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Lysophosphatidic acid

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https://www.readbyqxmd.com/read/27927603/lysophosphatidic-acid-signaling-through-its-receptor-initiates-profibrotic-epithelial-cell-fibroblast-communication-mediated-by-epithelial-cell-derived-connective-tissue-growth-factor
#1
Norihiko Sakai, Jerold Chun, Jeremy S Duffield, David Lagares, Takashi Wada, Andrew D Luster, Andrew M Tager
The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1 expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1 signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1(-/-)) or -sufficient (LPA1(+/+)) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I procollagen promoter (Col-GFP) to identify fibroblasts...
December 4, 2016: Kidney International
https://www.readbyqxmd.com/read/27918822/growth-differentiation-factor-15-induced-contractile-activity-and-extracellular-matrix-production-in-human-trabecular-meshwork-cells
#2
Arumugam Ramachandran Muralidharan, Rupalatha Maddala, Nikolai P Skiba, Ponugoti Vasantha Rao
Purpose: To determine the role and regulation of growth differentiation factor-15 (GDF-15), a TGF-β-related cytokine in human trabecular meshwork (TM) cells in the context of aqueous humor (AH) outflow and IOP. Methods: Regulation of expression by external cues, and the distribution and secretion of GDF-15 by human TM primary cell cultures, and the effects of recombinant (r) GDF-15 on TM cell contractile characteristics, actin cytoskeleton, cell adhesion, extracellular matrix (ECM), α-smooth muscle actin (αSMA), SMAD signaling, and gene expression were determined by immunoblot, immunofluorescence, mass spectrometry, cDNA microarray, and real-time quantitative PCR (RT-qPCR) analyses...
December 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27915992/plasma-phospholipids-are-associated-with-mild-cognitive-impairment-in-type-2-diabetic-patients
#3
Jin-Biao Zhang, Yan-Nan Cong, Zhen-Guang Li, Hai-Rong Sun, Jiang-Shan Zhang, Peng-Fei Wang, Qi-Zhan Wu
Phospholipids (PLs) and their metabolisms are closely allied to nosogenesis and aggravation of Type 2 diabetes mellitus and cognitive impairment. The aim of this study is to characterize the plasma levels of phospholipids in type 2 diabetes patients and type 2 diabetes patients with mild cognitive impairment (MCI), and to identify potential biomarkers of type 2 diabetes patients with MCI. In this cross-sectional study, A total of 374 type 2 diabetes patients were prospectively enrolled. There were 103 patients with MCI and 271 patients without MCI (control)...
December 1, 2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/27888146/a-rhodium-iii-based-inhibitor-of-autotaxin-with-antiproliferative-activity
#4
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...
November 23, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27885213/a-fret-biosensor-for-rock-based-on-a-consensus-substrate-sequence-identified-by-kiss-technology
#5
Chunjie Li, Ayako Imanishi, Naoki Komatsu, Kenta Terai, Mutsuki Amano, Kozo Kaibuchi, Michiyuki Matsuda
Genetically-encoded biosensors based on Förster/fluorescence resonance energy transfer (FRET) are versatile tools for studying the spatio-temporal regulation of signaling molecules within not only the cells but also tissues. Perhaps the hardest task in the development of a FRET biosensor for protein kinases is to identify the kinase-specific substrate peptide to be used in the FRET biosensor. To solve this problem, we took advantage of kinase-interacting substrate screening (KISS) technology, which deduces a consensus substrate sequence for the protein kinase of interest...
November 23, 2016: Cell Structure and Function
https://www.readbyqxmd.com/read/27883058/role-of-ectonucleotide-pyrophosphatase-phosphodiesterase-2-in-the-midline-axis-formation-of-zebrafish
#6
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/27883026/inhibition-of-lysophosphatidic-acid-receptors-1-and-3-attenuates-atherosclerosis-development-in-ldl-receptor-deficient-mice
#7
Eva Kritikou, Gijs H M van Puijvelde, Thomas van der Heijden, Peter J van Santbrink, Maarten Swart, Frank H Schaftenaar, Mara J Kröner, Johan Kuiper, Ilze Bot
Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425...
November 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27864940/endogenous-lpa1-receptor-agonists-demonstrate-ligand-bias-between-calcium-and-erk-signalling-pathways-in-human-lung-fibroblasts
#8
Afrah Sattikar, Mark R Dowling, Elizabeth M Rosethorne
BACKGROUND AND PURPOSE: Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a G protein-coupled receptor (GPCR) that responds to the endogenous lipid mediator lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11 , Gi/o and G12/13 proteins...
November 16, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27864362/identification-of-lysophosphatidic-acid-receptor-1-in-astroglial-cells-as-a-target-for-glial-cell-line-derived-neurotrophic-factor-expression-induced-by-antidepressants
#9
Naoto Kajitani, Kanako Miyano, Mami Okada-Tsuchioka, Hiromi Abe, Kei Itagaki, Kazue Hisaoka-Nakashima, Norimitsu Morioka, Yasuhito Uezono, Minoru Takebayashi
Preclinical and clinical evidence suggests that glial cell line-derived neurotrophic factor (GDNF) is important in the therapeutic effect of antidepressants. A previous study demonstrated that the tricyclic antidepressant amitriptyline induces Gαi/o activation, which leads to GDNF expression in astrocytes. However, the specific target expressed in astrocytes that mediates antidepressant-evoked Gαi/o activation has yet to be identified. Thus, the current study explored the possibility that antidepressant-induced Gαi/o activation depends on lysophosphatidic acid receptor 1 (LPAR1), a Gαi/o-coupled receptor...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27812432/treatment-of-rapidly-progressive-systemic-sclerosis-current-and-futures-perspectives
#10
Fabian A Mendoza, Maryah Mansoor, Sergio A Jimenez
INTRODUCTION: Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality. AREAS COVERED: This paper reviews currently available therapeutic approaches for rapidly progressive SSc and discuss novel drugs under study for SSc disease modification...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27808224/changeover-from-signalling-to-energy-provisioning-lipids-during-transition-from-colostrum-to-mature-milk-in-the-giant-panda-ailuropoda-melanoleuca
#11
Tong Zhang, David G Watson, Rong Zhang, Rong Hou, I Kati Loeffler, Malcolm W Kennedy
Among the large placental mammals, ursids give birth to the most altricial neonates with the lowest neonatal:maternal body mass ratios. This is particularly exemplified by giant pandas. To examine whether there is compensation for the provision of developmentally important nutrients that other species groups may provide in utero, we examined changes in the lipids of colostrum and milk with time after birth in giant pandas. Lipids that are developmental signals or signal precursors, and those that are fundamental to nervous system construction, such as docosahexaenoic acid (DHA) and phosphatidylserines, appear early and then fall dramatically in concentration to a baseline at 20-30 days...
November 3, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27808166/lpa-receptor-activity-is-basal-specific-and-coincident-with-early-pregnancy-and-involution-during-mammary-gland-postnatal-development
#12
Deanna Acosta, Susmita Bagchi, Pilib Ó Broin, Daniel Hollern, Silvia E Racedo, Bernice Morrow, Rani S Sellers, John M Greally, Aaron Golden, Eran Andrechek, Teresa Wood, Cristina Montagna
During pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages...
November 3, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27805252/expression-of-lpa2-is-associated-with-poor-prognosis-in-human-breast-cancer-and-regulates-hif-1%C3%AE-expression-and-breast-cancer-cell-growth
#13
Min Li, Dong Xiao, Jia Zhang, Hangying Qu, Ya Yang, Yan Yan, Xu Liu, Jizhao Wang, Lin Liu, Jiansheng Wang, Xiaoyi Duan
Breast cancer (BC) generally exhibits poor prognosis owing to its invasive and metastatic characteristics and is the leading cause of cancer-related deaths in women worldwide. Lysophosphatidic acid receptor 2 (LPA2) and hypoxia inducible factor-1α (HIF-1α) were found to be correlated with BC invasion and metastasis, respectively. However, the effect of LPA2 on BC in Chinese women has not yet been reported, nor have the overall survival and prognostic significance of LPA2 or its association with HIF-1α in BC...
October 26, 2016: Oncology Reports
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)...
October 26, 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 autotoxin-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...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774128/discovery-of-ono-7300243-from-a-novel-class-of-lysophosphatidic-acid-receptor-1-antagonists-from-hit-to-lead
#16
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Hiroshi Kohno, Taku Fujimoto, Hiroshi Saga, Shinji Nakade, Hiromu Habashita, Yoshikazu Takaoka, Takuya Seko
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH)...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27771709/novel-insights-in-the-regulation-of-phosphatidylserine-exposure-in-human-red-blood-cells
#17
Mauro C Wesseling, Lisa Wagner-Britz, Duc Bach Nguyen, Salome Asanidze, Judy Mutua, Nagla Mohamed, Benjamin Hanf, Mehrdad Ghashghaeinia, Lars Kaestner, Ingolf Bernhardt
BACKGROUND/AIMS: In previous publications we were able to demonstrate the exposure of phosphatidylserine (PS) in the outer membrane leaflet after activation of red blood cells (RBCs) by lysophosphatidic acid (LPA), phorbol-12 myristate-13acetate (PMA), or 4-bromo-A23187 (A23187). It has been concluded that three different mechanisms are responsible for the PS exposure in human RBCs: (i) Ca2+-stimulated scramblase activation (and flippase inhibition) by A23187, LPA, and PMA; (ii) PKCα activation by LPA and PMA; and (iii) enhanced lipid flip flop caused by LPA...
October 24, 2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27767105/monoacylglycerol-lipase-a-novel-potential-therapeutic-target-and-prognostic-indicator-for-hepatocellular-carcinoma
#18
Junyong Zhang, Zuojin Liu, Zhengrong Lian, Rui Liao, Yi Chen, Yi Qin, Jinlong Wang, Qing Jiang, Xiaobo Wang, Jianping Gong
Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism that is demonstrated to be involved in tumor progression through both energy supply of fatty acid (FA) oxidation and enhancing cancer cell malignance. The aim of this study was to investigate whether MAGL could be a potential therapeutic target and prognostic indicator for hepatocellular carcinoma (HCC). To evaluate the relationship between MAGL levels and clinical characteristics, a tissue microarray (TMA) of 353 human HCC samples was performed...
October 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27765516/effects-of-gintonin-enriched-fraction-on-hippocampal-cell-proliferation-in-wild-type-mice-and-an-appswe-psen-1-double-tg-mouse-model-of-alzheimer-s-disease
#19
Hyeon-Joong Kim, Dae-Joong Kim, Eun-Ju Shin, Byung-Hwan Lee, Sun-Hye Choi, Sung-Hee Hwang, Hyewhon Rhim, Ik-Hyun Cho, Hyoung-Chun Kim, Seung-Yeol Nah
We previously showed that gintonin, an exogenous lysophosphatidic acid (LPA) receptor ligand, attenuated β-amyloid plaque formation in the cortex and hippocampus, and restored β-amyloid-induced memory dysfunction. Both endogenous LPA and LPA receptors play a key role in embryonic brain development. However, little is known about whether gintonin can induce hippocampal cell proliferation in adult wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease (AD). In the present study, we examined the effects of gintonin on the proliferation of hippocampal neural progenitor cells (NPCs) in vitro and its effects on the hippocampal cell proliferation in wild-type mice and a transgenic AD mouse model...
December 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27760754/lysophosphatidic-acid-induced-vascular-neointimal-formation-in-mouse-carotid-arteries-is-mediated-by-the-matricellular-protein-ccn1-cyr61
#20
Feng Hao, Fuqiang Zhang, Daniel Dongwei Wu, Dong An, Jing Shi, Guohong Li, Xuemin Xu, Mei-Zhen Cui
Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation...
October 19, 2016: American Journal of Physiology. Cell Physiology
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