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Autotaxin

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https://www.readbyqxmd.com/read/28073697/proliferation-of-mouse-endometrial-stromal-cells-in-culture-is-highly-sensitive-to-lysophosphatidic-acid-signaling
#1
Shizu Aikawa, Kuniyuki Kano, Asuka Inoue, Naoto Hama, Yoshiharu Iwabuchi, Junken Aoki
Endometrial stromal cells (ESCs) proliferate rapidly both in vivo and in vitro. Here we show that proliferation of ESCs in vitro is strongly dependent on lysophosphatidic acid (LPA) signaling. LPA is produced by autotaxin (ATX) and induces various kinds of cellular processes including migration, proliferation and inhibition of cell death possibly through six G protein-coupled receptors (LPA1-6). We found that ESCs proliferated rapidly in vitro in an autocrine manner and that the proliferation was prominently suppressed by either an ATX inhibitor (ONO-8430506) or an LPA1/3 antagonist (Ki16425)...
January 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28069607/lysophosphatidic-acid-converts-monocytes-into-macrophages-in-both-mice-and-humans
#2
Rashmi Ray, Vivek Rai
Monocytes and macrophages represent critical arms of the innate immune system and are considered regulators and effectors of inflammation and innate immune response. Monocytes can mobilize from bone marrow, traffic to their required destination and differentiate into effector cells depending on the local tissue environment to perform multiple roles during infection or inflammation, making them an important component of body's immune defense. Macrophages have diverse roles in tissue homeostasis, development as well as tissue repair following injury...
January 9, 2017: Blood
https://www.readbyqxmd.com/read/28052132/association-between-promoter-hypomethylation-and-overexpression-of-autotaxin-with-outcome-parameters-in-biliary-atresia
#3
Wanvisa Udomsinprasert, Nakarin Kitkumthorn, Apiwat Mutirangura, Voranush Chongsrisawat, Yong Poovorawan, Sittisak Honsawek
OBJECTIVE: Biliary atresia (BA) is a progressive fibroinflammatory liver disease. Autotaxin (ATX) has a profibrotic effect resulting from lysophosphatidic acid activity. The purpose of this study was to examine ATX expression and ATX promoter methylation in peripheral blood leukocytes and liver tissues from BA patients and controls and investigate their associations with outcome parameters in BA patients. METHODS: A total of 130 subjects (65 BA patients and 65 age-matched controls) were enrolled...
2017: PloS One
https://www.readbyqxmd.com/read/28028754/alteration-of-lysophosphatidylcholine-related-metabolic-parameters-in-the-plasma-of-mice-with-experimental-sepsis
#4
Won-Gyun Ahn, Jun-Sub Jung, Hyeok Yil Kwon, Dong-Keun Song
Plasma concentration of lysophosphatidylcholine (LPC) was reported to decrease in patients with sepsis. However, the mechanisms of sepsis-induced decrease in plasma LPC levels are not currently well known. In mice subjected to cecal ligation and puncture (CLP), a model of polymicrobial peritoneal sepsis, we examined alterations in LPC-related metabolic parameters in plasma, i.e., the plasma concentration of LPC-related substances (i.e., phosphatidylcholine (PC) and lysophosphatidic acid (LPA)), and activities or levels in the plasma of some enzymes that can be involved in the regulation of plasma LPC concentration (i...
December 28, 2016: Inflammation
https://www.readbyqxmd.com/read/28028180/dissecting-the-process-of-activation-of-cancer-promoting-zinc-requiring-ectoenzymes-by-zinc-metalation-mediated-by-znt-transporters
#5
Tokuji Tsuji, Yayoi Kurokawa, Johanna Chiche, Jacques Pouyssegur, Hiroshi Sato, Hideya Fukuzawa, Masaya Nagao, Taiho Kambe
Zinc-requiring ectoenzymes, including both secreted and membrane-bound enzymes, are considered to capture zinc in their active site for their activation in the early secretory pathway. This idea has been confirmed by our studies conducted using tissue nonspecific alkaline phosphatase (TNAP), which is elaborately activated by means of a two-step mechanism by Zn transporter 5 (ZnT5)-ZnT6 heterodimers and ZnT7 homodimers, through protein stabilization followed by enzyme activation with zinc in the early secretory pathway...
December 27, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27994727/benzyl-methyl-tetrazole-ligands-of-autotaxin-for-pet-imaging-techniques-and-diagnostic
#6
EDITORIAL
Gerard Rosse
No abstract text is available yet for this article.
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27991567/anti-melanoma-activity-of-forsythiae-fructus-aqueous-extract-in-mice-involves-regulation-of-glycerophospholipid-metabolisms-by-uplc-q-tof-ms-based-metabolomics-study
#7
Jiaolin Bao, Fang Liu, Chao Zhang, Kai Wang, Xuejing Jia, Xiaotong Wang, Meiwan Chen, Peng Li, Huanxing Su, Yitao Wang, Jian-Bo Wan, Chengwei He
Metabolomics is a comprehensive assessment of endogenous metabolites of a biological system in a holistic context. In this study, we evaluated the in vivo anti-melanoma activity of aqueous extract of Forsythiae Fructus (FAE) and globally explored the serum metabolome characteristics of B16-F10 melanoma-bearing mice. UPLC/Q-TOF MS combined with pattern recognition approaches were employed to examine the comprehensive metabolic signatures and differentiating metabolites. The results demonstrated that FAE exhibited remarkable antitumor activity against B16-F10 melanoma in C57BL/6 mice and restored the disturbed metabolic profile by tumor insult...
December 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27982588/structure-activity-relationships-of-small-molecule-autotaxin-inhibitors-with-a-discrete-binding-mode
#8
Lisa M Miller, Willem-Jan Keune, Diana Castagna, Louise C Young, Emma L Duffy, Frances Potjewyd, Fernando Salgado-Polo, Paloma Engel García, Dima Semaan, John M Pritchard, Anastassis Perrakis, Simon J F Macdonald, Craig Jamieson, Allan J B Watson
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold...
January 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27981605/hepatocyte-autotaxin-expression-promotes-liver-fibrosis-and-cancer
#9
Eleanna Kaffe, Aggeliki Katsifa, Nikos Xylourgidis, Ioanna Ninou, Markella Zannikou, Vaggelis Harokopos, Pelagia Foka, Alexios Dimitriadis, Kostas Evangelou, Anargyros N Moulas, Urania Georgopoulou, Vassilis G Gorgoulis, George N Dalekos, Vassilis Aidinis
: Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the production of lysophosphatidic acid (LPA), a pleiotropic growth factor-like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver diseases (CLDs) patients of different etiologies, associated with shorter overall survival...
December 16, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27911319/autotaxin-is-related-to-metabolic-dysfunction-and-predicts-alzheimer-s-disease-outcomes
#10
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
#11
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...
February 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27883058/role-of-ectonucleotide-pyrophosphatase-phosphodiesterase-2-in-the-midline-axis-formation-of-zebrafish
#12
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
#13
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
#14
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)...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27780639/discovery-of-potent-inhibitors-of-the-lysophospholipase-autotaxin
#15
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 autotaxin-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...
November 15, 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
#16
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
#17
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
#18
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
#19
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
#20
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
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