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Autotaxin

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https://www.readbyqxmd.com/read/28616586/the-autotaxin-lysophosphatidic-acid-pathway-emerges-as-a-therapeutic-target-to-prevent-liver-cancer
#1
Derek J Erstad, Andrew M Tager, Yujin Hoshida, Bryan C Fuchs
Using transcriptome meta-analysis, we recently identified the autotaxin (ATX)-lysophosphatidic acid (LPA) pathway as a regulator of hepatocellular carcinoma (HCC) risk in human cirrhosis patients. Pharmacological targeting of this pathway reduced fibrosis progression and HCC development in animals, identifying ATX-LPA signaling as a novel chemoprevention strategy for cirrhosis and HCC.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28598712/autotaxin-expression-in-hepatocellular-carcinoma
#2
Ilker Memet, Evanthia Tsalkidou, Alexandra K Tsaroucha, Maria Lambropoulou, Ekaterini Chatzaki, Gregory Trypsianis, Dimitrios Schizas, Michael Pitiakoudis, Constantinos Simopoulos
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Despite the important progress observed in liver surgery, the survival rates are discouraging. The aim of this study was to investigate the expression of autotaxin in hepatocellular carcinoma. MATERIALS AND METHODS: Liver tissues from 28 human hepatocellular carcinomas were evaluated for the expression of autotaxin by immunohistochemistry. The gender, age, histological grade, lymphovascular invasion, number of tumors, levels of serum alpha-fetoprotein (aFP), presence of liver cirrhosis, hepatitis, surgery and survival rates were recorded...
June 9, 2017: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
https://www.readbyqxmd.com/read/28588064/autotaxin-lysophosphatidic-acid-lpa3-signaling-at-the-embryo-epithelial-boundary-controls-decidualization-pathways
#3
Shizu Aikawa, Kuniyuki Kano, Asuka Inoue, Jiao Wang, Daisuke Saigusa, Takeshi Nagamatsu, Yasushi Hirota, Tomoyuki Fujii, Soken Tsuchiya, Yoshitaka Taketomi, Yukihiko Sugimoto, Makoto Murakami, Makoto Arita, Makoto Kurano, Hitoshi Ikeda, Yutaka Yatomi, Jerold Chun, Junken Aoki
During pregnancy, up-regulation of heparin-binding (HB-) EGF and cyclooxygenase-2 (COX-2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G-protein-coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA-producing enzyme autotaxin (ATX) in pregnant mice leads to HB-EGF and COX-2 down-regulation near embryos and attenuates decidual reactions...
June 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28578681/dysregulation-of-lysophosphatidic-acids-in-multiple-sclerosis-and-autoimmune-encephalomyelitis
#4
K Schmitz, R Brunkhorst, N de Bruin, C A Mayer, A Häussler, N Ferreiros, S Schiffmann, M J Parnham, S Tunaru, J Chun, S Offermanns, C Foerch, K Scholich, J Vogt, S Wicker, J Lötsch, G Geisslinger, I Tegeder
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR(1640) mice, and EAE in Lpar2 (-/-) mice...
June 2, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28564542/repurposing-suzuki-coupling-reagents-as-a-directed-fragment-library-targeting-serine-hydrolases-and-related-enzymes
#5
Marion Lanier, Derek C Cole, Yelena Istratiy, Michael G Klein, Phillip A Schwartz, Richard Tjhen, Andy Jennings, Mark S Hixon
Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE>0.6) often result. The utility of the approach is illustrated with the screening results against autotaxin - a phospholipase implicated in cardiovascular disease...
May 31, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28539367/implications-for-breast-cancer-treatment-from-increased-autotaxin-production-in-adipose-tissue-after-radiotherapy
#6
Guanmin Meng, Xiaoyun Tang, Zelei Yang, Matthew G K Benesch, Alison Marshall, David Murray, Denise G Hemmings, Frank Wuest, Todd P W McMullen, David N Brindley
We have previously established that adipose tissue adjacent to breast tumors becomes inflamed by tumor-derived cytokines. This stimulates autotaxin (ATX) secretion from adipocytes, whereas breast cancer cells produce insignificant ATX. Lysophosphatidate produced by ATX promotes inflammatory cytokine secretion in a vicious inflammatory cycle, which increases tumor growth and metastasis and decreases response to chemotherapy. We hypothesized that damage to adipose tissue during radiotherapy for breast cancer should promote lysophosphatidic acid (LPA) signaling and further inflammatory signaling, which could potentially protect cancer cells from subsequent fractions of radiation therapy...
May 24, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28535810/fibrates-for-the-treatment-of-cholestatic-itch-fitch-study-protocol-for-a-randomized-controlled-trial
#7
Ruth Bolier, Elsemieke S de Vries, Albert Parés, Jeltje Helder, E Marleen Kemper, Koos Zwinderman, Ronald P Oude Elferink, Ulrich Beuers
BACKGROUND: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus...
May 23, 2017: Trials
https://www.readbyqxmd.com/read/28496416/lysophosphatidic-acid-is-associated-with-atherosclerotic-plaque-instability-by-regulating-nf-%C3%AE%C2%BAb-dependent-matrix-metalloproteinase-9-expression-via-lpa2-in-macrophages
#8
Chun Gu, Fang Wang, Zhenwen Zhao, Hongyue Wang, Xiangfeng Cong, Xi Chen
Lysophosphatidic acid (LPA), one of the simplest phospholipid signaling molecules, participates in formation and disruption of atherosclerotic plaque. Matrix metalloproteinases (MMPs) contribute to atherosclerotic plaque rupture by involving in extracellular matrix (ECM) degradation and then thinning fibrous cap. Our previous study demonstrated that macrophage-derived MMP-9 was associated with coronary plaque instability, but the relationship between LPA and MMP-9 remains unclear. The present work therefore aimed at elucidating association between LPA and MMP-9 and the regulation mechanism of LPA on MMP-9 in macrophages...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28460477/inhibition-of-lysophosphatidic-acid-receptor-ameliorates-sj%C3%A3-gren-s-syndrome-in-nod-mice
#9
Eunhye Park, Donghee Kim, Song Mi Lee, Hee-Sook Jun
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28447479/autotaxin-inhibitors-a-patent-review-2012-2016
#10
REVIEW
Aikaterini Nikolaou, Maroula G Kokotou, Dimitris Limnios, Anastasia Psarra, George Kokotos
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases...
July 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28425454/association-of-serum-autotaxin-levels-with-liver-fibrosis-in-patients-with-chronic-hepatitis-c
#11
Tomoo Yamazaki, Satoru Joshita, Takeji Umemura, Yoko Usami, Ayumi Sugiura, Naoyuki Fujimori, Soichiro Shibata, Yuki Ichikawa, Michiharu Komatsu, Akihiro Matsumoto, Koji Igarashi, Eiji Tanaka
Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn's index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28414242/discovery-of-2-2-ethyl-6-4-2-3-hydroxyazetidin-1-yl-2-oxoethyl-piperazin-1-yl-8-methylimidazo-1-2-a-pyridin-3-yl-methylamino-4-4-fluorophenyl-thiazole-5-carbonitrile-glpg1690-a-first-in-class-autotaxin-inhibitor-undergoing-clinical-evaluation-for-the-treatment
#12
Nicolas Desroy, Christopher Housseman, Xavier Bock, Agnès Joncour, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Emilie Rondet, Christophe Peixoto, Jean-Marie Grassot, Olivier Picolet, Denis Annoot, Nicolas Triballeau, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, Roland Blanque, Celine Cottereaux, Nele Vandervoort, Thierry Christophe, Patrick Mollat, Marieke Lamers, Marielle Auberval, Boska Hrvacic, Jovica Ralic, Line Oste, Ellen van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28347252/the-critical-role-and-potential-target-of-the-autotaxin-lysophosphatidate-axis-in-pancreatic-cancer
#13
REVIEW
Ming Quan, Jiu-Jie Cui, Xiao Feng, Qian Huang
Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6)...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28328321/ultrafast-and-predictive-mass-spectrometry-based-autotaxin-assays-for-label-free-potency-screening
#14
Tom Bretschneider, Andreas Harald Luippold, Helmut Romig, Daniel Bischoff, Klaus Klinder, Paul Nicklin, Wolfgang Rist
Autotaxin (ATX) is a promising drug target for the treatment of several diseases, such as cancer and fibrosis. ATX hydrolyzes lysophosphatidyl choline (LPC) into bioactive lysophosphatidic acid (LPA). The potency of ATX inhibitors can be readily determined by using fluorescence-based LPC derivatives. While such assays are ultra-high throughput, they are prone to false positives compared to assays based on natural LPC. Here we report the development of ultrafast mass spectrometry-based ATX assays enabling the measurement of data points within 13 s, which is 10 times faster than classic liquid chromatography-mass spectrometry...
April 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28324037/autotaxin-is-regulated-by-glucose-and-insulin-in-adipocytes
#15
Kenneth D'Souza, Daniel A Kane, Mohamed Touaibia, Erin E Kershaw, Thomas Pulinilkunnil, Petra C Kienesberger
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response...
April 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28298439/selective-export-of-autotaxin-from-the-endoplasmic-reticulum
#16
Lin Lyu, Baolu Wang, Chaoyang Xiong, Xiaotian Zhang, Xiaoyan Zhang, Junjie Zhang
Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation. The mechanism of ATX protein trafficking is largely unknown. Here, we demonstrated that p23, a member of the p24 protein family, was the protein-sorting receptor required for endoplasmic reticulum (ER) export of ATX. A di-phenylalanine (Phe-838/Phe-839) motif in the human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction...
April 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28240604/autocrine-lysophosphatidic-acid-signaling-activates-%C3%AE-catenin-and-promotes-lung-allograft-fibrosis
#17
Pengxiu Cao, Yoshiro Aoki, Linda Badri, Natalie M Walker, Casey M Manning, Amir Lagstein, Eric R Fearon, Vibha N Lama
Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28205098/enhanced-cellular-functions-through-induction-of-lpa2-by-cisplatin-in-fibrosarcoma-ht1080-cells
#18
Kaede Takahashi, Kaori Fukushima, Nobuyuki Fukushima, Kanya Honoki, Toshifumi Tsujiuchi
Lysophosphatidic acid (LPA) is a simple biophysical lipid which interacts with at least six subtypes of G protein-coupled LPA receptors (LPA1-LPA6). In cancer cells, LPA signaling via LPA receptors is involved in the regulation of malignant properties, such as cell growth, motility, and invasion. The aim of this study was to assess whether LPA receptors regulate cellular functions of fibrosarcoma cells treated with anticancer drug. HT1080 cells were maintained by the stepwise treatment of cisplatin (CDDP) at a range of 0...
February 15, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28170448/genome-wide-analysis-identifies-colonic-genes-differentially-associated-with-serum-leptin-and-insulin-concentrations-in-c57bl-6j-mice-fed-a-high-fat-diet
#19
Sung-Eun Kim, Jinsil Choo, Joon Yoon, Jae Ryang Chu, Yun Jung Bae, Seungyeoun Lee, Taesung Park, Mi-Kyung Sung
Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks...
2017: PloS One
https://www.readbyqxmd.com/read/28165241/rational-design-of-autotaxin-inhibitors-by-structural-evolution-of-endogenous-modulators
#20
Willem-Jan Keune, Frances Potjewyd, Tatjana Heidebrecht, Fernando Salgado-Polo, Simon J F Macdonald, Lakshman Chelvarajan, Ahmed Abdel Latif, Sony Soman, Andrew J Morris, Allan J B Watson, Craig Jamieson, Anastassis Perrakis
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery...
March 9, 2017: Journal of Medicinal Chemistry
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