature that could discriminate between the two cohorts with high accuracy. Furthermore, when the patient's exosomes were compared to exosomes isolated from carboplatin resistant cell lines, several putative biomarkers were found to be shared.

Conclusions: The findings of this study highlight the significance of exosomes in the potential transfer of drug resistance, and the discovery of novel biomarkers for the development of liquid biopsies to better guide personalized chemotherapy treatment.
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http://dx.doi.org/10.1186/s12935-021-01943-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088716PMC
May 2021

Plant growth and metabolic changes in 'Super Hot' chili fruit (Capsicum annuum) exposed to supplemental LED lights.

Plant Sci 2021 Apr 14;305:110826. Epub 2021 Jan 14.

Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331, USA. Electronic address:

Light-emitting diodes (LEDs) of different colors improve plant growth and increase levels of secondary metabolites. This study aimed to determine the effect of red, blue, and red + blue LEDs (1:1) on the secondary metabolites composition in chili, focusing on capsaicinoids, at the top and middle of the plant canopy in 'Super Hot' chili. The accumulated yield of the chili fruit was the highest for control, followed by blue, red and red + blue LEDs, with the top canopy giving twice more yield than the middle canopy. UPLC-MS/MS analysis of chili fruit's methanolic extracts was used to determine capsaicinoids levels. Blue LEDs significantly increased nordihydrocapsaicin, capsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin contents by 57 %, 43 %, 56 %, 28 %, and 54 %, respectively, compared to the control. Also, 24 tentatively annotated metabolites, including phenylalanine, cinnamate, and valine, which are involved in the biosynthesis of capsaicinoids, were semi-quantitatively evaluated to determine the impact of LED exposure on the biosynthetic pathway of capsaicinoids. Supplemental blue LED placed at the top and between the canopy may boost the levels of capsaicinoids in chili fruit grown in greenhouses.
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http://dx.doi.org/10.1016/j.plantsci.2021.110826DOI Listing
April 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

Visualisation tools for dependent peptide searches to support the exploration of in vitro protein modifications.

PLoS One 2020 8;15(7):e0235263. Epub 2020 Jul 8.

Department of Chemistry, Oregon State University, Corvallis, OR, United States of America.

Dependent peptide searching is a method for discovering covalently-modified peptides-and therefore proteins-in mass-spectrometry-based proteomics experiments. Being more permissive than standard search methods, it has the potential to discover novel modifications (e.g., post-translational modifications occurring in vivo, or modifications introduced in vitro). However, few studies have explored dependent peptide search results in an untargeted way. In the present study, we sought to evaluate dependent peptide searching as a means of characterising proteins that have been modified in vitro. We generated a model data set by analysing N-ethylmaleimide-treated bovine serum albumin, and performed dependent peptide searches using the popular MaxQuant software. To facilitate interpretation of the search results (hundreds of dependent peptides), we developed a series of visualisation tools (R scripts). We used the tools to assess the diversity of putative modifications in the albumin, and to pinpoint hypothesised modifications. We went on to explore the tools' generality via analyses of public data from studies of rat and human proteomes. Of 19 expected sites of modification (one in rat cofilin-1 and 18 across six different human plasma proteins), eight were found and correctly localised. Apparently, some sites went undetected because chemical enrichment had depleted necessary analytes (potential 'base' peptides). Our results demonstrate (i) the ability of the tools to provide accurate and informative visualisations, and (ii) the usefulness of dependent peptide searching for characterising in vitro protein modifications. Our model data are available via PRIDE/ProteomeXchange (accession number PXD013040).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343161PMC
September 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

Bioactive peptides from brown rice protein hydrolyzed by bromelain: Relationship between biofunctional activities and flavor characteristics.

J Food Sci 2020 Mar 11;85(3):707-717. Epub 2020 Feb 11.

Dept. of Chemistry, Oregon State Univ., Corvallis, OR, 97331, U.S.A.

This study evaluated the biological properties of peptides from brown rice protein hydrolyzed by bromelain (eb-RPH) in relation to flavor characteristic. The fractionation into peptides < 1 kDa was observed to improve the DPPH, ABTS, and hydroxyl radical-scavenging activities (0.19, 2.28, and 24.64 mM Trolox, respectively), angiotensin-converting enzyme (ACE)-inhibitory activity (IC value of 0.20 ± 0.011 mg protein/mL), as well as bitter and umami tastes. The < 1 kDa fraction was further analyzed by liquid chromatography-electrospray ionization/mass spectrometry to identify amino acid sequence associated with biological activities and flavor characteristics. Eight peptides were identified. Most of the identified peptides contained features of previously reported ACE inhibitory and antioxidant peptides, especially peptide FGGSGGPGG and FGGGGAGAGG. Evaluation of flavor characteristics using BIOPEP database demonstrated that they had high occurrence frequencies of umami peptides (ESDVVSDL, GSGVGGAK, and SSVGGGSAG) and low Q-value (938.75 to 282.22), suggesting that these peptides may be used as a fortifying health ingredient with good taste. PRACTICAL APPLICATION: The fractionated brown rice protein hydrolysate (< 1 kDa) has the potential to serve as a functional food ingredient in nutraceutical food and beverage products that can provide health benefits with good taste. Information on amino acid composition and spatial conformation of peptide may aid us to better understand the molecular mechanisms involved in bioactivities and flavor of brown rice peptide for industrial applications.
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http://dx.doi.org/10.1111/1750-3841.15052DOI Listing
March 2020

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.

Sci Rep 2020 01 20;10(1):727. Epub 2020 Jan 20.

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

Osteosarcoma (OS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. The proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMPOS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z - z|), and "sensitivity" score (|z - z) to quantitatively evaluate the proteome shifts exhibited by OS cells in response to hypoxia. Evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.
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http://dx.doi.org/10.1038/s41598-019-56878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971036PMC
January 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

The omics approach to bee nutritional landscape.

Metabolomics 2019 09 20;15(10):127. Epub 2019 Sep 20.

Department of Horticulture, Oregon State University, Corvallis, OR, 97331, USA.

Background: Significant annual honey bee colony losses have been reported in the USA and across the world over the past years. Malnutrition is one among several causative factors for such declines. Optimal nutrition serves as the first line of defense against multiple stressors such as parasites/pathogens and pesticides. Given the importance of nutrition, it is imperative to understand bee nutrition holistically, identifying dietary sources that may fulfill bee nutritional needs. Pollen is the primary source of protein for bees and is critical for brood rearing and colony growth. Currently, there is significant gap in knowledge regarding the chemical and nutritional composition of pollen.

Methods: Targeted sterol analysis and untargeted metabolomics were conducted on five commercially available crop pollens, three bee-collected crop pollens, three vegetable oils (often added to artificial protein supplements by beekeepers), and one commonly used artificial protein supplement.

Results: This study reports key phytosterols and metabolites present across a spectrum of bee diets, including some of the major bee-pollinated crop pollens in the western United States. Significant differences were observed in sterol concentrations among the dietary sources tested. Among all quantified sterols, the highest concentrations were observed for 24-methylenecholesterol and further, pollen samples exhibited the highest 24-methylenecholesterol among all diet sources that were tested. Also, 236 metabolites were identified across all dietary sources examined.

Conclusion: Information gleaned from this study is crucial in understanding the nutritional landscape available to all bee pollinators and may further assist in future efforts to develop comprehensive database of nutrients and metabolites present in all bee diets.
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http://dx.doi.org/10.1007/s11306-019-1590-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753177PMC
September 2019

Isolation and characterisation of antioxidative peptides from bromelain-hydrolysed brown rice protein by proteomic technique.

Process Biochem 2018 Jul 27;70:179-187. Epub 2018 Mar 27.

Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA.

In this study, proteins from Thai brown rice (Khao Dawk Mali 105) were separated into albumin (2.18 %), globulin (3.98 %), glutelin (84.23 %), and prolamin (9.61 %) fractions, and were hydrolysed with various bromelain concentrations and hydrolysis times. Liquid chromatography-electrospray ionization/mass spectrometry (LC-ESI-MS/MS) was conducted to assess the composition, molecular weight (MW) distribution, and sequence of the resulting peptides, and showed that most peptides have a MW below 2000 Da (60-70 %). Glutelin fraction hydrolysates exhibited the highest 2,2'-azino-bis 3-ethylbenzthiazoline-6-sulfonic (ABTS) radical-scavenging (0.69 ± 0.04 µM trolox) and copper chelating (4.12 ± 0.01 mg ethylenediaminetetraacetic acid; EDTA) activities, which was further fractionated into six fractions using reversed-phase high-performance liquid chromatography. The fourth fraction showed the highest ABTS scavenging (1.08 ± 0.03 mM trolox) and copper chelating (5.00 ± 0.02 mg EDTA) activity. LC-MS/MS analysis revealed that the peptides with MW less than 1500 Da and hydrophobic or aromatic N-terminal residues, such as SPFWNINAHS, MPVDVIANAYR, VVYFDQTQAQA, and VEVGGGARAP, possibly contributed to the highest antioxidant activity in fourth fraction.
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http://dx.doi.org/10.1016/j.procbio.2018.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481950PMC
July 2018

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

Ordered opening of LDL receptor binding domain of human apolipoprotein E3 revealed by hydrogen/deuterium exchange mass spectrometry and fluorescence spectroscopy.

Biochim Biophys Acta Proteins Proteom 2018 11 21;1866(11):1165-1173. Epub 2018 Aug 21.

Department of Chemistry and Biochemistry, California State University Long Beach, Long Beach, California 90840, USA. Electronic address:

Apolipoprotein E3 (apoE3) is an exchangeable apolipoprotein that plays a critical role in cholesterol homeostasis. The N-terminal (NT) domain of apoE3 (residues 1-191) is folded into a helix bundle comprised of 4 amphipathic α-helices: H1, H2, H3 and H4, flanked by flexible helices N1 and N2, and Hinge Helix 1 (Hinge H1), at the N-and C-terminal sides of the helix bundle, respectively. The NT domain plays a critical role in binding to the low density lipoprotein receptor (LDLR), which eventually leads to lowering of plasma cholesterol levels. In order to be recognized by the LDLR, the helix bundle has to open and undergo a conformational change. The objective of the study was to understand the mechanism of opening of the helix bundle. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) revealed that apoE3 NT domain adopts several disordered and unfolded regions, with H2 exhibiting relatively little protection against exchange-in compared to H1, H3, and H4. Site-directed fluorescence labeling indicated that H2 not only has the highest degree of solvent exposure but also the most flexibility in the helix bundle. It also indicated that the lipoprotein behavior of H1 was significnatly different from that of H2, H3 and H4. These results suggest that the opening of the helix bundle is likely initiated at the flexible end of H2 and the loop linking H2/H3, and involves movement of H2/H3 away from H1/H4. Together, these observations offer mechanistic insight suggesting a regulated helix bundle opening of apoE3 NT domain can be triggered by lipid binding.
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http://dx.doi.org/10.1016/j.bbapap.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407697PMC
November 2018

Integrated identification and quantification of cyanobacterial toxins from Pacific Northwest freshwaters by Liquid Chromatography and High-resolution Mass Spectrometry.

J Mex Chem Soc 2018 ;62(2)

Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA.

The occurrence of harmful algal blooms in nutrient-rich freshwater bodies has increased world-wide, including in the Pacific Northwest. Some cyanobacterial genera have the potential to produce secondary metabolites that are highly toxic to humans, livestock and wildlife. Reliable methods for the detection of cyanobacterial toxins with high specificity and low limits of detection are in high demand. Here we test a relatively new hybrid high resolution accurate mass quadrupole time-of-flight mass spectrometry platform (TripleTOF) for the analysis of cyanobacterial toxins in freshwater samples. We developed a new method that allows the quantitative analysis of four commonly observed microcystin congeners (LR, LA, YR, and RR) and anatoxin-a in a 6-min LC run without solid-phase enrichment. Limits of detection for the microcystin congeners (LR, LA, YR, and RR) and anatoxin-a were <5 ng/L (200-fold lower than the guideline value of 1 μg/L as maximum allowable concentration of MC-LR in drinking water). The method was applied for screening freshwaters in the Pacific Northwest during the bloom and post-bloom periods. The use of high resolution mass spectrometry and concomitant high sensitivity detection of specific fragment ions with high mass accuracy provides an integrated approach for the simultaneous identification and quantification of cyanobacterial toxins. The method is sensitive enough for detecting the toxins in single colonies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133267PMC
http://dx.doi.org/10.29356/jmcs.v62i2.386DOI Listing
January 2018

A Preliminary Proteomic Investigation of Circulating Exosomes and Discovery of Biomarkers Associated with the Progression of Osteosarcoma in a Clinical Model of Spontaneous Disease.

Transl Oncol 2018 Oct 24;11(5):1137-1146. Epub 2018 Jul 24.

Carlson College of Veterinary Medicine, Department of Clinical Sciences, Oregon State University, Corvallis, OR, USA. Electronic address:

Circulating cancer exosomes are microvesicles which originate from malignant cells and other organs influenced by the disease and can be found in blood. The exosomal proteomic cargo can often be traced to the cells from which they originated, reflecting the physiological status of these cells. The similarities between cancer exosomes and the tumor cells they originate from exhibit the potential of these vesicles as an invaluable target for liquid biopsies. Exosomes were isolated from the serum of eight osteosarcoma-bearing dogs, five healthy dogs, and five dogs with traumatic fractures. We also characterized exosomes which were collected longitudinally from patients with osteosarcoma prior and 2 weeks after amputation, and eventually upon detection of lung metastasis. Exosomal proteins fraction were analyzed by label-free mass spectrometry proteomics and were validated with immunoblots of selected proteins. Ten exosomal proteins were found that collectively discriminate serum of osteosarcoma patients from serum healthy or fractured dogs with an accuracy of 85%. Additionally, serum from different disease stages could be distinguished with an accuracy of 77% based on exosomal proteomic composition. The most discriminating protein changes for both sample group comparisons were related to complement regulation, suggesting an immune evasion mechanism in early stages of osteosarcoma as well as in advanced disease.
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http://dx.doi.org/10.1016/j.tranon.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077151PMC
October 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

- 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

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

Total synthesis of [ C] -, [ C] -, and [ C] -isotopomers of xanthohumol, the principal prenylflavonoid from hops.

J Labelled Comp Radiopharm 2017 12 20;60(14):639-648. Epub 2017 Nov 20.

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

Xanthohumol [(E)-6'-methoxy-3'-(3-methylbuten-2-yl)-2',4',4″-trihydroxychalcone], he principal prenylated flavonoid from hops, has a complex bioactivity profile, and C-labeled isotopomers of this compound are of potential use as molecular probes and as analytical standards to study metabolism and mode of action. 1,3-[ C] -Xanthohumol was prepared by an adaptation of the total synthesis of Khupse and Erhardt in 7 steps and 5.7% overall yield from phloroglucinol by a route incorporating a cascade Claisen-Cope rearrangement to install the 3'-prenyl moiety from a 5'-prenyl aryl ether and an aldol condensation between 1-[ C]-2',4'-bis(benzyloxymethyloxy)-6'-methoxy-3'-(3-methylbuten-2-yl)acetophenone and 1'-[ C]-4-(methoxymethyloxy)benzaldehyde. The C-atom in the methyl ketone was derived from 1-[ C]-acetyl chloride while that in the aryl aldehyde was derived from [ C]-iodomethane. Tri- and penta- C-labeled xanthohumols were similarly prepared by applying minor modifications to the route.
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http://dx.doi.org/10.1002/jlcr.3571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832448PMC
December 2017

Exosomes from Osteosarcoma and normal osteoblast differ in proteomic cargo and immunomodulatory effects on T cells.

Exp Cell Res 2017 09 14;358(2):369-376. Epub 2017 Jul 14.

Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA. Electronic address:

Background: Canine osteosarcoma (OSA) is the most common cancer of the appendicular skeleton and is associated with high metastatic rate to the lungs and poor prognosis. Recent studies have shown the impact of malignant-derived exosomes on immune cells and the facilitation of immune evasion. In the current study, we have characterized the proteomic profile of exosomes derived from healthy osteoblasts and osteosarcoma cell lines. We investigated the direct impact of these exosomes on healthy T cells.

Results: Proteomic cargo of the malignant exosomes was markedly different from osteoblastic exosomes and contained immunosuppressive proteins including TGF-β, α fetoprotein and heat shock proteins. OSA exosomes directly attenuated the rate of T cell proliferation, increased a regulatory (FoxP3+) CD4+ phenotype and diminished the expression of the activation marker CD25+ on CD8+ cells. Exosomes of osteoblasts also demonstrated a direct impact on T cells, but to a lesser degree.

Conclusions: Osteosarcoma-derived exosomes compared to normal osteoblasts contain an immunomodulatory cargo, which reduced the rate of T cell proliferation and promoted T regulatory phenotype. Osteoblast-derived exosomes can also reduce T cell activity, but to lesser degree compared to OSA exosomes and without promoting a T regulatory phenotype.
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http://dx.doi.org/10.1016/j.yexcr.2017.07.011DOI Listing
September 2017