Search results for: Theodore R. Holman

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Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Svetlana N. Samovich, Karolina Mikulska‐Ruminska, Haider H. Dar, Yulia Y. Tyurina, more

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non‐oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA‐PLs, particularly sn2‐arachidonoyl(AA)‐ and sn2‐adrenoyl(AdA)‐containing phosphatidylethanolamines...

article

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Svetlana N. Samovich, Karolina Mikulska‐Ruminska, Haider H. Dar, Yulia Y. Tyurina, more

Angewandte Chemie International Edition > 63 > 9 > n/a - n/a

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DHA 12‐LOX‐derived oxylipins regulate platelet activation and thrombus formation through a PKA‐dependent signaling pathway

Adriana Yamaguchi, Livia Stanger, Cody J. Freedman, Melissa Standley, more

Journal of Thrombosis and Haemostasis > 19 > 3 > 839 - 851

Background The effects of docosahexaenoic acid (DHA) on cardiovascular disease are controversial and a mechanistic understanding of how this omega‐3 polyunsaturated fatty acid (ω‐3 PUFA) regulates platelet reactivity and the subsequent risk of a thrombotic event is warranted. In platelets, DHA is oxidized by 12‐lipoxygenase (12‐LOX) producing the oxidized lipids (oxylipins) 11‐HDHA and 14‐HDHA. We...

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N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Saravanan S. Karuppagounder, Lauren Alin, Yingxin Chen, David Brand, more

Annals of Neurology > 84 > 6 > 854 - 872

Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic...

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PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

Sally E. Wenzel, Yulia Y. Tyurina, Jinming Zhao, Claudette M. St. Croix, more

Cell > 2017 > 171 > 3 > 628-641.e26

Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We...

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A potent and selective inhibitor targeting human and murine 12/15-LOX

Michelle M. Armstrong, Cody J. Freedman, Joo Eun Jung, Yi Zheng, more

Bioorganic & Medicinal Chemistry > 2016 > 24 > 6 > 1183-1190

Human reticulocyte 12/15-lipoxygenase (h12/15-LOX) is a lipid-oxidizing enzyme that can directly oxidize lipid membranes in the absence of a phospholipase, leading to a direct attack on organelles, such as the mitochondria. This cytotoxic activity of h12/15-LOX is up-regulated in neurons and endothelial cells after a stroke and thought to contribute to both neuronal cell death and blood–brain barrier...

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Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5‐Lipo‐Oxygenase

Carolina Mascayano, Victoria Espinosa, Silvia Sepúlveda‐Boza, Eric K. Hoobler, more

Chemical Biology & Drug Design > 86 > 1 > 114 - 121

Continuing our search to find more potent and selective 5‐LOX inhibitors, we present now the enzymatic evaluation of seventeen isoflavones (IR) and nine isoflavans (HIR), and their in vitro and in cellulo potency against human leukocyte 5‐LOX. Of the 26 compounds tested, 10 isoflavones and 9 isoflavans possessed micromolar potency, but only three were selective against 5‐LOX (IR‐2, HIR‐303, and HIR‐309),...

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A high-throughput mass spectrometric assay for discovery of human lipoxygenase inhibitors and allosteric effectors

J. Brian Jameson, Victor Kenyon, Theodore R. Holman

Analytical Biochemistry > 2015 > 476 > Complete > 45-50

Lipoxygenases (LOXs) regulate inflammation through the production of a variety of molecules whose specific downstream effects are not entirely understood due to the complexity of the inflammation pathway. The generation of these biomolecules can potentially be inhibited and/or allosterically regulated by small synthetic molecules. The current work describes the first mass spectrometric high-throughput...

article

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

David A. Taylor-Fishwick, Jessica Weaver, Lindsey Glenn, Norine Kuhn, more

Diabetologia > 2015 > 58 > 3 > 549-557

Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were...

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Inhibitory and mechanistic investigations of oxo-lipids with human lipoxygenase isozymes

Michelle M. Armstrong, Giovanni Diaz, Victor Kenyon, Theodore R. Holman

Bioorganic & Medicinal Chemistry > 2014 > 22 > 15 > 4293-4297

Oxo-lipids, a large family of oxidized human lipoxygenase (hLOX) products, are of increasing interest to researchers due to their involvement in different inflammatory responses in the cell. Oxo-lipids are unique because they contain electrophilic sites that can potentially form covalent bonds through a Michael addition mechanism with nucleophilic residues in protein active sites and thus increase...

article

Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases

Eric K. Hoobler, Charles Holz, Theodore R. Holman

Bioorganic & Medicinal Chemistry > 2013 > 21 > 13 > 3894-3899

Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234nM decomposition (UV) and...

article

Inhibition of 12/15‐lipoxygenase as therapeutic strategy to treat stroke

Kazim Yigitkanli, Anton Pekcec, Hulya Karatas, Stefanie Pallast, more

Annals of Neurology > 73 > 1 > 129 - 135

Targeting newly identified damage pathways in the ischemic brain can help to circumvent the currently severe limitations of acute stroke therapy. Here we show that the activity of 12/15‐lipoxygenase was increased in the ischemic mouse brain, and 12/15‐lipoxygenase colocalized with a marker for oxidized lipids, MDA2. This colocalization was also detected in the brain of 2 human stroke patients, where...

article

Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

Jessica R. Weaver, Theodore R. Holman, Yumi Imai, Ajit Jadhav, more

Molecular and Cellular Endocrinology > 2012 > 358 > 1 > 88-95

Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with...

article

Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12- Lipoxygenase

Victor Kenyon, Ganesha Rai, Ajit Jadhav, Lena Schultz, more

Journal of Medicinal Chemistry > 2011 > 54 > 15 > 5485 - 5497

article

Discovery of Potent and Selective Inhibitors of Human Reticulocyte 15-Lipoxygenase-1

Ganesha Rai, Victor Kenyon, Ajit Jadhav, Lena Schultz, more

Journal of Medicinal Chemistry > 2010 > 53 > 20 > 7392 - 7404

article

Using Enzyme Assays to Evaluate the Structure and Bioactivity of Sponge-Derived Meroterpenes

Sarah J. Robinson, Eric K. Hoobler, Michelle Riener, Steven T. Loveridge, more

Journal of Natural Products > 2009 > 72 > 10 > 1857 - 1863

article

Kinetic and Structural Investigations of the Allosteric Site in Human Epithelial 15-Lipoxygenase-2

Aaron T. Wecksler, Victor Kenyon, Natalie K. Garcia, Joshua D. Deschamps, more

Biochemistry > 2009 > 48 > 36 > 8721 - 8730

article

Substrate specificity effects of lipoxygenase products and inhibitors on soybean lipoxygenase-1

Aaron T. Wecksler, Natalie K. Garcia, Theodore R. Holman

Bioorganic & Medicinal Chemistry > 2009 > 17 > 18 > 6534-6539

Recently, it has been shown that lipoxygenase (LO) products affect the substrate specificity of human 15-LO. In the current paper, we demonstrate that soybean LO-1 (sLO-1) is not affected by its own products, however, inhibitors which bind the allosteric site, oleyl sulfate (OS) and palmitoleyl sulfate (PS), not only lower catalytic activity, but also change the substrate specificity, by increasing...

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Mechanistic Investigations of Human Reticulocyte 15- and Platelet 12-Lipoxygenases with Arachidonic Acid

Aaron T. Wecksler, Cyril Jacquot, Wilfred A. van der Donk, Theodore R. Holman

Biochemistry > 2009 > 48 > 26 > 6259 - 6267

article

Geometric Structure Determination of N694C Lipoxygenase: A Comparative Near-Edge X-Ray Absorption Spectroscopy and Extended X-Ray Absorption Fine Structure Study

Ritimukta Sarangi, Rosalie K. Hocking, Michael L. Neidig, Maurizio Benfatto, more

Inorganic Chemistry > 2008 > 47 > 24 > 11543 - 11550

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INFONA - science communication portal

Search results for: Theodore R. Holman

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

Strikingly High Activity of 15‐Lipoxygenase Towards Di‐Polyunsaturated Arachidonoyl/Adrenoyl‐Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

DHA 12‐LOX‐derived oxylipins regulate platelet activation and thrombus formation through a PKA‐dependent signaling pathway

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

A potent and selective inhibitor targeting human and murine 12/15-LOX

Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5‐Lipo‐Oxygenase

A high-throughput mass spectrometric assay for discovery of human lipoxygenase inhibitors and allosteric effectors

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

Inhibitory and mechanistic investigations of oxo-lipids with human lipoxygenase isozymes

Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases

Inhibition of 12/15‐lipoxygenase as therapeutic strategy to treat stroke

Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12- Lipoxygenase

Discovery of Potent and Selective Inhibitors of Human Reticulocyte 15-Lipoxygenase-1

Using Enzyme Assays to Evaluate the Structure and Bioactivity of Sponge-Derived Meroterpenes

Kinetic and Structural Investigations of the Allosteric Site in Human Epithelial 15-Lipoxygenase-2

Substrate specificity effects of lipoxygenase products and inhibitors on soybean lipoxygenase-1

Mechanistic Investigations of Human Reticulocyte 15- and Platelet 12-Lipoxygenases with Arachidonic Acid

Geometric Structure Determination of N694C Lipoxygenase: A Comparative Near-Edge X-Ray Absorption Spectroscopy and Extended X-Ray Absorption Fine Structure Study

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