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Fibrosis autotaxin

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https://www.readbyqxmd.com/read/27780639/discovery-of-potent-inhibitors-of-the-lysophospholipase-autotaxin
#1
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/27754931/selective-inhibition-of-autotaxin-is-efficacious-in-mouse-models-of-liver-fibrosis
#2
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/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
#3
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/27390295/an-autotaxin-lysophosphatidic-acid-interleukin-6-amplification-loop-drives-scleroderma-fibrosis
#4
Flavia V Castelino, Gretchen Bain, Veronica A Pace, Katharine E Black, Leaya George, Clemens K Probst, Lance Goulet, Robert Lafyatis, Andrew M Tager
OBJECTIVE: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA-producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin-6 (IL-6) pathways in SSc. METHODS: We evaluated the effect of a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the mouse model of bleomycin-induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA-induced expression of IL-6, and IL-6-induced expression of ATX...
December 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27075612/steroid-binding-to-autotaxin-links-bile-salts-and-lysophosphatidic-acid-signalling
#5
Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P Joosten, Manjula Sunkara, Andrew J Morris, Elisa Matas-Rico, Wouter H Moolenaar, Ronald P Oude Elferink, Anastassis Perrakis
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids...
April 14, 2016: Nature Communications
https://www.readbyqxmd.com/read/27043297/structural-basis-for-specific-inhibition-of-autotaxin-by-a-dna-aptamer
#6
Kazuki Kato, Hisako Ikeda, Shin Miyakawa, Satoshi Futakawa, Yosuke Nonaka, Masatoshi Fujiwara, Shinichi Okudaira, Kuniyuki Kano, Junken Aoki, Junko Morita, Ryuichiro Ishitani, Hiroshi Nishimasu, Yoshikazu Nakamura, Osamu Nureki
ATX is a plasma lysophospholipase D that hydrolyzes lysophosphatidylcholine (LPC) and produces lysophosphatidic acid. To date, no ATX-inhibition-mediated treatment strategies for human diseases have been established. Here, we report anti-ATX DNA aptamers that inhibit ATX with high specificity and efficacy. We solved the crystal structure of ATX in complex with the anti-ATX aptamer RB011, at 2.0-Å resolution. RB011 binds in the vicinity of the active site through base-specific interactions, thus preventing the access of the choline moiety of LPC substrates...
May 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27006447/autotaxin-activity-increases-locally-following-lung-injury-but-is-not-required-for-pulmonary-lysophosphatidic-acid-production-or-fibrosis
#7
Katharine E Black, Evgeny Berdyshev, Gretchen Bain, Flavia V Castelino, Barry S Shea, Clemens K Probst, Benjamin A Fontaine, Irina Bronova, Lance Goulet, David Lagares, Neil Ahluwalia, Rachel S Knipe, Viswanathan Natarajan, Andrew M Tager
Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis...
June 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/26897854/-the-laboratory-medicine-of-lipid-mediators
#8
REVIEW
Yutaka Yatomi
Lysophospholipids such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS) are attracting attention as second-generation lipid mediators. We have pursued the clinical introduction of the assays of lysophospholipids and related proteins, and in this review, the clinical application of the assay of LPA and autotaxin(ATX), which produces LPA from lysophosphatidylcholine through its lysophospholipase D activity, is mainly described. The assay of ATX is promising as a useful laboratory test, especially for the diagnosis and staging of liver fibrosis...
October 2015: Rinsho Byori. the Japanese Journal of Clinical Pathology
https://www.readbyqxmd.com/read/26391552/understanding-the-multifaceted-role-of-ectonucleotide-pyrophosphatase-phosphodiesterase-2-enpp2-and-its-altered-behaviour-in-human-diseases
#9
REVIEW
R P Cholia, H Nayyar, R Kumar, A K Mantha
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) also known as Autotaxin, is a secreted lysophospholipase D, which hydrolyzes lysophosphatidylcholine (LPC) into Lysophosphatidic acid (LPA). LPA is the bioactive product of ENPP2 enzyme, which induces diverse signalling pathways via six LPA-G-protein coupled receptors (GPCRs). ENPP2 is an essential protein for normal development and its altered expression is associated with various human diseases. Cellular ENPP2 silencing results in lethality at the embryonic stage in mice...
2015: Current Molecular Medicine
https://www.readbyqxmd.com/read/26371182/structural-basis-for-inhibition-of-human-autotaxin-by-four-potent-compounds-with-distinct-modes-of-binding
#10
Adam J Stein, Gretchen Bain, Pat Prodanovich, Angelina M Santini, Janice Darlington, Nina M P Stelzer, Ranjinder S Sidhu, Jeffrey Schaub, Lance Goulet, Dave Lonergan, Imelda Calderon, Jilly F Evans, John H Hutchinson
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases...
December 2015: Molecular Pharmacology
https://www.readbyqxmd.com/read/26297977/the-autotaxin-lysophosphatidic-acid-pathway-in-pathogenesis-of-rheumatoid-arthritis
#11
REVIEW
Beatriz Orosa, Samuel García, Carmen Conde
Lysophosphatidic acid (LPA) is a phospholipid that is mainly produced by the hydrolysis of lysophosphatidylcholine (LPC) by lysophospholipase D, which is also called autotaxin (ATX). LPA interacts with specific G-protein coupled receptors and is involved in the regulation of cellular survival, proliferation, differentiation and motility. LPA also has roles in several pathological disorders, such as cancer and pulmonary, dermal and renal fibrosis. The involvement of the ATX-LPA pathway has recently been demonstrated in inflammatory responses and apoptosis of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis and during the development of experimental arthritis...
October 15, 2015: European Journal of Pharmacology
https://www.readbyqxmd.com/read/25464168/lysophosphatidic-acid-mediates-fibrosis-in-injured-joints-by-regulating-collagen-type-i-biosynthesis
#12
L Wu, F A Petrigliano, K Ba, S Lee, J Bogdanov, D R McAllister, J S Adams, A K Rosenthal, B Van Handel, G M Crooks, Y Lin, D Evseenko
OBJECTIVE: Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury. DESIGN: Rat knee joint models were used to mimic cartilage defects after acute injury...
February 2015: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/25062038/serum-autotaxin-is-a-parameter-for-the-severity-of-liver-cirrhosis-and-overall-survival-in-patients-with-liver-cirrhosis-a-prospective-cohort-study
#13
Thomas Pleli, Daniel Martin, Bernd Kronenberger, Friederike Brunner, Verena Köberle, Georgios Grammatikos, Harald Farnik, Yolanda Martinez, Fabian Finkelmeier, Sandra Labocha, Nerea Ferreirós, Stefan Zeuzem, Albrecht Piiper, Oliver Waidmann
BACKGROUND: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients. METHODS: Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact...
2014: PloS One
https://www.readbyqxmd.com/read/24747415/a-novel-highly-potent-autotaxin-enpp2-inhibitor-produces-prolonged-decreases-in-plasma-lysophosphatidic-acid-formation-in-vivo-and-regulates-urethral-tension
#14
Hiroshi Saga, Akira Ohhata, Akio Hayashi, Makoto Katoh, Tatsuo Maeda, Hirotaka Mizuno, Yuka Takada, Yuka Komichi, Hiroto Ota, Naoya Matsumura, Masami Shibaya, Tetsuya Sugiyama, Shinji Nakade, Katsuya Kishikawa
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo...
2014: PloS One
https://www.readbyqxmd.com/read/24642343/increased-serum-autotaxin-levels-in-hepatocellular-carcinoma-patients-were-caused-by-background-liver-fibrosis-but-not-by-carcinoma
#15
Mayuko Kondo, Takeaki Ishizawa, Kenichiro Enooku, Yasunori Tokuhara, Ryunosuke Ohkawa, Baasanjav Uranbileg, Hayato Nakagawa, Ryosuke Tateishi, Haruhiko Yoshida, Norihiro Kokudo, Kazuhiko Koike, Yutaka Yatomi, Hitoshi Ikeda
BACKGROUND: Controversy exists as to whether autotaxin (ATX) may be importantly associated with pathophysiology of hepatocellular carcinoma (HCC). METHODS: We evaluated serum ATX levels and its mRNA expression in consecutive 148 HCC patients treated with radiofrequency ablation (RFA) and 30 patients with hepatic resection. RESULTS: Although increased serum ATX levels were observed in almost all the patients treated with RFA, they were not reduced after RFA...
June 10, 2014: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/24560789/autotaxin-in-the-crosshairs-taking-aim-at-cancer-and-other-inflammatory-conditions
#16
REVIEW
Matthew G K Benesch, Yi M Ko, Todd P W McMullen, David N Brindley
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer...
August 19, 2014: FEBS Letters
https://www.readbyqxmd.com/read/24278115/non-invasive-imaging-of-tumors-by-monitoring-autotaxin-activity-using-an-enzyme-activated-near-infrared-fluorogenic-substrate
#17
Damian Madan, Colin G Ferguson, Won Yong Lee, Glenn D Prestwich, Charles A Testa
Autotaxin (ATX), an autocrine motility factor that is highly upregulated in metastatic cancer, is a lysophospholipase D enzyme that produces the lipid second messenger lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Dysregulation of the lysolipid signaling pathway is central to the pathophysiology of numerous cancers, idiopathic pulmonary fibrosis, rheumatoid arthritis, and other inflammatory diseases. Consequently, the ATX/LPA pathway has emerged as an important source of biomarkers and therapeutic targets...
2013: PloS One
https://www.readbyqxmd.com/read/24175745/development-of-lysophosphatidic-acid-pathway-modulators-as-therapies-for-fibrosis
#18
REVIEW
David C Budd, Yimin Qian
Lysophosphatidic acid (LPA) is a class of bioactive phospholipid that displays a wide range of cellular effects via LPA receptors, of which six have been identified (LPAR1-6). In serum and plasma, LPA production occurs mainly by the hydrolysis of lysophosphatidylcholine by the phospholipase D activity of autotaxin (ATX). The involvement of the LPA pathway in driving chronic wound-healing conditions, such as idiopathic pulmonary fibrosis, has suggested targets in this pathway could provide potential therapeutic approaches...
October 2013: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/23688339/screening-and-x-ray-crystal-structure-based-optimization-of-autotaxin-enpp2-inhibitors-using-a-newly-developed-fluorescence-probe
#19
Mitsuyasu Kawaguchi, Takayoshi Okabe, Shinichi Okudaira, Hiroshi Nishimasu, Ryuichiro Ishitani, Hirotatsu Kojima, Osamu Nureki, Junken Aoki, Tetsuo Nagano
Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), was originally identified as a tumor cell autocrine motility factor and was found to be identical to plasma lysophospholipase D, which is the predominant contributor to lysophosphatidic acid (LPA) production from lysophospholipids. ATX is therefore considered to regulate the physiological and pathological roles of LPA, including angiogenesis, lymphocyte trafficking, tissue fibrosis, and cancer cell invasion and metastasis...
August 16, 2013: ACS Chemical Biology
https://www.readbyqxmd.com/read/23125419/autotaxin-emerges-as-a-therapeutic-target-for-idiopathic-pulmonary-fibrosis-limiting-fibrosis-by-limiting-lysophosphatidic-acid-synthesis
#20
EDITORIAL
Andrew M Tager
No abstract text is available yet for this article.
November 2012: American Journal of Respiratory Cell and Molecular Biology
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