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Ryunosuke Ohkawa, Makoto Kurano, Noboru Sakai, Tatsuya Kishimoto, Takahiro Nojiri, Koji Igarashi, Shigemi Hosogaya, Yukio Ozaki, Tomotaka Dohi, Katsumi Miyauchi, Hiroyuki Daida, Junken Aoki, Shigeo Okubo, Hitoshi Ikeda, Minoru Tozuka, Yutaka Yatomi
Blood choline has been proposed as a predictor of acute coronary syndrome (ACS), however different testing procedures might affect the choline concentration because the lysophospholipase D activity of autotaxin (ATX) can convert lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline in human blood. Although the influences of ATX on LPA levels are well known in vivo and in vitro, those on choline have not been elucidated. Therefore, we established suitable sampling conditions and evaluated the usefulness of plasma choline concentrations as a biomarker for ACS...
March 16, 2018: Scientific Reports
Matthew G K Benesch, Iain T K MacIntyre, Todd P W McMullen, David N Brindley
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance...
March 15, 2018: Cancers
Makoto Kurano, Tomomitsu Miyagaki, Takuya Miyagawa, Koji Igarashi, Satoshi Shimamoto, Hitoshi Ikeda, Junken Aoki, Shinichi Sato, Yutaka Yatomi
Autotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine-specific phospholipase A1 (PS-PLA1 ) is a producing enzyme for lysophosphatidylserine, a similar glycero-lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS-PLA1 levels and melanoma...
March 3, 2018: Journal of Dermatology
Anand Balupuri, Myeong Hwi Lee, Sangeun Chae, Eunmi Jung, Woosub Yoon, Yunki Kim, So Jung Son, Jeonghee Ryu, Dae-Hyuck Kang, Young-Jae Yang, Ji-Na You, Hyunjin Kwon, Jong-Woo Jeong, Tae-Sung Koo, Dae-Yon Lee, Nam Sook Kang
Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies...
February 17, 2018: European Journal of Medicinal Chemistry
Deron R Herr, Jolin Hwee-Jing Ong, Wei-Yi Ong
Autotaxin is a dual-function ecto-enzyme, encoded by the gene ENPP2, which is the primary source of the bioactive signaling lipid, lysophosphatidic acid. Aberrations in autotaxin/lysophosphatidic acid signaling have been associated with a number of neurological, psychiatric, neoplastic, and neurodevelopmental conditions, such as pain, pruritus, glioblastoma multiforme, multiple sclerosis, Alzheimer's disease, hydrocephalus, and schizophrenia. This Viewpoint offers a brief overview of the likely indications for therapeutic targeting of autotaxin, in disorders affecting the nervous system...
February 19, 2018: ACS Chemical Neuroscience
Yoshinori Okamoto, Akira Aoki, Koji Ueda, Hideto Jinno
Estrogen is reported to be involved in mammary tumorigenesis. To unveil metabolic signatures for estrogen-induced mammary tumorigenesis, we carried out serum metabolomic analysis in an estrogen-induced mammary tumor model, female August Copenhagen-Irish/Segaloff (ACI/Seg) rats, using liquid chromatography-mass spectrometry. In contrast to the control group, all rats with an implanted 17β-estradiol (E2) pellet developed mammary tumors during this experiment. E2 treatment significantly suppressed body weight gain...
February 15, 2018: Toxicology Letters
Sha She, Min Yang, Huaidong Hu, Peng Hu, Yixuan Yang, Hong Ren
BACKGROUND/AIMS: Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Therefore, we aimed to obtain further information on HBV pathogenesis, and to search for novel putative molecules for anti-HBV therapy. METHODS: We utilized Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to identify the secretory proteins that are differentially expressed in the HBV DNA-transfected HepG2.2.15 cell line and its parental HepG2 cell line...
February 1, 2018: Cellular Physiology and Biochemistry
Megumi Honjo, Nozomi Igarashi, Makoto Kurano, Yutaka Yatomi, Koji Igarashi, Kuniyuki Kano, Junken Aoki, Robert N Weinreb, Makoto Aihara
Purpose: To compare the levels of autotaxin (ATX), lysophosphatidic acid (LPA), and lysophosphatidylcholine (LPC) in the aqueous humor (AH) of healthy control subjects with those of patients with different subtypes of glaucoma, and also to investigate the relationship of the ATX-LPA pathway with IOP and subtype of glaucoma. Methods: This study included 164 eyes of 164 consecutive cases of cataract and glaucoma surgery (37 healthy, 31 normal tension glaucoma, 49 primary open angle glaucoma, 28 secondary open angle glaucoma, and 19 exfoliation glaucoma)...
February 1, 2018: Investigative Ophthalmology & Visual Science
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
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
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
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 to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs 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. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear...
February 2018: British Journal of Pharmacology
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...
January 1, 2018: Life Sciences
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
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
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
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
AIM: 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...
March 2018: Hepatology Research: the Official Journal of the Japan Society of Hepatology
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
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
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
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