John W. Newman

University of California, Davis

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Theresa L. Pedersen

University of California, Davis

Kamil Borkowski

University of California, Davis

Oliver Fiehn

University of California, Davis

Bruce D. Hammock

University of California, Davis

Nancy L. Keim

Western Human Nutrition Research Center

Sean H. Adams

University of California, Davis

Charles B. Stephensen

Western Human Nutrition Research Center

Gregory C. Shearer

University of South Dakota

Andrew M. Q. King

The Pirbright Institute

Cécile Gladine

Centre de Recherche en Nutrition Humaine d'Auvergne

Cooperative Institutions

University of California, Davis

338

Western Human Nutrition Research Center

108

Agricultural Research Service

United States Department of Agriculture

University of California, San Francisco

Harvard University

National Institutes of Health

University of California System

Johns Hopkins University

University of Copenhagen

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Increased Accumulation of Long‐chain Fatty Acids in Skeletal Muscle May Contribute Insulin Resistance in Znt7 Knockout Mice

The FASEB Journal (2015)

Surapun Tepaamorndech Catherine P. Kirschke Theresa L. Pedersen William R. Keyes John W. Newman

The Slc30a7 (Znt7) gene encodes a ubiquitously expressed zinc transporter involved in transporting cytoplasmic zinc into the Golgi apparatus and vesicles. The Znt7 knockout (KO) mouse is mildly zinc deficient. Our previous studies have demonstrated that insulin resistance may underlie severe glucose intolerance in Znt7 KO mice fed a high fat diet (45% Kcal). In humans, insulin resistance in peripheral tissues is a precursor to Type 2 diabetes (T2D). Abnormal lipid metabolism in peripheral tissues is implicated in the development of insulin resistance in humans and in mouse models of T2D. To understand the mechanisms underlying insulin resistance in Znt7 KO mice, we used a metabolomics approach to detect changes in major metabolites related to fatty acid metabolism in peripheral tissues including skeletal muscle, liver and fat between Znt7 KO and age-matched control mice. We found that Znt7 KO mice had elevated triglycerides in skeletal muscle. Fatty acid levels including palmitic acid, stearic acid, oleic acid, linoleic acid, and arachidonic acid in skeletal muscle and subcutaneous fat tissues of Znt7 KO mice were 2-fold higher than the control. As a result, metabolic products from these free fatty acids, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 12,13-dihydroxyo (12,13-DiHOME) were also elevated in the skeletal muscle and subcutaneous fat of Znt7 KO mice. These data suggest that abnormal free fatty acid metabolism may contribute to muscle and fat insulin resistance in Znt7 KO mice.

Fatty Acid Metabolism

10.1096/fasebj.29.1_supplement.748.5

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383 Doxycycline effects on the gut and skin microbiomes and lipidome in acne

Journal of Investigative Dermatology (2018)

Kelly Haas Manisha Notay W. Rodríguez Matthew Rolston Ashley K. Clark

10.1016/j.jid.2018.03.389

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Citations (4)

Clinical Pharmacology & Therapeutics (1970)

Walter Modell P. Schein Ruth D. Davis S. Carter John W. Newman

Prediction of drug toxicity in. man Antidepressant activity of cyclazocine Dosage forms of chlorpromazine Effect of stress on central actions of scopolamine Atropine and pralidoxime combination Diuretic action of an azido pyrimidinePerhexiline maleate

10.1002/cpt.1970.11.issue-1

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An Epoxide Hydrolase Inhibitor, 12-(3-Adamantan-1-yl-ureido)dodecanoic Acid (AUDA), Reduces Ischemic Cerebral Infarct Size in Stroke-Prone Spontaneously Hypertensive Rats

Journal of Cardiovascular Pharmacology (2005)

Anne M. Dorrance Nicole Rupp David M. Pollock John W. Newman Bruce D. Hammock

Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 +/- 0.4 ng/mL, and the urinary excretion rate was 99 +/- 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 +/- 4% vs 53 +/- 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.

Epoxide hydrolase 2

Cerebral circulation

Stroke

10.1097/01.fjc.0000189600.74157.6d

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Citations (123)

Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Insha Zahoor Jeffrey Waters Nasar Ata Indrani Datta Theresa L. Pedersen

ABSTRACT Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.

Pathogenesis

Relapsing remitting

10.1101/2024.01.04.574253

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imDEV: a graphical user interface to R multivariate analysis tools in Microsoft Excel

Bioinformatics (2012)

Dmitry Grapov John W. Newman

Abstract Summary: Interactive modules for Data Exploration and Visualization (imDEV) is a Microsoft Excel spreadsheet embedded application providing an integrated environment for the analysis of omics data through a user-friendly interface. Individual modules enables interactive and dynamic analyses of large data by interfacing R's multivariate statistics and highly customizable visualizations with the spreadsheet environment, aiding robust inferences and generating information-rich data visualizations. This tool provides access to multiple comparisons with false discovery correction, hierarchical clustering, principal and independent component analyses, partial least squares regression and discriminant analysis, through an intuitive interface for creating high-quality two- and a three-dimensional visualizations including scatter plot matrices, distribution plots, dendrograms, heat maps, biplots, trellis biplots and correlation networks. Availability and implementation: Freely available for download at http://sourceforge.net/projects/imdev/. Implemented in R and VBA and supported by Microsoft Excel (2003, 2007 and 2010). Contact: John.Newman@ars.usda.gov Supplementary Information: Installation instructions, tutorials and users manual are available at http://sourceforge.net/projects/imdev/.

Microsoft excel

Graphical user interface

Interface (matter)

Microsoft Office

10.1093/bioinformatics/bts439

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Citations (36)

Metabolic Flexibility in Response to a High-Fat Meal Challenge Is Not a Universal Indicator of Overall Metabolic Health

Current Developments in Nutrition (2024)

Mary M. Ahern John W. Newman Nancy L. Keim Sridevi Krishnan

10.1016/j.cdnut.2024.102786

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Unveiling the “hidden quality” of the walnut pellicle: a precious source of bioactive lipids

Frontiers in Plant Science (2024)

Ramona Abbattista Noah G. Feinberg Isabel F. Snodgrass John W. Newman Abhaya M. Dandekar

Tree nut consumption has been widely associated with various health benefits, with walnuts, in particular, being linked with improved cardiovascular and neurological health. These benefits have been attributed to walnuts’ vast array of phenolic antioxidants and abundant polyunsaturated fatty acids. However, recent studies have revealed unexpected clinical outcomes related to walnut consumption, which cannot be explained simply with the aforementioned molecular hallmarks. With the goal of discovering potential molecular sources of these unexplained clinical outcomes, an exploratory untargeted metabolomics analysis of the isolated walnut pellicle was conducted. This analysis revealed a myriad of unusual lipids, including oxylipins and endocannabinoids. These lipid classes, which are likely present in the pellicle to enhance the seeds’ defenses due to their antimicrobial properties, also have known potent bioactivities as mammalian signaling molecules and homeostatic regulators. Given the potential value of this tissue for human health, with respect to its “bioactive” lipid fraction, we sought to quantify the amounts of these compounds in pellicle-enriched waste by-products of mechanized walnut processing in California. An impressive repertoire of these compounds was revealed in these matrices, and in notably significant concentrations. This discovery establishes these low-value agriculture wastes promising candidates for valorization and translation into high-value, health-promoting products; as these molecules represent a potential explanation for the unexpected clinical outcomes of walnut consumption. This “hidden quality” of the walnut pellicle may encourage further consumption of walnuts, and walnut industries may benefit from a revaluation of abundant pellicle-enriched waste streams, leading to increased sustainability and profitability through waste upcycling.

Health Benefits

10.3389/fpls.2024.1395543

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P16-040-23 Dietary DHA Supports Glucose Use by Muscle in Association With Improved Endocannabinoid System Gene Expression in C57bl/6 Mice

Current Developments in Nutrition (2023)

Bruce A. Watkins Jeffrey Kim John W. Newman Kirk L. Pappan

Association (psychology)

10.1016/j.cdnut.2023.100800

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Effects of Extra Virgin Olive Oil (EVOO) Oleocanthal and Oleacein Content on Platelet Reactivity in Healthy Adults

The FASEB Journal (2016)

Karan Agrawal Roberta R. Holt Xuequi Shirley Li Eleni Melliou Theresa Lynn Pedersen

Data from limited dietary intervention trials suggest that the cardiovascular health benefit of EVOOs may increase as their phenolic antioxidants content increases. However, while EVOOs contain an array of bioactive compounds, little information exists regarding the physiological effects of specific chemical species. Among the EVOO‐derived phenolics with demonstrated anti‐inflammatory and antioxidant effects in animal and in vitro models is oleocanthal, an inhibitor of cyclooxygenase (COX). The current study compared the impact of acute intake (40 mL) of EVOO on platelet reactivity in healthy adult males (n=9). Three EVOOs were characterized and chosen for equivalency in their total phenolic content and fatty acid profiles, but differing in their oleocanthal to oleacein ratio. In a randomized double‐blind cross‐over study design, subjects consumed EVOOs that provided either a ~2:1 oleocanthal/oleacein (Oleo + ) or 2:1 oleacein compared to oleocanthal (Olea + ). A third EVOO served as a control, providing minimal amounts of oleocanthal and oleacein but had a similar total phenolic content in the form of free tyrosol (Oleo − Olea − ). A positive control for to platelet response was obtained after the intake of 400 mg of ibuprofen on a fourth study visit. Blood samples for optical platelet aggregometry were collected at baseline, and 2 hours post EVOO intake; with samples for oxylipin analysis collected from the activated platelet supernatants. Maximum platelet aggregation (Pmax) was significantly reduced 2 hours after Ibuprofen intake compared to all EVOOs when platelets were activated with either 1 μg/mL or 3 μg/mL of collagen. No significant differences between EVOOs for Pmax were observed with 3 μg/mL of collagen. However, scaling each individuals’ response to their range of responses on the 4 treatments, 1 μg/mL collagen‐induced Pmax was significantly reduced (repeated measures ANOVA, p<0.05) for Oleo + , but not Olea + compared to Oleo − Olea − 2 hours after intake (7.33 ± 7.9, −12.4 ± 12, and −29.3 ± 11, mean ± SEM percent basal activity, respectively). These changes in Pmax were strongly correlated with the change in the sum of COX and 12‐lipoxygenase (LOX) (r 2 = 0.53), although considerable individual variability in both platelet response and COX and LOX product formation was noted. Taken together the data suggests that platelet response after EVOO intake is dependent on the presence of specific phenolics. Support or Funding Information This project was supported by funds from the Captain Vassilis Foundation, GAEA Products SA, and USDA Intramural project 2032‐51530‐022‐00D. The USDA is an equal opportunity provider and employeer.

Tyrosol

Ibuprofen

10.1096/fasebj.30.1_supplement.1175.11

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Citations (1)