Dean P Jones

Publications of Dean P Jones

• Children with NAFLD Are More Sensitive to the Adverse Metabolic Effects of Fructose Beverages than Children without NAFLD.

  Authors: Ran Jin, Ngoc-Anh Le, Shuling Liu, Monica Farkas Epperson, Thomas R Ziegler, Jean A Welsh, Dean P Jones, Craig J McClain, Miriam B Vos

  The Journal of clinical endocrinology and metabolism. 04/2012;

  Context:Dietary fructose induces unfavorable lipid alterations in animal models and adult studies. Little is known regarding metabolic tolerance of dietary fructose in children.Objectives:The aim ofContext:Dietary fructose induces unfavorable lipid alterations in animal models and adult studies. Little is known regarding metabolic tolerance of dietary fructose in children.Objectives:The aim of the study was to evaluate whether dietary fructose alters plasma lipids in children with nonalcoholic fatty liver disease (NAFLD) and in healthy children.Design and Setting:We performed a 2-d, crossover feeding study at the Inpatient Clinical Interaction Site of the Atlanta Clinical and Translational Science Institute at Emory University Hospital.Participants and Intervention:Nine children with NAFLD and 10 matched controls without NAFLD completed the study. We assessed plasma lipid levels over two nonconsecutive, randomly assigned, 24-h periods under isocaloric, isonitrogenous conditions with three macronutrient-balanced, consecutive meals and either: 1) a fructose-sweetened beverage (FB); or 2) a glucose beverage (GB) being consumed with each meal.Main Outcome Measures:Differences in plasma glucose, insulin, triglyceride, apolipoprotein B, high-density lipoprotein cholesterol, and nonesterified free fatty acid levels were assessed using mixed models and 24-h incremental areas under the time-concentration curve.Results:After FB, triglyceride incremental area under the curve was higher vs. after GB both in children with NAFLD (P = 0.011) and those without NAFLD (P = 0.027); however, incremental response to FB was greater in children with NAFLD than those without NAFLD (P = 0.019). For all subjects, high-density lipoprotein cholesterol declined in the postprandial and overnight hours with FB, but not with GB (P = 0.0006). Nonesterified fatty acids were not impacted by sugar but were significantly higher in NAFLD.Conclusions:The dyslipidemic effect of dietary fructose occurred in both healthy children and those with NAFLD; however, children with NAFLD demonstrated increased sensitivity to the impact of dietary fructose.

• Nutritional Metabolomics: Progress in Addressing Complexity in Diet and Health.

  Authors: Dean P Jones, Youngja Park, Thomas R Ziegler

  Annual review of nutrition. 04/2012;

  Nutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical toNutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical to facilitate transition of nutritional sciences from population-based to individualbased criteria for nutritional research, assessment, and management. This review addresses progress in making these approaches manageable for nutrition research. Important concept developments concerning the exposome, predictive health, and complex pathobiology serve to emphasize the central role of diet and nutrition in integrated biosystems models of health and disease. Improved analytic tools and databases for targeted and nontargeted metabolic profiling, along with bioinformatics, pathway mapping, and computational modeling, are now used for nutrition research on diet, metabolism, microbiome, and health associations. These new developments enable metabolome-wide association studies (MWAS) and provide a foundation for nutritional metabolomics, along with genomics, epigenomics, and health phenotyping, to support the integrated models required for personalized diet and nutrition forecasting. Expected final online publication date for the Annual Review of Nutrition Volume 32 is July 17, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

• Differences in Systemic Oxidative Stress Based on Race and the Metabolic Syndrome: The Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study.

  Authors: Alanna A Morris, Liping Zhao, Riyaz S Patel, Dean P Jones, Yusuf Ahmed, Neli Stoyanova, Gary H Gibbons, Viola Vaccarino, Rebecca Din-Dzietham, Arshed A Quyyumi

  Metabolic syndrome and related disorders. 03/2012;

  Abstract Background: Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans.Abstract Background: Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans. Oxidative stress results from an imbalance of prooxidants and antioxidants and leads to endothelial dysfunction that promotes vascular inflammation and atherosclerosis. Aminothiol markers of oxidative stress are associated with CVD risk factors and metabolic syndrome; however, little is known about racial differences in levels of oxidative stress. We sought to investigate whether oxidative stress would be higher in African Americans compared to whites independently of traditional risk factor burden. Methods: We assessed oxidative stress in a biracial, community-based cohort. In 620 subjects (59% female, 52% African American) in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study, we measured plasma levels of glutathione, an intracellular antioxidant, and its redox potential as a ratio of reduced and oxidized glutathione (E(h) glutathione). Results: African Americans had lower glutathione levels (P<0.001) compared to whites. There was a trend toward more oxidized E(h) glutathione (P=0.07) in African Americans; however, this did not reach statistical significance. After adjustment for demographics and CVD risk factors, African-American race remained a significant correlate of lower glutathione levels (P<0.001) and a more oxidized E(h) glutathione (P=0.04). After further adjustment for high-sensitivity C-reactive protein (hsCRP), glutathione remained significantly lower in African Americans (P=0.001). African Americans with or without metabolic syndrome had lower glutathione levels compared to whites with or without metabolic syndrome, respectively (both P≤0.001), and African Americans without metabolic syndrome had a more oxidized E(h) glutathione compared to whites without metabolic syndrome (P=0.003). Conclusions: African Americans have higher levels of oxidative stress than whites, even after adjustment for differences in CVD risk factors and inflammation. Racial differences in oxidative stress may play a key role in understanding observed racial disparities in CVD.

• High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring.

  Authors: Youngja H Park, Kichun Lee, Quinlyn A Soltow, Frederick H Strobel, Kenneth L Brigham, Richard E Parker, Mark E Wilson, Roy L Sutliff, Keith G Mansfield, Lynn M Wachtman, Thomas R Ziegler, Dean P Jones

  Toxicology. 02/2012; 295(1-3):47-55.

  High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but hasHigh-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: (1) whether more chemicals are detected in humans living in a less controlled environment than captive species and (2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537-3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.

• Glutathione redox control of asthma: From molecular mechanisms to therapeutic opportunities.

  Authors: Anne M Fitzpatrick, Dean P Jones, Lou Ann S Brown

  Antioxidants & redox signaling. 02/2012;

  Asthma is a chronic inflammatory disorder of the airways associated with airway hyperresponsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important forAsthma is a chronic inflammatory disorder of the airways associated with airway hyperresponsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important for tissue regeneration and wound healing, the profound and sustained inflammatory response associated with asthma may result in airway "remodeling" which involves smooth muscle hypertrophy, epithelial goblet-cell hyperplasia and permanent deposition of airway extracellular matrix proteins. Although the specific mechanisms responsible for asthma are still being unraveled, free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of airway tissue damage that are increased in subjects with asthma. There is also a growing body of literature implicating disturbances in oxidation/reduction ("redox") reactions and impaired antioxidant defenses as a risk factor for asthma development and asthma severity. Ultimately, these redox-related perturbations result in a vicious cycle of airway inflammation and injury that is not always amenable to current asthma therapy, particularly in cases of severe asthma. This review will discuss disruptions of redox signaling and control in asthma with a focus on the thiol, glutathione (GSH). First, GSH synthesis, GSH distribution, and GSH function and homeostasis are discussed. We then review the literature related to GSH redox balance in health and asthma, with an emphasis on human studies. Finally, therapeutic opportunities to restore the GSH redox balance in subjects with asthma are discussed.

• Detailed mitochondrial phenotyping by high resolution metabolomics.

  Authors: James R Roede, Youngja Park, Shuzhao Li, Frederick H Strobel, Dean P Jones

  PloS one. 01/2012; 7(3):e33020.

  Mitochondrial phenotype is complex and difficult to define at the level of individual cell types. Newer metabolic profiling methods provide information on dozens of metabolic pathways from aMitochondrial phenotype is complex and difficult to define at the level of individual cell types. Newer metabolic profiling methods provide information on dozens of metabolic pathways from a relatively small sample. This pilot study used "top-down" metabolic profiling to determine the spectrum of metabolites present in liver mitochondria. High resolution mass spectral analyses and multivariate statistical tests provided global metabolic information about mitochondria and showed that liver mitochondria possess a significant phenotype based on gender and genotype. The data also show that mitochondria contain a large number of unidentified chemicals.

• Redox equivalents and mitochondrial bioenergetics.

  Authors: James R Roede, Young-Mi Go, Dean P Jones

  Methods in molecular biology (Clifton, N.J.). 01/2012; 810:249-80.

  Mitochondrial energy metabolism depends upon high-flux and low-flux electron transfer pathways. The former provide the energy to support chemiosmotic coupling for oxidative phosphorylation. TheMitochondrial energy metabolism depends upon high-flux and low-flux electron transfer pathways. The former provide the energy to support chemiosmotic coupling for oxidative phosphorylation. The latter provide mechanisms for signaling and control of mitochondrial functions. Few practical methods are available to measure rates of individual mitochondrial electron transfer reactions; however, a number of approaches are available to measure steady-state redox potentials (E (h)) of donor/acceptor couples, and these can be used to gain insight into rate-controlling reactions as well as mitochondrial bioenergetics. Redox changes within the respiratory electron transfer pathway are quantified by optical spectroscopy and measurement of changes in autofluorescence. Low-flux pathways involving thiol/disulfide redox couples are measured by redox western blot and mass spectrometry-based redox proteomics. Together, the approaches provide the opportunity to develop integrated systems biology descriptions of mitochondrial redox signaling and control mechanisms.

• Regulation of prostate cancer cell invasion by modulation of extra- and intracellular redox balance.

  Authors: Luksana Chaiswing, Weixiong Zhong, Yongliang Liang, Dean P Jones, Terry D Oberley

  Free radical biology & medicine. 11/2011; 52(2):452-61.

  Recent metabolic profiles of human prostate cancer tissues showed a significant increase in cysteine (Cys) and a significant decrease in reduced glutathione (GSH) during cancer progression from low-Recent metabolic profiles of human prostate cancer tissues showed a significant increase in cysteine (Cys) and a significant decrease in reduced glutathione (GSH) during cancer progression from low- to high-grade Gleason scores. Cys is primarily localized extracellularly, whereas GSH is present mostly inside the cell. We hypothesized that extra- or intracellular redox state alterations differentially regulate cell invasion in PC3 prostate carcinoma cells versus PrEC normal prostate epithelial cells. Cells were exposed to media with calculated Cys/CySS redox potentials (E(h)CySS) ranging from -60 to -180mV. After 3h exposure to a reducing extracellular redox state (E(h)CySS=-180mV), matrix metalloprotease (MMP), gelatinase, and NADPH oxidase activities increased, correlating with increases in cell invasion, cell migration, and extracellular hydrogen peroxide levels in PC3 cells but not PrECs. Knockdown of NADPH oxidase or MMP with silencing RNAs during cultivation with E(h)CySS=-180mV medium significantly decreased PC3 cell invasion. Modulation of extra- and intracellular redox states by exposure of PC3 cells to Cys/CySS-free medium (approx E(h)CySS=-87mV) containing 500μMN-acetylcysteine resulted in a more reducing intracellular redox state and a significant decrease in cell invasive ability. The decrease in PC3 cell invasion induced by these conditions correlated with a decrease in MMP activity. Our studies demonstrated that an extracellular redox state that was more reducing than a physiologic microenvironment redox state increased PC3 cancer cell invasive ability, whereas an intracellular redox environmental that was more reducing than an intracellular physiologic redox state inhibited PC3 cell invasive ability.

• Hepatic oxidative stress in fructose-induced Fatty liver is not caused by sulfur amino Acid insufficiency.

  Authors: Sachin S Kunde, James R Roede, Miriam B Vos, Michael L Orr, Young-Mi Go, Youngja Park, Thomas R Ziegler, Dean P Jones

  Nutrients. 11/2011; 3(11):987-1002.

  Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreasedFructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (E(h)GSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress.

• Protein Cysteines Map to Functional Networks According to Steady-state Level of Oxidation.

  Authors: Young-Mi Go, Duc M Duong, Junmin Peng, Dean P Jones

  Journal of proteomics & bioinformatics. 10/2011; 4(10):196-209.

  The cysteine (Cys) proteome serves critical roles in protein structure, function and regulation, and includes key targets in oxidative mechanisms of disease. Thioredoxins maintain Cys residues inThe cysteine (Cys) proteome serves critical roles in protein structure, function and regulation, and includes key targets in oxidative mechanisms of disease. Thioredoxins maintain Cys residues in thiol forms, and previous research shows that the redox potential of thioredoxin in mitochondria and nuclei is more reduced than cytoplasm, suggesting that proteins in these compartments may have different steady-state oxidation. This study measured fractional oxidation of 641 peptidyl Cys residues from 333 proteins in HT29 cells by mass spectrometry. Average oxidation of cytoplasmic, nuclear and mitochondrial proteins was similar (15.8, 15.5, 14%, respectively). Pathway analysis showed that more reduced cytoplasmic Cys were in proteins associated with the cytoskeleton, more reduced nuclear Cys with Ran signaling and RNA post-transcriptional modifcation, and more reduced mitochondrial Cys with energy metabolism, cell growth and cell proliferation. More oxidized cytoplasmic Cys included associations with PI3/Akt, Myc-mediated apoptosis and 14-3-3-mediated signaling. Weaker associations of oxidized nuclear and mitochondrial Cys occurred with granzyme B signaling and intermediary metabolism, respectively. Thus, steady-state peptidyl Cys oxidation is associated with functional pathways rather than simply with organellar distribution. This suggests that oxidative mechanisms of disease could target functional pathways or networks rather than individual proteins or subcellular compartments.

• Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy.

  Authors: Lindsey R Fischer, Yingjie Li, Seneshaw A Asress, Dean P Jones, Jonathan D Glass

  Experimental neurology. 09/2011; 233(1):163-71.

  Oxidative stress is commonly implicated in the pathogenesis of motor neuron disease. However, the cause and effect relationship between oxidative stress and motor neuron degeneration is poorlyOxidative stress is commonly implicated in the pathogenesis of motor neuron disease. However, the cause and effect relationship between oxidative stress and motor neuron degeneration is poorly defined. We recently identified denervation at the neuromuscular junction in mice lacking the antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1) (Fischer et al., 2011). These mice show a phenotype of progressive muscle atrophy and weakness in the setting of chronic oxidative stress. Here, we investigated further the extent of motor neuron pathology in this model, and the relationship between motor pathology and oxidative stress. We report preferential denervation of fast-twitch muscles beginning between 1 and 4 months of age, with relative sparing of slow-twitch muscle. Motor axon terminals in affected muscles show widespread sprouting and formation of large axonal swellings. We confirmed, as was previously reported, that spinal motor neurons and motor and sensory nerve roots in these mice are preserved, even out to 18 months of age. We also found preservation of distal sensory fibers in the epidermis, illustrating the specificity of pathology in this model for distal motor axons. Using HPLC measurement of the glutathione redox potential, we quantified oxidative stress in peripheral nerve and muscle at the onset of denervation. SOD1 knockout tibial nerve, but not gastrocnemius muscle, showed significant oxidation of the glutathione pool, suggesting that axonal degeneration is a consequence of impaired redox homeostasis in peripheral nerve. We conclude that the SOD1 knockout mouse is a model of oxidative stress-mediated motor axonopathy. Pathology in this model primarily affects motor axon terminals at the neuromuscular junction, demonstrating the vulnerability of this synapse to oxidative injury.

• Sulfur amino acid-free diet results in increased glutamate in human midbrain: a pilot magnetic resonance spectroscopic study.

  Authors: Youngja Park, Tiejun Zhao, Nana Gletsu Miller, Seoung Bum Kim, Carolyn Jonas Accardi, Thomas R Ziegler, Xiaoping Hu, Dean P Jones

  Nutrition (Burbank, Los Angeles County, Calif.). 09/2011; 28(3):235-41.

  This pilot study was designed to determine if metabolic effects in different brain regions (left and right parietal lobes, midbrain) caused by 3 d of food consumption without methionine or cysteineThis pilot study was designed to determine if metabolic effects in different brain regions (left and right parietal lobes, midbrain) caused by 3 d of food consumption without methionine or cysteine could be detected by proton magnetic resonance spectroscopy. Healthy individuals 18 to 36 y old (n = 8) were studied by magnetic resonance spectroscopy after receiving a diet with adequate sulfur amino acids (SAAs) or with zero SAA for 3 d. Pulse sequences were used to selectively measure glutathione (GSH), and linear combination modeling of spectra was used to measure other high-abundance brain metabolites and expressed relative to creatine (Cr). Although dietary SAAs are required to maintain GSH, the 3-d SAA insufficiency resulted in no significant change in GSH/Cr in the three brain regions. Principal component analysis of 16 metabolites measured by linear combination modeling showed that the metabolic pattern in the midbrain, but not in the parietal lobes, was distinguished according to the dietary SAAs. Multivariate statistical analysis showed that the major discriminating factors were signals of glutamate/Cr, (glutamate + glutamine)/Cr, and myoinositol/Cr. Correlation analyses between midbrain metabolites and GSH-related metabolites in plasma showed that midbrain glutamate/Cr had an inverse correlation with plasma cystine. The data show that magnetic resonance spectroscopy is a non-invasive tool suitable for nutritional assessment and suggest that nutritional imbalance caused by 3 d of SAA-free food more selectively affects the midbrain than the parietal lobes.

• Substitution of standard soybean oil with olive oil-based lipid emulsion in parenteral nutrition: comparison of vascular, metabolic, and inflammatory effects.

  Authors: Joselita Siqueira, Dawn Smiley, Christopher Newton, Ngoc-Anh Le, Aidar R Gosmanov, Ronnie Spiegelman, Limin Peng, Samantha J Osteen, Dean P Jones, Arshed A Quyyumi, Thomas R Ziegler, Guillermo E Umpierrez

  The Journal of clinical endocrinology and metabolism. 08/2011; 96(10):3207-16.

  Soybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have been raisedSoybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have been raised due to the proinflammatory effects that may lead to increased complications because they are rich in ω-6 polyunsaturated fatty acids. This was a prospective, randomized, controlled, crossover study comparing the vascular, metabolic, immune, and inflammatory effects of 24-h infusion of PN containing soybean oil-based lipid emulsion (Intralipid), olive oil-based (ClinOleic), lipid free, and normal saline in 12 healthy subjects. Soybean oil-PN increased systolic blood pressure compared with olive oil-PN (P < 0.05). Soybean oil PN reduced brachial artery flow-mediated dilatation from baseline (-23% at 4 h and -25% at 24 h, both P < 0.01); in contrast, olive oil PN, lipid free PN, and saline did not change either systolic blood pressure or flow-mediated dilatation. Compared with saline, soybean oil PN, olive oil PN, and lipid free PN similarly increased glucose and insulin concentrations during infusion (P < 0.05). There were no significant changes in plasma free fatty acids, lipid profile, inflammatory and oxidative stress markers, immune function parameters, or sympathetic activity between soybean oil- and olive oil-based lipid emulsions. The 24-h infusion of PN containing soybean oil-based lipid emulsion increased blood pressure and impaired endothelial function compared with PN containing olive oil-based lipid emulsion and lipid-free PN in healthy subjects. These vascular changes may have significant implications in worsening outcome in subjects receiving nutrition support. Randomized controlled trials with relevant clinical outcome measures are needed in patients receiving PN with olive oil-based and soybean oil-based lipid emulsions.

• Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial.

  Authors: Myfanwy H Hopkins, Joy Owen, Thomas Ahearn, Veronika Fedirko, W Dana Flanders, Dean P Jones, Roberd M Bostick

  Cancer prevention research (Philadelphia, Pa.). 06/2011; 4(10):1645-54.

  Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium andVitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for developing colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92) of 2 g/d calcium and/or 800 IU/d vitamin D(3) supplementation versus placebo over 6 months. Plasma concentrations of proinflammatory markers [C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-1β, and IL-8] and an anti-inflammatory marker (IL-10) were measured using ELISAs. After 6 months of treatment, in the vitamin D(3) supplementation group, CRP decreased 32% overall (P = 0.11), 37% in men (P = 0.05), and 41% among non-nonsteroidal anti-inflammatory drug (NSAID) users (P = 0.05) relative to placebo. In the vitamin D(3) supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (P = 0.003) in the vitamin D(3) treatment group overall, 83% (P = 0.01) among men, and 48% among non-NSAID users (P = 0.01). There was no evidence of synergy between vitamin D(3) and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D(3) or calcium supplementation alone and support further investigation of vitamin D(3) as a chemopreventive agent against inflammation and colorectal neoplasms.

• Metabolic effects of albumin therapy in acute lung injury measured by proton nuclear magnetic resonance spectroscopy of plasma: a pilot study.

  Authors: Youngja Park, Dean P Jones, Thomas R Ziegler, Kichun Lee, Kavitha Kotha, Tianwei Yu, Greg S Martin

  Critical care medicine. 06/2011; 39(10):2308-13.

  Improved means to monitor and guide interventions could be useful in the intensive care unit. Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers ofImproved means to monitor and guide interventions could be useful in the intensive care unit. Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers of disease development and progression. This pilot study evaluated plasma proton nuclear magnetic resonance spectroscopy as a means to monitor metabolism following albumin administration in acute lung injury patients. This study was conducted on plasma samples from six albumin-treated and six saline-treated patients from a larger double-blind trial. The albumin group was administered 25 g of 25% human albumin in 0.9% saline every 8 hrs for a total of nine doses over 72 hrs. A 0.9% concentration of saline was used as a placebo. Blood samples were collected immediately before, 1 hr after, and 4 hrs after the albumin/saline administration for the first, fourth, and seventh doses (first dose of each day for 3 days). Samples were analyzed by proton nuclear magnetic resonance spectroscopy, and spectra were analyzed by principal component analysis and biostatistical methods. None. After 1 day of albumin therapy, changes in small molecules, including amino acids and plasma lipids, were evident with principal component analysis. Differences remained 3 days after the last albumin administration. Analysis of data along with spectra from healthy controls showed that spectra for patients receiving albumin had a trajectory toward the spectra observed for healthy individuals while those of the placebo controls did not. The data suggest that metabolic changes detected by proton nuclear magnetic resonance spectroscopy and the bioinformatics tool may be a useful approach to clinical research, especially in acute lung injury.

• A sulfur amino acid-free meal increases plasma lipids in humans.

  Authors: Youngja Park, Ngoc-Anh Le, Tianwei Yu, Fred Strobel, Nana Gletsu-Miller, Carolyn J Accardi, Kichun S Lee, Shaoxiong Wu, Thomas R Ziegler, Dean P Jones

  The Journal of nutrition. 06/2011; 141(8):1424-31.

  The content of sulfur amino acid (SAA) in a meal affects postprandial plasma cysteine concentrations and the redox potential of cysteine/cystine. Because such changes can affect enzyme, transporter,The content of sulfur amino acid (SAA) in a meal affects postprandial plasma cysteine concentrations and the redox potential of cysteine/cystine. Because such changes can affect enzyme, transporter, and receptor activities, meal content of SAA could have unrecognized effects on metabolism during the postprandial period. This pilot study used proton NMR ((1)H-NMR) spectroscopy of human plasma to test the hypothesis that dietary SAA content changes macronutrient metabolism. Healthy participants (18-36 y, 5 males and 3 females) were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (depletion), and then fed isoenergetic, isonitrogenous meals containing 56 mg·kg(-1)·d(-1) SAA for 4.5 d (repletion). On the first and last day of consuming the chemically defined meals, a morning meal containing 60% of the daily food intake was given and plasma samples were collected over an 8-h postprandial time course for characterization of metabolic changes by (1)H-NMR spectroscopy. SAA-free food increased peak intensity in the plasma (1)H-NMR spectra in the postprandial period. Orthogonal signal correction/partial least squares-discriminant analysis showed changes in signals associated with lipids, some amino acids, and lactate, with notable increases in plasma lipid signals (TG, unsaturated lipid, cholesterol). Conventional lipid analyses confirmed higher plasma TG and showed an increase in plasma concentration of the lipoprotein lipase inhibitor, apoC-III. The results show that plasma (1)H-NMR spectra can provide useful macronutrient profiling following a meal challenge protocol and that a single meal with imbalanced SAA content alters postprandial lipid metabolism.

• Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2.

  Authors: Anne M Fitzpatrick, Susan T Stephenson, Graham R Hadley, Leandrea Burwell, Madhuri Penugonda, Dawn M Simon, Jason Hansen, Dean P Jones, Lou Ann S Brown

  The Journal of allergy and clinical immunology. 06/2011; 127(6):1604-11.

  Airway thiol redox disturbances, including depletion of the antioxidant, glutathione, are differentiating features of severe asthma in children. Given the role of the transcription factor nuclearAirway thiol redox disturbances, including depletion of the antioxidant, glutathione, are differentiating features of severe asthma in children. Given the role of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in maintaining glutathione homeostasis and antioxidant defense, we quantified expression and activity of Nrf2 and its downstream targets in the airways and systemic circulation of children with asthma. We hypothesized that Nrf2 activation and function would be impaired in severe asthma, resulting in depletion of thiol pools and insufficient glutathione synthesis and conjugation. PBMCs and airway lavage cells were collected from children 6 to 17 years with severe (n = 51) and mild-to-moderate asthma (n = 38). The thiols glutathione and cysteine were quantified, and expression and activity of Nrf2 and its downstream targets were assessed. Children with severe asthma had greater oxidation and lower concentrations of glutathione and cysteine in the plasma and airway lavage. Although Nrf2 mRNA and protein increased in severe asthma as a function of increased thiol oxidation, the Nrf2 expressed was highly dysfunctional. Nrf2 activation and downstream targets of Nrf2 binding, including glutathione-dependent enzymes, were not different between groups. The duration of asthma was a key factor associated with Nrf2 dysfunction in severe asthma. Children with severe asthma have a global disruption of thiol redox signaling and control in both the airways and systemic circulation that is associated with posttranslational modification of Nrf2. We conclude that the Nrf2 pathway is disrupted in severe asthma as a function of chronic oxidative stress, which ultimately inhibits glutathione synthesis and antioxidant defense.

• The role of plasma aminothiols in the prediction of coronary microvascular dysfunction and plaque vulnerability.

  Authors: Saurabh S Dhawan, Parham Eshtehardi, Michael C McDaniel, Lucy V Fike, Dean P Jones, Arshed A Quyyumi, Habib Samady

  Atherosclerosis. 05/2011; 219(1):266-72.

  Although oxidative stress is considered a key pathogenic step in mediating vascular dysfunction and atherosclerosis development, their association has not been evaluated in human coronary circulationAlthough oxidative stress is considered a key pathogenic step in mediating vascular dysfunction and atherosclerosis development, their association has not been evaluated in human coronary circulation in vivo. Accordingly, we hypothesized that higher oxidative stress would be associated with abnormal coronary epicardial structure and microvascular function. We measured coronary flow velocity reserve (CFVR) and hyperemic microvascular resistance (HMR) as indices of microvascular function, and epicardial plaque volume and necrotic core using intravascular ultrasound (IVUS) in 47 patients undergoing cardiac catheterization. Plasma glutathione, cystine and their ratio served as measures of oxidative stress while high-sensitivity C-reactive protein (hs-CRP) served as a measure of inflammation. Lower glutathione, a measure of increased oxidative stress was associated with impaired microvascular function [CFVR (r=0.39, p=0.01) and HMR (r=-0.43, p=0.004)], greater plaque burden (r=-0.32, p=0.03) and necrotic core (r=-0.39, p=0.008). Similarly, higher cystine/glutathione ratio was associated with impaired microvascular function [CFVR (r=-0.29, p=0.04)] and greater necrotic core (r=0.37, p=0.01). In comparison, higher hs-CRP was associated only with greater necrotic core (r=0.45, p=0.003). After multivariate adjustment for age, gender, hypertension, diabetes, acute coronary syndrome presentation, body mass index, tobacco abuse, statin use and hs-CRP, glutathione remained an independent predictor of CFVR, HMR and necrotic core (p<0.05). Lower plasma glutathione level a measure of increased oxidative stress, was an independent predictor of impaired coronary microvascular function and plaque necrotic core.

• Clinical trials of antioxidants as cancer prevention agents: past, present, and future.

  Authors: Michael Goodman, Roberd M Bostick, Omer Kucuk, Dean P Jones

  Free radical biology & medicine. 05/2011; 51(5):1068-84.

  The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies,The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included β-carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials.

• Oxidative stress is associated with impaired arterial elasticity.

  Authors: Riyaz S Patel, Ibhar Al Mheid, Alanna A Morris, Yusuf Ahmed, Nino Kavtaradze, Sarfraz Ali, Kaustubh Dabhadkar, Kenneth Brigham, W Craig Hooper, R Wayne Alexander, Dean P Jones, Arshed A Quyyumi

  Atherosclerosis. 05/2011; 218(1):90-5.

  Arterial stiffening may lead to hypertension, greater left ventricular after-load and adverse clinical outcomes. The underlying mechanisms influencing arterial elasticity may involve oxidative injuryArterial stiffening may lead to hypertension, greater left ventricular after-load and adverse clinical outcomes. The underlying mechanisms influencing arterial elasticity may involve oxidative injury to the vessel wall. We sought to examine the relationship between novel markers of oxidative stress and arterial elastic properties in healthy humans. We studied 169 subjects (mean age 42.6 ± 14 years, 51.6% male) free of traditional cardiovascular risk factors. Indices of arterial stiffness and wave reflections measured included carotid-femoral Pulse Wave Velocity (PWV), Augmentation Index (Aix) and Pulse Pressure Amplification (PPA). Non-free radical oxidative stress was assessed as plasma oxidized and reduced amino-thiol levels (cysteine/cystine, glutathione/GSSG) and their ratios (redox potentials), and free radical oxidative stress as derivatives of reactive oxygen metabolites (dROMs). Inflammation was assessed as hsCRP and interleukin-6 levels. The non-free radical marker of oxidative stress, cystine was significantly correlated with all arterial indices; PWV (r=0.38, p<0.001), Aix (r=0.35, p<0.001) and PPA (r=-0.30, p<0.001). Its redox potential, was also associated with PWV (r=0.22, p=0.01), while the free radical marker of oxidative stress dROMS was associated with Aix (r=0.25, p<0.01). After multivariate adjustment for age, gender, arterial pressure, height, weight, heart rate and CRP, of these oxidative stress markers, only cystine remained independently associated with PWV (p=0.03), Aix (p=0.01) and PPA (p=0.05). In healthy subjects without confounding risk factors or significant systemic inflammation, a high cystine level, reflecting extracellular oxidant burden, is associated with increased arterial stiffness and wave reflections. This has implications for understanding the role of oxidant burden in pre-clinical vascular dysfunction.