Publications by authors named "Susan McRitchie"

33 Publications

Information enhanced model selection for Gaussian graphical model with application to metabolomic data.

Biostatistics 2021 Mar 15. Epub 2021 Mar 15.

Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

In light of the low signal-to-noise nature of many large biological data sets, we propose a novel method to learn the structure of association networks using Gaussian graphical models combined with prior knowledge. Our strategy includes two parts. In the first part, we propose a model selection criterion called structural Bayesian information criterion, in which the prior structure is modeled and incorporated into Bayesian information criterion. It is shown that the popular extended Bayesian information criterion is a special case of structural Bayesian information criterion. In the second part, we propose a two-step algorithm to construct the candidate model pool. The algorithm is data-driven and the prior structure is embedded into the candidate model automatically. Theoretical investigation shows that under some mild conditions structural Bayesian information criterion is a consistent model selection criterion for high-dimensional Gaussian graphical model. Simulation studies validate the superiority of the proposed algorithm over the existing ones and show the robustness to the model misspecification. Application to relative concentration data from infant feces collected from subjects enrolled in a large molecular epidemiological cohort study validates that metabolic pathway involvement is a statistically significant factor for the conditional dependence between metabolites. Furthermore, new relationships among metabolites are discovered which can not be identified by the conventional methods of pathway analysis. Some of them have been widely recognized in biological literature.
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http://dx.doi.org/10.1093/biostatistics/kxab006DOI Listing
March 2021

Metabolomics reveals biomarkers of opioid use disorder.

Transl Psychiatry 2021 Feb 4;11(1):103. Epub 2021 Feb 4.

Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Opioid use disorder (OUD) is diagnosed using the qualitative criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnostic biomarkers for OUD do not currently exist. Our study focused on developing objective biological markers to differentiate chronic opiate users with OUD from chronic opiate users without OUD. Using biospecimens from the Golestan Cohort Study, we compared the metabolomics profiles of high opium users who were diagnosed as OUD positive with high opium users who were diagnosed as OUD negative. High opium use was defined as maximum weekly opium usage greater than or equal to the median usage (2.4 g per week), and OUD was defined as having 2 or more DSM-5 criteria in any 12-month period. Among the 218 high opium users in this study, 80 were diagnosed as OUD negative, while 138 were diagnosed as OUD positive. Seven hundred and twelve peaks differentiated high opium users diagnosed as OUD positive from high opium users diagnosed as OUD negative. Stepwise logistic regression modeling of subject characteristics data together with the 712 differentiating peaks revealed a signature that is 95% predictive of an OUD positive diagnosis, a significant (p < 0.0001) improvement over a 63% accurate prediction based on subject characteristic data for these samples. These results suggest that a metabolic profile can be used to predict an OUD positive diagnosis.
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http://dx.doi.org/10.1038/s41398-021-01228-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862627PMC
February 2021

Untargeted Metabolomics: Biochemical Perturbations in Golestan Cohort Study Opium Users Inform Intervention Strategies.

Front Nutr 2020 22;7:584585. Epub 2020 Dec 22.

Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Over 50 million people worldwide are estimated to use opioids, of which ~30 million use opiates (opium and its derivatives). Use of opiates has been associated with a variety of adverse complications such as neurological and behavioral outcomes, addiction, cancers, diabetes, and cardiovascular disease. While it is well known that opiates exert their neurobiological effects through binding with mu, kappa, and delta receptors to exert analgesic and sedative effects, mechanistic links to other health effects are not well understood. Our study focuses on the identification of biochemical perturbations in Golestan Cohort Study (GCS) opium users. We used untargeted metabolomics to evaluate the metabolic profiles of 218 opium users and 80 non-users participating in the GCS. Urine samples were obtained from adult (age 40-75) opium users living in the Golestan Province of Iran. Untargeted analysis of urine was conducted using a UPLC-Q-Exactive HFx Mass Spectrometry and a 700 MHz NMR Spectrometry. These GCS opium users had a significantly higher intake of tobacco and alcohol and a significantly decreased BMI compared with non-users. Metabolites derived from opium (codeine, morphine, and related glucuronides), nicotine, and curing or combustion of plant material were increased in opium users compared with non-users. Endogenous compounds which differentiated the opium users and non-users largely included vitamins and co-factors, metabolites involved in neurotransmission, Kreb's cycle, purine metabolism, central carbon metabolism, histone modification, and acetylation. Our study reveals biochemical perturbations in GCS opium users that are important to the development of intervention strategies to mitigate against the development of adverse effects of substance abuse.
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http://dx.doi.org/10.3389/fnut.2020.584585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783045PMC
December 2020

Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients.

Sci Rep 2020 11 19;10(1):20202. Epub 2020 Nov 19.

Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.

Alterations in hemodialysis patients' serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients' chromium and antimony levels exceeded established accepted upper limits of normal.
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http://dx.doi.org/10.1038/s41598-020-77311-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677396PMC
November 2020

Maternal Liver Metabolic Response to Chronic Vitamin D Deficiency Is Determined by Mouse Strain Genetic Background.

Curr Dev Nutr 2020 Aug 20;4(8):nzaa106. Epub 2020 Jun 20.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Liver metabolite concentrations have the potential to be key biomarkers of systemic metabolic dysfunction and overall health. However, for most conditions we do not know the extent to which genetic differences regulate susceptibility to metabolic responses. This limits our ability to detect and diagnose effects in heterogeneous populations.

Objectives: Here, we investigated the extent to which naturally occurring genetic differences regulate maternal liver metabolic response to vitamin D deficiency (VDD), particularly during perinatal periods when such changes can adversely affect maternal and fetal health.

Methods: We used a panel of 8 inbred Collaborative Cross (CC) mouse strains, each with a different genetic background (72 dams, 3-6/treatment group, per strain). We identified robust maternal liver metabolic responses to vitamin D depletion before and during gestation and lactation using a vitamin-D-deficient (VDD; 0 IU vitamin D/kg) or -sufficient diet (1000 IU vitamin D/kg). We then identified VDD-induced metabolite changes influenced by strain genetic background.

Results: We detected a significant VDD effect by orthogonal partial least squares discriminant analysis (Q2 = 0.266, pQ2 = 0.002): primarily, altered concentrations of 78 metabolites involved in lipid, amino acid, and nucleotide metabolism (variable importance to projection score ≥1.5). Metabolites in unsaturated fatty acid and glycerophospholipid metabolism pathways were significantly enriched [False Discovery Rate (FDR) <0.05]. VDD also significantly altered concentrations of putative markers of uremic toxemia, acylglycerols, and dipeptides. The extent of the metabolic response to VDD was strongly dependent on genetic strain, ranging from robustly responsive to nonresponsive. Two strains (CC017/Unc and CC032/GeniUnc) were particularly sensitive to VDD; however, each strain altered different pathways.

Conclusions: These novel findings demonstrate that maternal VDD induces different liver metabolic effects in different genetic backgrounds. Strains with differing susceptibility and metabolic response to VDD represent unique tools to identify causal susceptibility factors and further elucidate the role of VDD-induced metabolic changes in maternal and/or fetal health for ultimately translating findings to human populations.
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http://dx.doi.org/10.1093/cdn/nzaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439094PMC
August 2020

Analysis of NMR Metabolomics Data.

Methods Mol Biol 2020 ;2104:61-97

Department of Nutrition, School of Public Health, NIH Eastern Regional Comprehensive Metabolomics Resource Core (ERCMRC), Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.

In this chapter, we summarize data preprocessing and data analysis strategies used for analysis of NMR data for metabolomics studies. Metabolomics consists of the analysis of the low molecular weight compounds in cells, tissues, or biological fluids, and has been used to reveal biomarkers for early disease detection and diagnosis, to monitor interventions, and to provide information on pathway perturbations to inform mechanisms and identifying targets. Metabolic profiling (also termed metabotyping) involves the analysis of hundreds to thousands of molecules using mainly state-of-the-art mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy technologies. While NMR is less sensitive than mass spectrometry, NMR does provide a wealth of complex and information rich metabolite data. NMR data together with the use of conventional statistics, modeling methods, and bioinformatics tools reveals biomarker and mechanistic information. A typical NMR spectrum, with up to 64k data points, of a complex biological fluid or an extract of cells and tissues consists of thousands of sharp signals that are mainly derived from small molecules. In addition, a number of advanced NMR spectroscopic methods are available for extracting information on high molecular weight compounds such as lipids or lipoproteins. There are numerous data preprocessing, data reduction, and analysis methods developed and evolving in the field of NMR metabolomics. Our goal is to provide an extensive summary of NMR data preprocessing and analysis strategies by providing examples and open source and commercially available analysis software and bioinformatics tools.
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http://dx.doi.org/10.1007/978-1-0716-0239-3_5DOI Listing
January 2021

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Metabolomics.

Kidney Int Rep 2020 Jan 19;5(1):81-93. Epub 2019 Sep 19.

National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core (ERCMRC) at University of North Carolina, Chapel Hill, North Carolina, USA.

Introduction: Nephrotic syndrome (NS) is a kidney disease that affects both children and adults. Glucocorticoids have been the primary therapy for >60 years but are ineffective in approximately 20% of children and approximately 50% of adult patients. Unfortunately, patients with steroid-resistant NS (SRNS; vs. steroid-sensitive NS [SSNS]) are at high risk for both glucocorticoid-induced side effects and disease progression.

Methods: We performed proton nuclear magnetic resonance (H NMR) metabolomic analyses on plasma samples ( = 86) from 45 patients with NS (30 SSNS and 15 SRNS) obtained at initial disease presentation before glucocorticoid initiation and after approximately 7 weeks of glucocorticoid therapy to identify candidate biomarkers able to either predict SRNS before treatment or define critical molecular pathways/targets regulating steroid resistance.

Results: Stepwise logistic regression models identified creatinine concentration and glutamine concentration (odds ratio [OR]: 1.01; 95% confidence interval [CI]: 0.99-1.02) as 2 candidate biomarkers predictive of SRNS, and malonate concentration (OR: 0.94; 95% CI: 0.89-1.00) as a third candidate predictive biomarker using a similar model (only in children >3 years). In addition, paired-sample analyses identified several candidate biomarkers with the potential to identify mechanistic molecular pathways/targets that regulate clinical steroid resistance, including lipoproteins, adipate, pyruvate, creatine, glucose, tyrosine, valine, glutamine, and sn-glycero-3-phosphcholine.

Conclusion: Metabolomic analyses of serial plasma samples from children with SSNS and SRNS identified elevated creatinine and glutamine concentrations, and reduced malonate concentrations, as auspicious candidate biomarkers to predict SRNS at disease onset in pediatric NS, as well as additional candidate biomarkers with the potential to identify mechanistic molecular pathways that may regulate clinical steroid resistance.
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http://dx.doi.org/10.1016/j.ekir.2019.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943762PMC
January 2020

Multi-omics studies in cellular models of methylmalonic acidemia and propionic acidemia reveal dysregulation of serine metabolism.

Biochim Biophys Acta Mol Basis Dis 2019 12 23;1865(12):165538. Epub 2019 Aug 23.

Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, United States of America. Electronic address:

Background: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are related disorders of mitochondrial propionate metabolism, caused by defects in methylmalonyl-CoA mutase (MUT) and propionyl-CoA carboxylase (PCC), respectively. These biochemical defects lead to a complex cascade of downstream metabolic abnormalities, and identification of these abnormal pathways has important implications for understanding disease pathophysiology. Using a multi-omics approach in cellular models of MMA and PA, we identified serine and thiol metabolism as important areas of metabolic dysregulation.

Methods: We performed global proteomic analysis of fibroblasts and untargeted metabolomics analysis of plasma from individuals with MMA to identify novel pathways of dysfunction. We probed these novel pathways in CRISPR-edited, MUT and PCCA null HEK293 cell lines via targeted metabolomics, gene expression analysis, and flux metabolomics tracing utilization of C-glucose.

Results: Proteomic analysis of fibroblasts identified upregulation of multiple proteins involved in serine synthesis and thiol metabolism including: phosphoserine amino transferase (PSAT1), cystathionine beta synthase (CBS), and mercaptopyruvate sulfurtransferase (MPST). Metabolomics analysis of plasma revealed significantly increased levels of cystathionine and glutathione, central metabolites in thiol metabolism. CRISPR-edited MUT and PCCA HEK293 cells recapitulate primary defects of MMA and PA and have upregulation of transcripts associated with serine and thiol metabolism including PSAT1. C-glucose flux metabolomics in MUT and PCCA null HEK293 cells identified increases in serine de novo biosynthesis, serine transport, and abnormal downstream TCA cycle utilization.

Conclusion: We identified abnormal serine metabolism as a novel area of cellular dysfunction in MMA and PA, thus introducing a potential new target for therapeutic investigation.
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http://dx.doi.org/10.1016/j.bbadis.2019.165538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923996PMC
December 2019

LC-MS-based metabolomics analysis to identify meprin-β-associated changes in kidney tissue from mice with STZ-induced type 1 diabetes and diabetic kidney injury.

Am J Physiol Renal Physiol 2019 10 14;317(4):F1034-F1046. Epub 2019 Aug 14.

Department of Biology, North Carolina A&T State University, Greensboro, North Carolina.

Meprin metalloproteases have been implicated in the pathophysiology of diabetic kidney disease (DKD). Single-nucleotide polymorphisms in the meprin-β gene have been associated with DKD in Pima Indians, a Native American ethnic group with an extremely high prevalence of DKD. In African American men with diabetes, urinary meprin excretion positively correlated with the severity of kidney injury. In mice, meprin activity decreased at the onset of diabetic kidney injury. Several studies have identified meprin targets in the kidney. However, it is not known how proteolytic processing of the targets by meprins impacts the metabolite milieu in kidneys. In the present study, global metabolomics analysis identified differentiating metabolites in kidney tissues from wild-type and meprin-β knockout mice with streptozotocin (STZ)-induced type 1 diabetes. Kidney tissues were harvested at 8 wk post-STZ and analyzed by hydrophilic interaction liquid chromatography ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Principal component analysis identified >200 peaks associated with diabetes. Meprin expression-associated metabolites with strong variable importance of projection scores were indoxyl sulfate, -γ-l-glutamyl-l-aspartic acid, -methyl-4-pyridone-3-carboxamide, inosine, and -5-decenedioic acid. -methyl-4-pyridone-3-carboxamide has been previously implicated in kidney injury, and its isomers, 4-PY and 2-PY, are markers of peroxisome proliferation and inflammation that correlate with creatinine clearance and glucose tolerance. Meprin deficiency-associated differentiating metabolites with high variable importance of projection scores were cortisol, hydroxymethoxyphenylcarboxylic acid--sulfate, and isovaleryalanine. The data suggest that meprin-β activity enhances diabetic kidney injury in part by altering the metabolite balance in kidneys, favoring high levels of uremic toxins such as indoxyl sulfate and -methyl-pyridone-carboxamide.
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http://dx.doi.org/10.1152/ajprenal.00166.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843037PMC
October 2019

Meprin β metalloproteases associated with differential metabolite profiles in the plasma and urine of mice with type 1 diabetes and diabetic nephropathy.

BMC Nephrol 2019 04 25;20(1):141. Epub 2019 Apr 25.

Department of Biology, North Carolina A&T State University, Greensboro, NC, 27411, USA.

Background: Meprin metalloproteases are abundantly expressed in the brush border membranes of kidney proximal tubules and small intestines. Meprins are also expressed in podocytes and leukocytes (monocytes and macrophages). Meprins are implicated in the pathophysiology of diabetic nephropathy (DN) but underlying mechanisms are not fully understood. Single nucleotide polymophisms (SNPs) in the meprin β gene were associated with DKD in human subjects. Furthermore, meprin α and β double deficiency resulted in more severe kidney injury and higher mortality rates in mice with Streptozotocin (STZ)-induced type 1 diabetes. Identification of meprin substrates has provided insights on how meprins could modulate kidney injury. Meprin targets in the kidney include extracellular matrix (ECM) proteins, modulators of inflammation, and proteins involved in the protein kinase A (PKA) and PKC signaling pathways. The current study used a global metabolomics approach to determine how meprin β expression impacts the metabolite milieu in diabetes and DKD.

Methods: Low dose STZ was used to induce type 1 diabetes in 8-week old wild-type (WT) and meprin β knockout (βKO) mice. Blood and urine samples were obtained at 4 and 8 weeks post-STZ injection. Assays for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule - 1 (KIM-1), and cystatin C were used for biochemical assessment of kidney injury. Data for biomarkers of kidney injury utilized two-way ANOVA. Metabolomics data analysis utilized UPLC-QTOF MS and multivariate statistics.

Results: The number of metabolites with diabetes-associated changes in levels were significantly higher in the WT mice when compared to meprin βKO counterparts. Annotated meprin β expression-associated metabolites with strong variable importance in projection (VIP) scores play roles in lipid metabolism (LysoPC(16:1(9Z)), taurocholic acid), amino acid metabolism (indoxyl sulfate, hippuric acid), and neurotransmitter/stress hormone synthesis (cortisol, 3-methoxy-4-hydroxyphenylethylene glycolsulfate, homovanillic acid sulfate). Metabolites that associated with meprin β deficiency include; 3,5-dihydroxy-3',4'-dimethoxy-6,7-methylenedioxyflavone 3-glucuronide, pantothenic acid, and indoxyl glucuronide (all decreased in plasma).

Conclusion: Taken together, the annotated metabolites suggest that meprin β impacts complications of diabetes such as DKD by altering distinct metabolite profiles.
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http://dx.doi.org/10.1186/s12882-019-1313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485094PMC
April 2019

Broad spectrum metabolomics for detection of abnormal metabolic pathways in a mouse model for retinitis pigmentosa.

Exp Eye Res 2019 07 16;184:135-145. Epub 2019 Mar 16.

Eastern Regional Comprehensive Metabolomics Resource Core, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; RTI International, 3040 Cornwallis Drive, Research Triangle Park, NC, USA. Electronic address:

Retinitis pigmentosa (RP) is a degenerative disease of the retina that affects approximately 1 million people worldwide. There are multiple genetic causes of this disease, for which, at present, there are no effective therapeutic strategies. In the present report, we utilized broad spectrum metabolomics to identify perturbations in the metabolism of the rd10 mouse, a genetic model for RP that contains a mutation in Pde6β. These data provide novel insights into mechanisms that are potentially critical for retinal degeneration. C57BL/6J and rd10 mice were raised in cyclic light followed by either light or dark adaptation at postnatal day (P) 18, an early stage in the degeneration process. Mice raised entirely in the dark until P18 were also evaluated. After euthanasia, retinas were removed and extracted for analysis by ultra-performance liquid chromatography-time of flight-mass spectrometry (UPLC-QTOF-MS). Compared to wild type mice, rd10 mice raised in cyclic light or in complete darkness demonstrate significant alterations in retinal pyrimidine and purine nucleotide metabolism, potentially disrupting deoxynucleotide pools necessary for mitochondrial DNA replication. Other metabolites that demonstrate significant increases are the Coenzyme A intermediate, 4'-phosphopantothenate, and acylcarnitines. The changes in these metabolites, identified for the first time in a model of RP, are highly likely to disrupt normal energy metabolism. High levels of nitrosoproline were also detected in rd10 retinas relative to those from wild type mice. These results suggest that nitrosative stress may be involved in retinal degeneration in this mouse model.
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http://dx.doi.org/10.1016/j.exer.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570542PMC
July 2019

A Metabolomics Approach to Investigate Kukoamine B-A Potent Natural Product With Anti-diabetic Properties.

Front Pharmacol 2018 22;9:1575. Epub 2019 Jan 22.

NIH Eastern Regional Comprehensive Metabolomics Resource Core, Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Kannapolis, NC, United States.

Due to the surge in type 2 diabetes mellitus (T2DM), treatments for chronic metabolic dysregulations with fewer side-effects are sought. Lycii Cortex (LyC), a traditional Chinese Medicine (TCM) herb has a long history of being widely prescribed to treat T2DM as alternative medicine; however, the bioactive molecules and working mechanism remained unknown. Previous studies revealed kukoamine B (KB) as a major and featured compound for LyC with bioactivities for anti-oxidation and acute inflammation, which may be related to anti-diabetes properties. This study aims to understand the efficacy and the mode of action of KB in the diabetic (db/db) mouse model using a metabolomics approach. Parallel comparison was conducted using the first-line anti-diabetic drugs, metformin and rosligtazone, as positive controls. The db/db mice were treated with KB (50 mg kg day) for 9 weeks. Bodyweight and fasting blood glucose were monitored every 5 and 7 days, respectively. Metabolomics and high-throughput molecular approaches, including lipidomics, targeted metabolomics (Biocrates p180), and cytokine profiling were applied to measure the alteration of serum metabolites and inflammatory biomarkers between different treatments vs. control (db/db mice treated with vehicle). After 9 weeks of treatment, KB lowered blood glucose, without the adverse effects of bodyweight gain and hepatomegaly shown after rosiglitazone treatment. Lipidomics analysis revealed that KB reduced levels of circulating triglycerides, cholesterol, phosphatidylethanolamine, and increased levels of phosphatidylcholines. KB also increased acylcarnitines, and reduced systemic inflammation (cytokine array). Pathway analysis suggested that KB may regulate nuclear transcription factors (e.g., NF-κB and/or PPAR) to reduce inflammation and facilitate a shift toward metabolic and inflammatory homeostasis. Comparison of KB with first-line drugs suggests that rosiglitazone may over-regulate lipid metabolism and anti-inflammatory responses, which may be associated with adverse side effects, while metformin had less impact on lipid and anti-inflammation profiles. Our research from holistic and systemic views supports the conclusion that KB is the bioactive compound of LyC for managing T2DM, and suggests KB as a nutraceutical or a pharmaceutical candidate for T2D treatment. In addition, our research provides insights related to metformin and rosiglitazone action, beyond lowering blood glucose.
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http://dx.doi.org/10.3389/fphar.2018.01575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350459PMC
January 2019

The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes.

ISME J 2019 05 16;13(5):1280-1292. Epub 2019 Jan 16.

Department of Medicine, New York University Langone Medical Center, New York, NY, 10016, USA.

The high-fat, high-calorie diets of westernized cultures contribute to the global obesity epidemic, and early life exposure to antibiotics may potentiate those dietary effects. Previous experiments with mice had shown that sub-therapeutic antibiotic treatment (STAT)-even restricted to early life-affected the gut microbiota, altered host metabolism, and increased adiposity throughout the lifetime of the animals. Here we carried out a large-scale cohousing experiment to investigate whether cohousing STAT and untreated (Control) mice would transfer the STAT-perturbed microbiota and transmit its impact on weight. We exposed pregnant dams and their young offspring to either low-dose penicillin (STAT) or water (Control) until weaning, and then followed the offspring as they grew and endured a switch from normal to high-fat diet at week 17 of life. Cohousing, which started at week 4, rapidly approximated the microbiota within cages, lowering the weight of STAT mice relative to non-cohoused mice. The effect, however, varied between cages, and was restricted to the first 16 weeks when diet consisted of normal chow. Once mice switched to high-fat diet, the microbiota α- and β-diversity expanded and the effect of cohousing faded: STAT mice, again, were heavier than control mice independently of cohousing. Metabolomics revealed serum metabolites associated with STAT exposure, but no significant differences were detected in glucose or insulin tolerance. Our results show that cohousing can partly ameliorate the impact of STAT on the gut microbiota but not prevent increased weight with high-fat diet. These observations have implications for microbiota therapies aimed to resolve the collateral damage of antibiotics and their load on human obesity.
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http://dx.doi.org/10.1038/s41396-019-0349-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474226PMC
May 2019

Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines.

Int J Breast Cancer 2018 30;2018:2063540. Epub 2018 Sep 30.

NIH Eastern Regional Comprehensive Metabolomics Resource Core, Department of Nutrition, University of North Carolina at Chapel Hill Nutrition Research Institute, Kannapolis, NC 28081, USA.

Purpose: To conduct an exploratory study to identify mechanisms that differentiate Luminal A (BT474 and MCF-7) and triple-negative (MDA-MB-231 and MDA-MB-468) breast cancer (BCa) cell lines to potentially provide novel therapeutic targets based on differences in energy utilization.

Methods: Cells were cultured in media containing either [U-C]-glucose or [U-C]-glutamine for 48 hours. Conditioned media and cellular extracts were analyzed by H and C NMR spectroscopy.

Results: MCF-7 cells consumed the most glucose, producing the most lactate, demonstrating the greatest Warburg effect-associated energy utilization. BT474 cells had the highest tricarboxylic acid cycle (TCA) activity. The majority of energy utilization patterns in MCF-7 cells were more similar to MDA-MB-468 cells, while the patterns for BT474 cells were more similar to MDA-MB-231 cells. Compared to the Luminal A cell lines, TNBC cell lines consumed more glutamine and less glucose. BT474 and MDA-MB-468 cells produced high amounts of C-glycine from media [U-C]-glucose which was integrated into glutathione, indicating synthesis.

Conclusions: Stable isotopic resolved metabolomics using C substrates provided mechanistic information about energy utilization that was difficult to interpret using H data alone. Overall, cell lines that have different hormone receptor status have different energy utilization requirements, even if they are classified by the same clinical BCa subtype; and these differences offer clues about optimizing treatment strategies.
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http://dx.doi.org/10.1155/2018/2063540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186330PMC
September 2018

Plasma metabolomics analysis in sickle cell disease patients with albuminuria - an exploratory study.

Br J Haematol 2019 05 10;185(3):620-623. Epub 2018 Sep 10.

Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN, USA.

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http://dx.doi.org/10.1111/bjh.15592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409098PMC
May 2019

Correlated metabolomic, genomic, and histologic phenotypes in histologically normal breast tissue.

PLoS One 2018 18;13(4):e0193792. Epub 2018 Apr 18.

National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core, Department of Nutrition, University of North Carolina at Chapel Hill, Nutrition Research Institute, Kannapolis, North Carolina, United States of America.

Breast carcinogenesis is a multistep process accompanied by widespread molecular and genomic alterations, both in tumor and in surrounding microenvironment. It is known that tumors have altered metabolism, but the metabolic changes in normal or cancer-adjacent, nonmalignant normal tissues and how these changes relate to alterations in gene expression and histological composition are not well understood. Normal or cancer-adjacent normal breast tissues from 99 women of the Normal Breast Study (NBS) were evaluated. Data of metabolomics, gene expression and histological composition was collected by mass spectrometry, whole genome microarray, and digital image, respectively. Unsupervised clustering analysis determined metabolomics-derived subtypes. Their association with genomic and histological features, as well as other breast cancer risk factors, genomic and histological features were evaluated using logistic regression. Unsupervised clustering of metabolites resulted in two main clusters. The metabolite differences between the two clusters suggested enrichment of pathways involved in lipid metabolism, cell growth and proliferation, and migration. Compared with Cluster 1, subjects in Cluster 2 were more likely to be obese (body mass index ≥30 kg/m2, p<0.05), have increased adipose proportion (p<0.01) and associated with a previously defined Active genomic subtype (p<0.01). By the integrated analyses of histological, metabolomics and transcriptional data, we characterized two distinct subtypes of non-malignant breast tissue. Further research is needed to validate our findings, and understand the potential role of these alternations in breast cancer initiation, progression and recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905995PMC
July 2018

The Effects of Glaucoma Drainage Devices on Oxygen Tension, Glycolytic Metabolites, and Metabolomics Profile of Aqueous Humor in the Rabbit.

Transl Vis Sci Technol 2018 Feb 2;7(1):14. Epub 2018 Feb 2.

Department of Ophthalmology, Tulane University School of Medicine, New Orleans, LA, USA.

Purpose: Glaucoma drainage device (GDD) implantation can lead to corneal decompensation. We evaluated changes over time in oxygen tension and in the metabolic environment of the aqueous humor after GDD implantation in the rabbit eye.

Methods: Ahmed Glaucoma Valves were implanted in the left eyes of eight male New Zealand white rabbits. Right eyes were used as a control. Oxygen tension was measured immediately before surgery and at 1 and 2 months postoperation. Aqueous humor was collected from the surgical and control eyes at 1, 2, and 5 months postoperation. Aqueous humor samples collected at 1 and 5 months postoperation were selected for broad-spectrum metabolomics analysis using ultra-performance liquid chromatography-time of flight-mass spectrometry (UPLC TOF-MS). Multivariate analysis methods were used to identify metabolite profiles that separated the surgical and control eye at 1 and 5 months.

Results: There was a significant decrease in oxygen tension in aqueous humor of the surgical eyes (9 mm Hg, 95% confidence interval [CI]: -14.7 to -3.5). Differences in the metabolic profiles between the surgical and control eye at 1 and 5 months were observed, as were differences for the surgical eye at 1 and 5 months. In addition, a metabolite profile was identified that differentiated the surgical eyes at 1 and 5 months.

Conclusion: Changes in the oxygen tension and metabolic intermediates occur within the aqueous humor as early as 1 month after GDD implantation.

Translational Relevance: Corneal decompensation following GDD implantation could be secondary to disruption of the normal aqueous circulation, resulting in hypoxia and an altered metabolic profile. Alterations to the GDD design might minimize aqueous disruption and prevent corneal decompensation.
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http://dx.doi.org/10.1167/tvst.7.1.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802326PMC
February 2018

EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain.

Endocr Connect 2018 Feb 19;7(2):305-324. Epub 2018 Jan 19.

Department of Biological SciencesNorth Carolina State University, Raleigh, North Carolina, USA

Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, composed of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity has raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300 or 1000 µg/day) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.
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http://dx.doi.org/10.1530/EC-17-0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817967PMC
February 2018

Effect of endotoxin and alum adjuvant vaccine on peanut allergy.

J Allergy Clin Immunol 2018 02 18;141(2):791-794.e8. Epub 2017 Sep 18.

Department of Pathology, Duke University School of Medicine, Durham, NC. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.07.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803373PMC
February 2018

Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke.

J Appl Physiol (1985) 2017 Sep 8;123(3):544-557. Epub 2017 Jun 8.

Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts.

It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (T) of male, C57BL/6J mice ( = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4°C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (T)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to T, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at T, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury. This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity.
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http://dx.doi.org/10.1152/japplphysiol.00242.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625077PMC
September 2017

Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics.

Vaccine 2017 03 3;35(9):1238-1245. Epub 2017 Feb 3.

NIH Common Fund Eastern Regional Comprehensive Metabolomics Resource Core, RTI International, 3040 E Cornwallis Road, Research Triangle Park, NC 27709, USA. Electronic address:

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers.
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http://dx.doi.org/10.1016/j.vaccine.2017.01.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347534PMC
March 2017

Metabolic profiling of a chronic kidney disease cohort reveals metabolic phenotype more likely to benefit from a probiotic.

Int J Probiotics Prebiotics 2017 21;12(1):43-54. Epub 2017 Aug 21.

NIH Eastern Regional Comprehensive Metabolomics Resource Core, RTI International, 3040 E Cornwallis Rd., Durham, NC 27709, USA.

Scope: Persistent reduction in Glomerular Filtration Rate (GFR) is a hallmark of Chronic Kidney Disease (CKD) and is associated with an elevation of Blood Urea Nitrogen (BUN). This metabolomics pilot study sought to identify metabolites that differentiated patients with CKD whose BUN decreased on a probiotic and possible mechanisms.

Methods And Results: Metabolomics was used to analyze baseline plasma samples previously diagnosed with CKD Stage III-IV. Patients had participated in a dose escalation study of the probiotic Renadyl™. A total of 24 samples were categorized depending on whether BUN increased or decreased from baseline after 4 months of probiotic use. Multivariate analysis was used to analyze the data and determine the metabolites that best differentiated the phenotypic groups. The sixteen patients who had a decrease in BUN were not significantly different based on demographic and clinical measures from those whose BUN increased or did not change with the exception of age. Eleven of the fourteen metabolites that differentiated the groups were known to be modulated by gut microflora, which may eventually provide a mechanistic link between probiotic and outcomes.

Conclusions: Metabolomics revealed metabolites at baseline that may predict individuals with CKD that would most benefit from a probiotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377160PMC
August 2017

Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure.

Environ Sci Technol 2017 01 20;51(1):625-633. Epub 2016 Dec 20.

RTI International, Research Triangle Park, North Carolina 27709, United States.

Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gómez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure.
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http://dx.doi.org/10.1021/acs.est.6b04374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460981PMC
January 2017

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice.

Nat Microbiol 2016 Aug 22;1(11):16140. Epub 2016 Aug 22.

Departments of Medicine and Microbiology, Human Microbiome Program, New York University Langone Medical Center, Medical Service, New York, New York 10016, USA.

The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and T proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.
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http://dx.doi.org/10.1038/nmicrobiol.2016.140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808443PMC
August 2016

Impact of a western diet on the ovarian and serum metabolome.

Maturitas 2016 Oct 14;92:134-142. Epub 2016 Jul 14.

Department of Pathology Wake Forest School of Medicine, Winston Salem, NC, United States. Electronic address:

Objective: The objective of this investigation was to determine differences in the profiles of endogenous metabolites (metabolomics) among ovaries and serum derived from Old World nonhuman primates fed prudent or Western diets.

Design: A retrospective, observational study was done using archived ovarian tissue and serum from midlife cynomolgus monkeys (Macaca fasicularis). Targeted and broad spectrum metabolomics analysis was used to compare ovarian tissue and serum from monkeys that had been exposed to a prudent diet or a Western diet. Monkeys in the prudent diet group (n=13) were research naïve and had been exposed only to a commercial monkey chow diet (low in cholesterol and saturated fats, high in complex carbohydrates). Western diet monkeys (n=8) had consumed a diet that was high in cholesterol, saturated animal fats and soluble carbohydrates for 2 years prior to ovarian tissue and serum collection.

Outcome Measures: Metabolomic analyses were done on extracts of homogenized ovary tissue samples, and extracts of serum. Targeted analysis was conducted using the Biocrates p180 kit and broad spectrum analysis was conducted using UPLC-TOF-MS, resulting in the detection of 3500 compound ions.

Results: Using metabolomics methods, which capture thousands of signals for metabolites, 64 metabolites were identified in serum and 47 metabolites were identified in ovarian tissue that differed by diet. Quantitative targeted analysis revealed 13 amino acids, 6 acrylcarnitines, and 2 biogenic amines that were significantly (p<0.05) different between the two diet groups for serum extracts, and similar results were observed for the ovary extracts.

Conclusions: These data demonstrate that dietary exposure had a significant impact on the serum and ovarian metabolome, and demonstrated perturbation in carnitine, lipids/fatty acid, and amino acid metabolic pathways.
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http://dx.doi.org/10.1016/j.maturitas.2016.07.008DOI Listing
October 2016

Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

J Proteome Res 2016 09 3;15(9):3225-40. Epub 2016 Aug 3.

NIH Eastern Regional Comprehensive Metabolomics Resource Core, RTI International , Research Triangle Park, North Carolina 27709, United States.

To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment.
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http://dx.doi.org/10.1021/acs.jproteome.6b00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034715PMC
September 2016

Preterm neonatal urinary renal developmental and acute kidney injury metabolomic profiling: an exploratory study.

Pediatr Nephrol 2017 01 19;32(1):151-161. Epub 2016 Jul 19.

RTI International, 3040 E. Cornwallis Road, Research Triangle Park, Triangle, NC, 27709, USA.

Background: Acute kidney injury (AKI) staging has been developed in the adult and pediatric populations, but these do not yet exist for the neonatal population. Metabolomics was utilized to uncover biomarkers of normal and AKI-associated renal function in preterm infants. The study comprised 20 preterm infants with an AKI diagnosis who were matched by gestational age and gender to 20 infants without an AKI diagnosis.

Methods: Urine samples from pre-term newborn infants collected on day 2 of life were analyzed using broad-spectrum nuclear magnetic resonance (NMR) metabolomics. Multivariate analysis methods were used to identify metabolite profiles that differentiated AKI and no AKI, and to identify a metabolomics profile correlating with gestational age in infants with and without AKI.

Results: There was a clear distinction between the AKI and no-AKI profiles. Two previously identified biomarkers of AKI, hippurate and homovanillate, differentiated AKI from no-AKI profiles. Pathway analysis revealed similarities to cholinergic neurons, prenatal nicotine exposure on pancreatic β cells, and amitraz-induced inhibition of insulin secretion. Additionally, a pH difference was noted. Both pH and the metabolites were found to be associated with AKI; however, only the metabotype was a significant predictor of AKI. Pathways for the no-AKI group that correlated uniquely with gestational age included aminoacyl-t-RNA biosynthesis, whereas pathways in the AKI group yielded potential metabolite changes in pyruvate metabolism.

Conclusions: Metabolomics was able to differentiate the urinary profiles of neonates with and without an AKI diagnosis and metabolic developmental profiles correlated with gestational age. Further studies in larger cohorts are needed to validate these results.
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http://dx.doi.org/10.1007/s00467-016-3439-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123933PMC
January 2017

Maternal Early Pregnancy Serum Metabolomics Profile and Abnormal Vaginal Bleeding as Predictors of Placental Abruption: A Prospective Study.

PLoS One 2016 14;11(6):e0156755. Epub 2016 Jun 14.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States of America.

Background & Objective: Placental abruption, an ischemic placental disorder, complicates about 1 in 100 pregnancies, and is an important cause of maternal and perinatal morbidity and mortality worldwide. Metabolomics holds promise for improving the phenotyping, prediction and understanding of pathophysiologic mechanisms of complex clinical disorders including abruption. We sought to evaluate maternal early pregnancy pre-diagnostic serum metabolic profiles and abnormal vaginal bleeding as predictors of abruption later in pregnancy.

Methods: Maternal serum was collected in early pregnancy (mean 16 weeks, range 15 to 22 weeks) from 51 abruption cases and 51 controls. Quantitative targeted metabolic profiles of serum were acquired using electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and the Absolute IDQ® p180 kit. Maternal sociodemographic characteristics and reproductive history were abstracted from medical records. Stepwise logistic regression models were developed to evaluate the extent to which metabolites aid in the prediction of abruption. We evaluated the predictive performance of the set of selected metabolites using a receiver operating characteristics (ROC) curve analysis and area under the curve (AUC).

Results: Early pregnancy vaginal bleeding, dodecanoylcarnitine/dodecenoylcarnitine (C12 / C12:1), and phosphatidylcholine acyl-alkyl C 38:1 (PC ae C38:1) strongly predict abruption risk. The AUC for these metabolites alone was 0.68, for early pregnancy vaginal bleeding alone was 0.65, and combined the AUC improved to 0.75 with the addition of quantitative metabolite data (P = 0.003).

Conclusion: Metabolomic profiles of early pregnancy maternal serum samples in addition to the clinical symptom, vaginal bleeding, may serve as important markers for the prediction of abruption. Larger studies are necessary to corroborate and validate these findings in other cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907440PMC
July 2017

Parent & Family Influences on Adopting Healthy Weight-Related Behaviors: Views and Perceptions of Obese African-American Female Adolescents.

J Natl Med Assoc 2015 Jun 2;107(2):74-9. Epub 2015 Dec 2.

Obesity and Metabolomics Signature Programs, Discovery Sciences, RTI International, Research Triangle Park, NC.

RTI International is acknowledged for supporting the time of Susan McRitchie, Keeley Pratt and Susan Sumner to participate in the design, execution, or analysis of this study. East Carolina University would like to acknowledge Brittney France for being a triangulated investigator for the qualitative analysis and to the Pitt Memorial Hospital Foundation for financial support of the healthy lifestyles camp. Our purpose was to evaluate the views of obese African-American (AA) female adolescents concerning parent and family factors relating to obesity and a healthy lifestyle. Obese AA female adolescents enrolled in a residential healthy lifestyle program completed inventories measuring family functioning and perceptions of parenting styles, and participated in focus groups to identify themes regarding parent and family involvement in healthy lifestyle change. The majority of participants' mothers were scored as "inductive/authoritative" and fathers were "indulgent". Mothers reportedly were seen as more likely to encourage dieting to control weight than fathers. Common themes of the focus groups included a desire for family involvement, identification of family behaviors that were supportive as well as those which were perceived as unhelpful. Though generalizability of these results is limited by a homogenous small sample size, our results suggest that obese adolescents seeking weight loss treatment desire significant family involvement in their efforts.
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http://dx.doi.org/10.1016/S0027-9684(15)30027-4DOI Listing
June 2015

Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways.

Biomed Microdevices 2016 06;18(3):51

Systems and Translational Sciences Discovery - Science - Technology, RTI International, 3040 Cornwallis Drive, Research Triangle Park, NC, 27709, USA.

Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time.
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http://dx.doi.org/10.1007/s10544-016-0076-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939818PMC
June 2016