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Autotaxin

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https://www.readbyqxmd.com/read/29328374/atx%C3%A2-lpa-axis-facilitates-estrogen%C3%A2-induced-endometrial-cancer-cell-proliferation-via-mapk-erk-signaling-pathway
#1
Guo Zhang, Yuan Cheng, Qi Zhang, Xiaoping Li, Jingwei Zhou, Jianliu Wang, Lihui Wei
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non‑carcinoma tissue...
January 8, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29305605/role-of-the-autotaxin-lpa-pathway-in-dexamethasone-induced-fibrotic-responses-and-extracellular-matrix-production-in-human-trabecular-meshwork-cells
#2
Megumi Honjo, Nozomi Igarashi, Junko Nishida, Makoto Kurano, Yutaka Yatomi, Koji Igarashi, Kuniyuki Kano, Junken Aoki, Makoto Aihara
Purpose: Dexamethasone (Dex) regulates aqueous humor outflow by inducing reorganization of the cytoskeleton and extracellular matrix (ECM) production. Rho kinase (ROCK) has an important role in this process, but the upstream pathway leading to its activation remains elusive. The purpose of the study was to determine the role of autotaxin (ATX), an enzyme involved in the generation of lysophosphatidic acid (LPA), in the Dex-induced fibrotic response and ECM production in human trabecular meshwork (HTM) cells...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29259743/discovery-of-bi-2545-a-novel-autotaxin-inhibitor-that-significantly-reduces-lpa-levels-in-vivo
#3
Christian A Kuttruff, Marco Ferrara, Tom Bretschneider, Stefan Hoerer, Sandra Handschuh, Bernd Nosse, Helmut Romig, Paul Nicklin, Gerald J Roth
In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies...
December 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29197066/characterisation-of-the-properties-of-a-selective-orally-bioavailable-autotaxin-inhibitor-in-preclinical-models-of-advanced-stages-of-liver-fibrosis
#4
Manuel Baader, Tom Bretschneider, Andre Broermann, Joerg F Rippmann, Birgit Stierstorfer, Christian A Kuttruff, Michael Mark
BACKGROUND AND PURPOSE: Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six G protein-coupled receptors expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis...
December 2, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29180002/melatonin-mitigates-thioacetamide-induced-hepatic-fibrosis-via-antioxidant-activity-and-modulation-of-proinflammatory-cytokines-and-fibrogenic-genes
#5
Mohamed A Lebda, Kadry M Sadek, Tarek K Abouzed, Hossam G Tohamy, Yasser S El-Sayed
AIMS: The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. MAIN METHODS: Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed...
November 24, 2017: Life Sciences
https://www.readbyqxmd.com/read/29175445/adipocyte-biology-in-breast-cancer-from-silent-bystander-to-active-facilitator
#6
REVIEW
Junjeong Choi, Yoon Jin Cha, Ja Seung Koo
Adipocytes account for the largest proportion among the cells that comprise breast tissue; therefore, they are considered to be a critical cell type in the tumor microenvironment of breast cancer. In breast cancer, adipocytes are not only found adjacent to cancer cells, but they also play an active role in the entire process of cancer development, progression, metastasis, and treatment response. Factors including the secretion of adipokines such as leptin and adiponectin, as well as autotaxin, interleukin 6, tumor necrosis factor alpha, and hepatic growth factor, metabolic remodeling that supports the growth of breast cancer by transfer of fatty acids to increase mitochondrial β-oxidation, extracellular matrix remodeling and endotrophin production from type IV collagen, and cancer-associated fibroblast phenotype changes have all been implicated in this comprehensive process...
November 21, 2017: Progress in Lipid Research
https://www.readbyqxmd.com/read/29162771/in-vivo-evidence-for-possible-up-regulating-roles-of-lysophosphatidic-acid-around-fertilization-in-rats
#7
Tae Takeda, Miki Shirasaka, Makoto Sugiyama, Ryota Terashihma, Mitsumori Kawaminami, Shiro Kurusu
Lysophosphatidic acid (LPA) produced by autotaxin (ATX) is recognized as a multi-functional mediator in mammalian reproduction. This study focused on possible effect(s) of LPA on ovulated cumulus-oocyte complexes (COCs) around fertilization in rats in vivo. Immunohistochemistry revealed the cell-type-dependent localization of candidates of synthetic enzymes, ATX and two phospholipases A2 isofroms, and LPA receptors LPA1~4 in ovulated COCs and in oviductal epithelium. The eggs ovulated with a form of COCs became denuded of cumulus cells and underwent fragmentation in the absence of fertilization...
November 21, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/29147686/lipoprotein-a-associated-molecules-are-prominent-components-in-plasma-and-valve-leaflets-in-calcific-aortic-valve-stenosis
#8
Michael Torzewski, Amir Ravandi, Calvin Yeang, Andrea Edel, Rahul Bhindi, Stefan Kath, Laura Twardowski, Jens Schmid, Xiaohong Yang, Ulrich F W Franke, Joseph L Witztum, Sotirios Tsimikas
The LPA gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets were categorized pathologically from Both ATX-apoB and ATX-apo(a) were measureable in plasma. Lp(a), autotaxin, OxPL and MDA epitopes progressively increased in immunostaining (p<0.001 for all). Six species of OxPL and LysoPA were identified following extraction from valve leaflets...
June 2017: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/29114991/serum-autotaxin-is-a-useful-liver-fibrosis-marker-in-patients-with-chronic-hepatitis-b-virus-infection
#9
Satoru Joshita, Yuki Ichikawa, Takeji Umemura, Yoko Usami, Ayumi Sugiura, Soichiro Shibata, Tomoo Yamazaki, Naoyuki Fujimori, Michiharu Komatsu, Akihiro Matsumoto, Koji Igarashi, Masao Ota, Eiji Tanaka
BACKGROUND AND AIMS: Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. METHODS: Serum ATX levels were retrospectively evaluated in 101 treatment-naïve patients with HBV-related chronic hepatitis or cirrhosis all of whom had undergone liver biopsy at our hospital. RESULTS: Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0...
November 8, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/29065699/annals-express-performance-of-autotaxin-as-a-serum-marker-of-liver-fibrosis
#10
Hitoshi Ikeda, Mariko Kobayashi, Hiromitsu Kumada, Kenichiro Enooku, Kazuhiko Koike, Makoto Kurano, Masaya Sato, Takahiro Nojiri, Tamaki Kobayashi, Ryunosuke Ohkawa, Satoshi Shimamoto, Koji Igarashi, Junken Aoki, Yutaka Yatomi
BACKGROUND: Because autotaxin (ATX) reportedly has a better performance than hyaluronic acid (HA) as a marker of liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of ATX in liver fibrosis of other etiologies. METHODS: ATX antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease (NAFLD) who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease (CKD), diabetes mellitus (DM), rheumatoid arthritis (RA) and cardiac dysfunction (CD)...
January 1, 2017: Annals of Clinical Biochemistry
https://www.readbyqxmd.com/read/29058512/maternal-serum-autotaxin-levels-in-early-and-late-onset-preeclampsia
#11
Hakan Erenel, Nevin Yilmaz, Tayfur Cift, Berk Bulut, Isik Sozen, Berna Aslan Cetin, Altay Gezer, Hakan Ekmekci, Baris Kaya, Abdullah Tuten
PURPOSE: We aimed to compare the serum autotaxin levels in early- and late- preeclamptic and healthy pregnant patients at a university hospital. METHODS: A total of 55 singleton preeclamptic women who delivered at Cerrahpasa Medical Faculty were included in the study. The patients were subdivided into two groups: early-onset preeclampsia (n = 31) and late-onset preeclampsia (n = 24). Demographic and clinical data were compared between early-onset and late-onset preeclamptic patients...
November 2017: Hypertension in Pregnancy
https://www.readbyqxmd.com/read/29028570/bovine-ovarian-follicular-growth-and-development-correlate-with-lysophosphatidic-acid-expression
#12
Emilia Sinderewicz, Katarzyna Grycmacher, Dorota Boruszewska, Ilona Kowalczyk-Zięba, Joanna Staszkiewicz, Tomasz Ślężak, Izabela Woclawek-Potocka
The basis of successful reproduction is proper ovarian follicular growth and development. In addition to prostaglandins and vascular endothelial growth factor, a number of novel factors are suggested as important regulators of follicular growth and development: PGES, TFG, CD36, RABGAP1, DBI and BTC. This study focuses on examining the expression of these factors in granulosa and thecal cells that originate from different ovarian follicle types and their link with the expression of lysophosphatidic acid (LPA), known local regulator of reproductive functions in the cow...
September 25, 2017: Theriogenology
https://www.readbyqxmd.com/read/28968864/atm-activated-autotaxin-atx-propagates-inflammation-and-dna-damage-in-lung-epithelial-cells-a-new-mode-of-action-for-silica-induced-dna-damage
#13
Huiyuan Zheng, Johan Högberg, Ulla Stenius
Silica exposure is a common risk factor for lung cancer. It has been claimed that key elements in cancer development are activation of inflammatory cells that indirectly induce DNA damage and proliferative stimuli in respiratory epithelial cells. We studied DNA damage induced by silica particles in respiratory epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). A549 and 16HBE lung epithelial cells were exposed silica particles. Reactive oxidative species (ROS), NLRP3 inflammasome activation, ATX, ataxia telangiectasia mutated (ATM), and DNA damage (γH2AX, pCHK1, pCHK2, comet assay) were endpoints...
September 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28931042/evaluation-of-the-cytotoxicity-of-the-bithionol-paclitaxel-combination-in-a-panel-of-human-ovarian-cancer-cell-lines
#14
Vijayalakshmi N Ayyagari, Paula L Diaz-Sylvester, Tsung-Han Jeff Hsieh, Laurent Brard
Previously, Bithionol (BT) was shown to enhance the chemosensitivity of ovarian cancer cell lines to cisplatin treatment. In the present study, we focused on the anti-tumor potential of the BT-paclitaxel combination when added to a panel of ovarian cancer cell lines. This in vitro study aimed to 1) determine the optimum schedule for combination of BT and paclitaxel and 2) assess the nature and mechanism(s) underlying BT-paclitaxel interactions. The cytotoxic effects of both drugs either alone or in combination were assessed by presto-blue cell viability assay using six human ovarian cancer cell lines...
2017: PloS One
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
#15
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...
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
#16
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. Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Upregulation 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 glycoprotein 130 (gp130)-mediated Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) activation was required for abundant ATX expression in adipocytes...
November 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28871044/lpp3-mediates-self-generation-of-chemotactic-lpa-gradients-by-melanoma-cells
#17
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
#18
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
#19
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
#20
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
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