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Cody Kime, Masayo Sakaki-Yumoto, Leeanne Goodrich, Yohei Hayashi, Salma Sami, Rik Derynck, Michio Asahi, Barbara Panning, Shinya Yamanaka, Kiichiro Tomoda
Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion...
October 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Spencer B Jones, Lance A Pfeifer, Thomas J Bleisch, Thomas J Beauchamp, Jim D Durbin, V Joseph Klimkowski, Norman E Hughes, Christopher J Rito, Yen Dao, Joseph M Gruber, Hai Bui, Mark G Chambers, Srinivasan Chandrasekhar, Chaohua Lin, Denis J McCann, Daniel R Mudra, Jennifer L Oskins, Craig A Swearingen, Kannan Thirunavukkarasu, Bryan H Norman
In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship...
September 8, 2016: ACS Medicinal Chemistry Letters
Natalie A Wheeler, Babette Fuss, Pamela E Knapp, ShiPing Zou
White matter injury has been frequently reported in HIV(+) patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is toxic to young, immature oligodendrocytes (OLGs). Adding Tat to the culture medium reduced the viability of immature OLGs, and the surviving OLGs exhibited reduced process networks. OLGs produce and secrete autotaxin (ATX), an ecto-enzyme containing a lysophospholipase D (lysoPLD) activity that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a lipid signaling molecule that stimulates OLG differentiation...
October 2016: ASN Neuro
Ivanka Dacheva, Christoph Ullmer, Karolina Ceglowska, Everson Nogoceke, Guido Hartmann, Stephan Müller, Robert Rejdak, Katarzyna Nowomiejska, Michael Reich, Matthias Nobl, Tamer Tandogan, Florian T A Kretz, Gerd U Auffarth, Michael J Koss
PURPOSE: To analyze the levels of lysophosphatidic acids (LPAs) and autotaxin (ATX) in undiluted vitreous of untreated patients with retinal vein occlusion (RVO). METHODS: Sixty-four vitreous samples (40 RVO, 24 controls with idiopathic floaters) were analyzed in this retrospective case series using LC/MS for LPAs 16:0, 18:0, 18:1, 20:4, and ELISA kits or Luminex technology for ATX, angiopoetin-1 (ANG-1), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), pigment epithelium-derived factor (PEDF), and vascular endothelial growth factor (VEGF)...
July 12, 2016: Retina
E Sinderewicz, K Grycmacher, D Boruszewska, I Kowalczyk-Zięba, I Woclawek-Potocka
Lysophosphatidic acid (LPA) exerts various actions on the mammalian reproductive system. In cows, LPA stimulates the synthesis and secretion of luteotropic factors in the ovary, which affects the growth and development of ovarian follicles. The role of LPA in granulosa cells, oocyte and oocyte-cumulus complex (COC) has previously been investigated; but its role in the theca layer, which is an important structural and functional component of the ovarian follicle, is still unclear. The goal of this study was to investigate the expression of LPA in theca cells originating from different bovine ovarian follicle types...
September 20, 2016: Reproduction in Domestic Animals, Zuchthygiene
Masahiko Kanehira, Tohru Fujiwara, Shinji Nakajima, Yoko Okitsu, Yasushi Onishi, Noriko Fukuhara, Ryo Ichinohasama, Yoshinori Okada, Hideo Harigae
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells...
September 19, 2016: Stem Cells
K Thirunavukkarasu, C A Swearingen, J L Oskins, C Lin, H H Bui, S B Jones, L A Pfeifer, B H Norman, P G Mitchell, M G Chambers
OBJECTIVE: Autotaxin is a secreted lysophospholipase that mediates the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a bioactive lipid mediator. Autotaxin levels in plasma and synovial fluid correlate with disease severity in patients with knee osteoarthritis (OA). The goal of this study was to develop and characterize a novel small molecule inhibitor of autotaxin to inhibit LPA production in vivo and determine its efficacy in animal models of musculoskeletal pain...
September 13, 2016: Osteoarthritis and Cartilage
Jinghai Hu, Fei Ye, Miao Cui, Peng Lee, Chengguo Wei, Yuanyuan Hao, Xiaoqing Wang, Yanbo Wang, Zhihua Lu, Matthew Galsky, Russell McBride, Li Wang, Dongwen Wang, Carlos Cordon-Cardo, Chunxi Wang, David Y Zhang
This study aimed to detect protein changes that can assist to understand the underlying biology of bladder cancer. The data showed forty five proteins were found to be differentially expressed comparing tumors vs non-tumor tissues, of which EGFR and cdc2p34 were correlated with muscle invasion and histological grade. Ten proteins (ß-catenin, HSP70, autotaxin, Notch4, PSTPIP1, DPYD, ODC, cyclinB1, calretinin and EPO) were able to classify muscle invasive BCa (MIBC) into 2 distinct groups, with group 2 associated with poorer survival...
2016: PloS One
Sotirios Katsamakas, Anastasios G Papadopoulos, Dimitra Hadjipavlou-Litina
Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kenichiro Enooku, Baasanjav Uranbileg, Hitoshi Ikeda, Makoto Kurano, Masaya Sato, Hiroki Kudo, Harufumi Maki, Kazuhiko Koike, Kiyoshi Hasegawa, Norihiro Kokudo, Yutaka Yatomi
Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression...
2016: PloS One
Asit Mittal
Cholestatic itch is a feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, the inherited form of cholestasis, and intrahepatic cholestasis of pregnancy. Although undervalued by physicians, cholestatic itch can be a source of great discomfort to the patient and significantly affects quality of life. Many pruritogens such as bile salts, opioids, serotonin, and histamine have been implicated in the pathogenesis of cholestatic itch, but no causative link has ever been established...
2016: Current Problems in Dermatology
Liron Gibbs-Bar, Hanoch Tempelhof, Rotem Ben-Hamo, Yona Ely, Alexander Brandis, Roy Hofi, Gabriella Almog, Tslil Braun, Ester Feldmesser, Sol Efroni, Karina Yaniv
OBJECTIVE: As they travel through the blood stream, plasma lipoproteins interact continuously with endothelial cells (ECs). Although the focus of research has mostly been guided by the importance of lipoproteins as risk factors for atherosclerosis, thrombosis, and other cardiovascular diseases, little is known about the mechanisms linking lipoproteins and angiogenesis under physiological conditions, and particularly, during embryonic development. In this work, we performed global mRNA expression profiling of endothelial cells from hypo-, and hyperlipidemic zebrafish embryos with the goal of uncovering novel mediators of lipoprotein signaling in the endothelium...
October 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Susanna A Jethwa, Emma J Leah, Qifeng Zhang, Nicholas A Bright, David Oxley, Martin D Bootman, Simon A Rudge, Michael J O Wakelam
Autotaxin (ATX; also known as ENPP2), the lysophospholipase responsible for generating the lipid receptor agonist lysophosphatidic acid (LPA), is a secreted enzyme. Here we show that, once secreted, ATX can bind to the surface of cell-secreted exosomes. Exosome-bound ATX is catalytically active and carries generated LPA. Once bound to a cell, through specific integrin interactions, ATX releases the LPA to activate cell surface G-protein-coupled receptors of LPA; inhibition of signalling by the receptor antagonist Ki1642 suggests that these receptors are LPAR1 and LPAR3...
October 15, 2016: Journal of Cell Science
Lauren E Ragle, Dilip J Palanisamy, Margaux J Joe, Rachel S Stein, Derek D Norman, Gabor Tigyi, Daniel L Baker, Abby L Parrill
Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket...
October 1, 2016: Bioorganic & Medicinal Chemistry
Lenche Kostadinova, Carey Shive, Chelsey Judge, Elizabeth Zebrowski, Anita Compan, Kelsey Rife, Amy Hirsch, Yngve Falck-Ytter, Dannie Schlatzer, Xiaolin Li, Mark Chance, Benigno Rodriguez, Daniel L Popkin, Donald D Anthony
BACKGROUND:  Immune activation predicts morbidity during HCV and HIV infection, though mechanisms underlying immune activation are unclear. Plasma autotaxin and its enzymatic product, lysophosphatidic-acid (LPA), are elevated during HCV infection, and LPA activates immunocytes, but whether this contributes to immune activation is unknown. METHODS:  We evaluated plasma autotaxin, IL-6, sCD14, sCD163, and Mac2-Binding Protein (Mac2BP) during HCV, HIV and HCV-HIV infection, and in uninfected controls, before and after HIV ART and IFN-free HCV therapy...
August 17, 2016: Journal of Infectious Diseases
Matthew G K Benesch, Xiaoyun Tang, Ganesh Venkatraman, Raie T Bekele, David N Brindley
Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity...
July 2016: Journal of Biomedical Research
Kannan Thirunavukkarasu, Bailin Tan, Craig A Swearingen, Guilherme Rocha, Hai H Bui, Denis J McCann, Spencer B Jones, Bryan H Norman, Lance A Pfeifer, Joy K Saha
Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain...
October 2016: Journal of Pharmacology and Experimental Therapeutics
Ewa Wunsch, Marcin Krawczyk, Malgorzata Milkiewicz, Jocelyn Trottier, Olivier Barbier, Markus F Neurath, Frank Lammert, Andreas E Kremer, Piotr Milkiewicz
Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1-60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration...
2016: Scientific Reports
David Y Hui
PURPOSE OF REVIEW: Phospholipids are major constituents in the intestinal lumen after meal consumption. This article highlights current literature suggesting the contributory role of intestinal phospholipid metabolism toward cardiometabolic disease manifestation. RECENT FINDINGS: Group 1b phospholipase A2 (PLA2g1b) catalyzes phospholipid hydrolysis in the intestinal lumen. The digestive product lysophospholipid, particularly lysophosphatidylcholine (LPC), has a direct role in mediating chylomicron assembly and secretion...
October 2016: Current Opinion in Lipidology
Junpei Yamamoto, Midori Omura, Koichiro Tuchiya, Mayumi Hidaka, Akira Kuwahara, Minoru Irahara, Tamotsu Tanaka, Akira Tokumura
Lysophosphatidic acid (LPA) exerts diverse physiological effects on various types of animal cells, including reproductive cells, through its binding to six LPA receptors. We previously found that LPA promoted maturation of the nucleus and cytoplasm of mouse and hamster oocytes surrounded by cumulus cells in vitro. Using gas-liquid chromatography, we previously reported detection of several species of LPA by analyzing the fatty acid methyl esters derived from thin layer chromatography-purified LPA in lipid extract from incubated follicular fluids programmed with in vitro fertilization...
July 12, 2016: Prostaglandins & Other Lipid Mediators
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