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Autotaxin

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https://www.readbyqxmd.com/read/27911319/autotaxin-is-related-to-metabolic-dysfunction-and-predicts-alzheimer-s-disease-outcomes
#1
Kelsey E McLimans, Auriel A Willette
BACKGROUND: Obesity and insulin resistance are associated with neuropathology and cognitive decline in Alzheimer's disease (AD). OBJECTIVE: Ecto-nucleotide pyrophosphatase/phosphodiesterase 2, also called autotaxin, is produced by beige adipose tissue, regulates metabolism, and is higher in AD prefrontal cortex (PFC). Autotaxin may be a novel biomarker of dysmetabolism and AD. METHODS: We studied Alzheimer's Disease Neuroimaging Initiative participants who were cognitively normal (CN; n = 86) or had mild cognitive impairment (MCI; n = 135) or AD (n = 66)...
December 1, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27888146/a-rhodium-iii-based-inhibitor-of-autotaxin-with-antiproliferative-activity
#2
Tian-Shu Kang, Wanhe Wang, Hai-Jing Zhong, Jia-Xin Liang, Chung-Nga Ko, Jin-Jian Lu, Xiu-Ping Chen, Dik-Lung Ma, Chung-Hang Leung
BACKGROUND: Cancer of the skin is by far the most common of all cancers. Melanoma accounts for only about 1% of skin cancers but causes a large majority of skin cancer deaths. Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), regulates physiological and pathological functions of lysophosphatidic acid (LPA), and is thus an important therapeutic target. METHODS: We synthesized ten metal-based complexes and a novel cyclometalated rhodium(III) complex 1 was identified as an ATX enzymatic inhibitor using multiple methods, including ATX enzymatic assay, thermal shift assay, western immunoblotting and so on...
November 23, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27883058/role-of-ectonucleotide-pyrophosphatase-phosphodiesterase-2-in-the-midline-axis-formation-of-zebrafish
#3
Frisca Frisca, Daniel Colquhoun, Yona Goldshmit, Minna-Liisa Änkö, Alice Pébay, Jan Kaslin
Lysophosphatidic acid (LPA) is a unique bioactive lysophospholipid that induces pleiotropic effects in various cell types and organisms by acting on its specific receptors. LPA is mainly synthetised extracellularly by the ectonucleotide pyrophosphatase/phosphodiesterase 2/autotaxin (enpp2). Altered LPA signalling is associated with embryonic abnormalities, suggesting critical roles for LPA during development. However, the role of LPA signalling during early embryogenesis is not well established. We demonstrate that enpp2/LPA signalling in the early zebrafish embryo results in altered axis and midline formation, defects in left right (L-R) patterning, ciliogenesis of the Kupffer's vesicle (KV), through the modulation of cell migration during gastrulation in a lpar1-3 Rho/ROCK-dependant manner...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27878658/role-of-matricellular-proteins-in-disorders-of-the-central-nervous-system
#4
A R Jayakumar, A Apeksha, M D Norenberg
Matricellular proteins (MCPs) are actively expressed non-structural proteins present in the extracellular matrix, which rapidly turnover and possess regulatory roles, as well as mediate cell-cell interactions. MCPs characteristically contain binding sites for other extracellular proteins, cell surface receptors, growth factors, cytokines and proteases, that provide structural support for surrounding cells. MCPs are present in most organs, including brain, and play a major role in cell-cell interactions and tissue repair...
November 23, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27784781/autotaxin-expression-is-regulated-at-the-post-transcriptional-level-by-the-rna-binding-proteins-hur-and-auf1
#5
Shuhong Sun, Xiaotian Zhang, Lin Lyu, Xixi Li, Siliang Yao, Junjie Zhang
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a lysophospholipid mediator that regulates cellular activities through its specific G protein-coupled receptors. The ATX-LPA axis plays an important role in various physiological and pathological processes, especially in inflammation and cancer development. Although the transcriptional regulation of ATX has been widely studied, the post-transcriptional regulation of ATX is largely unknown. In this study, we identified conserved adenylate-uridylate (AU)-rich elements in the ATX mRNA 3' untranslated region (3'UTR)...
October 26, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27780639/discovery-of-potent-inhibitors-of-the-lysophospholipase-autotaxin
#6
Pritom Shah, Anne Cheasty, Caroline Foxton, Tony Raynham, Muddasar Farooq, Irene Farre Gutierrez, Aurore Lejeune, Michelle Pritchard, Andrew Turnbull, Leon Pang, Paul Owen, Susan Boyd, Alexandra Stowell, Allan Jordan, Niall M Hamilton, James R Hitchin, Martin Stockley, Ellen MacDonald, Mar Jimenez Quesada, Elisabeth Trivier, Jana Skeete, Huib Ovaa, Wouter H Moolenaar, Hamish Ryder
The autotoxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27757783/overexpression-of-autotaxin-is-associated-with-human-renal-cell-carcinoma-and-bladder-carcinoma-and-their-progression
#7
Aihua Xu, Md Ahsanul Kabir Khan, Fangzhi Chen, Zhaohui Zhong, Han-Chun Chen, Yuanda Song
Autotaxin (ATX) as an important tumor cell motility-stimulating factor is upregulated in many different types of cancer. ATX, a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, possesses lysophospholipase D activity which hydrolyzes lysophosphatidylcholine to generate the potent tumor growth factor and mitogen lysophosphatidic acid (LPA). LPA acts on specific G-protein-coupled receptors, thereby regulating cell growth, migration, and survival. This study aimed to investigate the differences in gene expression pattern of ATX between cancerous and adjacent normal tissue of human renal cell carcinoma (RCC) and bladder carcinoma (BC) and find the correlation between ATX expression and clinicopathological features of both of these carcinomas...
November 2016: Medical Oncology
https://www.readbyqxmd.com/read/27754931/selective-inhibition-of-autotaxin-is-efficacious-in-mouse-models-of-liver-fibrosis
#8
Gretchen Bain, Kristen E Shannon, Fei Huang, Janice Darlington, Lance Goulet, Patricia Prodanovich, Gina L Ma, Angelina M Santini, Adam J Stein, Dave Lonergan, Christopher D King, Imelda Calderon, Andiliy Lai, John H Hutchinson, Jilly F Evans
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]...
January 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27738243/autotaxin-mediated-lipid-signaling-intersects-with-lif-and-bmp-signaling-to-promote-the-naive-pluripotency-transcription-factor-program
#9
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...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27660691/novel-autotaxin-inhibitors-for-the-treatment-of-osteoarthritis-pain-lead-optimization-via-structure-based-drug-design
#10
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
https://www.readbyqxmd.com/read/27659560/hiv-1-tat-inhibits-autotaxin-lysophospholipase-d-activity-and-modulates-oligodendrocyte-differentiation
#11
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
https://www.readbyqxmd.com/read/27648638/lysophosphatidic-acids-and-autotaxin-in-retinal-vein-occlusion
#12
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)...
December 2016: Retina
https://www.readbyqxmd.com/read/27644923/lysophosphatidic-acid-expression-in-theca-cells-depends-on-the-type-of-bovine-ovarian-follicle
#13
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
https://www.readbyqxmd.com/read/27641212/an-lysophosphatidic-acid-receptors-1-and-3-axis-governs-cellular-senescence-of-mesenchymal-stromal-cells-and-promotes-growth-and-vascularization-of-multiple-myeloma
#14
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
https://www.readbyqxmd.com/read/27638130/identification-and-pharmacological-characterization-of-a-novel-inhibitor-of-autotaxin-in-rodent-models-of-joint-pain
#15
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
https://www.readbyqxmd.com/read/27626805/protein-profiling-of-bladder-urothelial-cell-carcinoma
#16
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
https://www.readbyqxmd.com/read/27617984/boronic-acid-group-a-cumbersome-false-negative-case-in-the-process-of-drug-design
#17
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
https://www.readbyqxmd.com/read/27583415/higher-lpa2-and-lpa6-mrna-levels-in-hepatocellular-carcinoma-are-associated-with-poorer-differentiation-microvascular-invasion-and-earlier-recurrence-with-higher-serum-autotaxin-levels
#18
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
https://www.readbyqxmd.com/read/27578083/cholestatic-itch-management
#19
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
https://www.readbyqxmd.com/read/27562917/autotaxin-lysophosphatidic-acid-axis-acts-downstream-of-apoprotein-b-lipoproteins-in-endothelial-cells
#20
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
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