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Autotaxin

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https://www.readbyqxmd.com/read/28922661/lysophosphatidic-acid-inhibits-insulin-signaling-in-primary-rat-hepatocytes-via-the-lpa3-receptor-subtype-and-is-increased-in-obesity
#1
Susann Fayyaz, Lukasz Japtok, Fabian Schumacher, Dominik Wigger, Tim Julius Schulz, Kathrin Haubold, Erich Gulbins, Heinz Völler, Burkhard Kleuser
BACKGROUND/AIMS: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). METHODS: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes...
September 1, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28874440/blocking-gp130-signaling-suppresses-autotaxin-expression-in-adipocytes-and-improves-insulin-sensitivity-in-diet-induced-obesity
#2
Shuhong Sun, Ran Wang, Jianwen Song, Ming Guan, Na Li, Xiaotian Zhang, Zhenwen Zhao, Junjie Zhang
Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Up-regulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that gp130-mediated JAK-STAT3 activation was required for abundant ATX expression in adipocytes...
September 5, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28871044/lpp3-mediates-self-generation-of-chemotactic-lpa-gradients-by-melanoma-cells
#3
Olivia Susanto, Yvette W H Koh, Nick Morrice, Sergey Tumanov, Peter A Thomason, Matthew Nielson, Luke Tweedy, Andrew J Muinonen-Martin, Jurre J Kamphorst, Gillian M Mackay, Robert H Insall
Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then also migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency...
September 4, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28816078/pathobiology-of-lp-a-in-calcific-aortic-valve-disease
#4
Patrick Mathieu, Benoit J Arsenault, Marie-Chloé Boulanger, Yohan Bossé, Marlys L Koschinsky
Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder. Gene variant in the LPA gene, which encodes for apolipoprotein(a), has been associated at the genome-wide level with CAVD. The process whereby Lp(a) promotes the development of CAVD is under intensive investigation and recent data have shed important insights into disease biology. In this regard, autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes the mineralization of the aortic valve. Areas covered: In this paper, we are reviewing the biology of Lp(a) and the latest discoveries about the molecular processes that link this lipoprotein with the development of CAVD including the role of ATX...
August 24, 2017: Expert Review of Cardiovascular Therapy
https://www.readbyqxmd.com/read/28811491/high-fat-diet-induced-acceleration-of-osteoarthritis-is-associated-with-a-distinct-and-sustained-plasma-metabolite-signature
#5
Poulami Datta, Yue Zhang, Alexa Parousis, Anirudh Sharma, Evgeny Rossomacha, Helal Endisha, Brian Wu, Izabela Kacprzak, Nizar N Mahomed, Rajiv Gandhi, Jason S Rockel, Mohit Kapoor
Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28743508/design-synthesis-docking-and-biological-evaluation-of-4-phenyl-thiazole-derivatives-as-autotaxin-atx-inhibitors
#6
Anand Balupuri, Dae-Yon Lee, Myeong Hwi Lee, Sangeun Chae, Eunmi Jung, Yunki Kim, Jeonghee Ryu, Nam Sook Kang
The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC50=2.99 and 2.19nM, respectively)...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28731719/discovery-structure-activity-relationship-and-binding-mode-of-an-imidazo-1-2-a-pyridine-series-of-autotaxin-inhibitors
#7
Agnès Joncour, Nicolas Desroy, Christopher Housseman, Xavier Bock, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Christophe Peixoto, Denis Annoot, Luce Lepissier, Jörg Heiermann, Willem Jan Hengeveld, Gregor Pilzak, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, René Galien, Christelle David, Nele Vandervoort, Thierry Christophe, Katja Conrath, Mia Jans, Alexandre Wohlkonig, Sameh Soror, Jan Steyaert, Robert Touitou, Damien Fleury, Lionel Vercheval, Patrick Mollat, Nicolas Triballeau, Ellen van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site...
August 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28687529/design-synthesis-and-biological-evaluation-of-2-4-dihydropyrano-2-3-c-pyrazole-derivatives-as-autotaxin-inhibitors
#8
Tatu Pantsar, Prosanta Singha, Tapio J Nevalainen, Igor Koshevoy, Jukka Leppänen, Antti Poso, Juha M A Niskanen, Sanna Pasonen-Seppänen, Juha R Savinainen, Tuomo Laitinen, Jarmo T Laitinen
Inhibition of Autotaxin (ATX) is a potential treatment strategy for several diseases, including tumors with elevated ATX-lysophosphatidic acid (LPA) signaling. Combining structure-based virtual screening together with hen egg-white Autotaxin (ewATX) activity assays enabled the discovery of novel small-molecule ATX inhibitors with a 2,4-dihydropyrano[2,3-c]pyrazole scaffold. These compounds are suggested to bind to the lipophilic pocket, leaving the active site unrestrained. Our most potent compound, (S)-6-amino-4-(3,4-dichlorophenyl)-3-(4-[(4-fluorobenzyl)oxy]phenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile [(S)-25], inhibited human ATX (hATX) with an IC50-value of 134nM...
July 5, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28674249/effects-of-gintonin-enriched-fraction-in-an-atopic-dermatitis-animal-model-involvement-of-autotaxin-regulation
#9
Byung-Hwan Lee, Ho-Kyoung Kim, Minhee Jang, Hyeon-Joong Kim, Sun-Hye Choi, Sung-Hee Hwang, Hyoung-Chun Kim, Hyewhon Rhim, Ik-Hyun Cho, Seung-Yeol Nah
Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C18 : 2 with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28667502/lysophosphatidic-acid-protects-against-endotoxin-induced-acute-kidney-injury
#10
Koryun Mirzoyan, Colette Denis, Audrey Casemayou, Marion Gilet, Dimitri Marsal, Dominique Goudounéche, Stanislas Faguer, Jean-Loup Bascands, Joost P Schanstra, Jean-Sébastien Saulnier-Blache
Septic shock is the most common cause of acute kidney injury (AKI), but the underlying mechanisms remain unclear and no targeted therapies exist. Lysophosphatidic acid (LPA) is a bioactive lipid which in vivo administration was reported to mitigate inflammation and injuries caused by bacterial endotoxemia in the liver and lung. The objective of the present study was to determine whether LPA can protect against sepsis-associated AKI. C57BL/6 mice were treated with LPA 18:1 (5 mg/kg, i.p.) 1 h before being injected with the endotoxin lipopolysaccharide (LPS), and AKI was evaluated after 24 h...
June 30, 2017: Inflammation
https://www.readbyqxmd.com/read/28654680/serum-fatty-acid-binding-protein-4-fabp4-concentration-is-associated-with-insulin-resistance-in-peripheral-tissues-a-clinical-study
#11
Risa Nakamura, Tsuyoshi Okura, Yohei Fujioka, Keisuke Sumi, Kazuhiko Matsuzawa, Shoichiro Izawa, Etsuko Ueta, Masahiko Kato, Shin-Ichi Taniguchi, Kazuhiro Yamamoto
Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls...
2017: PloS One
https://www.readbyqxmd.com/read/28642310/metabolomics-analysis-identifies-sex-associated-metabotypes-of-oxidative-stress-and-the-autotaxin-lysopa-axis-in%C3%A2-copd
#12
Shama Naz, Johan Kolmert, Mingxing Yang, Stacey N Reinke, Muhammad Anas Kamleh, Stuart Snowden, Tina Heyder, Bettina Levänen, David J Erle, C Magnus Sköld, Åsa M Wheelock, Craig E Wheelock
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and a leading cause of mortality and morbidity worldwide. The aim of this study was to investigate the sex dependency of circulating metabolic profiles in COPD.Serum from healthy never-smokers (healthy), smokers with normal lung function (smokers), and smokers with COPD (COPD; Global Initiative for Chronic Obstructive Lung Disease stages I-II/A-B) from the Karolinska COSMIC cohort (n=116) was analysed using our nontargeted liquid chromatography-high resolution mass spectrometry metabolomics platform...
June 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28616586/the-autotaxin-lysophosphatidic-acid-pathway-emerges-as-a-therapeutic-target-to-prevent-liver-cancer
#13
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
#14
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
#15
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...
July 14, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28578681/dysregulation-of-lysophosphatidic-acids-in-multiple-sclerosis-and-autoimmune-encephalomyelitis
#16
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
#17
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 results against autotaxin, a phospholipase implicated in cardiovascular disease...
June 22, 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
#18
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
#19
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
#20
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
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