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Lysophosphatidic acid

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https://www.readbyqxmd.com/read/28815598/lpa1-is-a-key-mediator-of-intracellular-signalling-and-neuroprotection-triggered-by-tetracyclic-antidepressants-in-hippocampal-neurons
#1
Maria C Olianas, Simona Dedoni, Pierluigi Onali
Both lysophosphatidic acid (LPA) and antidepressants have been shown to affect neuronal survival and differentiation, but whether LPA signalling participates in the action of antidepressants is still unknown. In the present study we examined the role of LPA receptors in the regulation of ERK1/2 activity and neuronal survival by the tetracyclic antidepressants mianserin and mirtazapine in hippocampal neurons. In HT22 immortalized hippocampal cells antidepressants and LPA induced a time- and concentration-dependent stimulation of ERK1/2 phosphorylation...
August 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28814640/agpat4-lpaat%C3%AE-deficiency-highlights-the-molecular-heterogeneity-of-epididymal-and-perirenal-white-adipose-depots
#2
Emily B Mardian, Ryan M Bradley, Juan J Aristizabal Henao, Phillip M Marvyn, Katherine A Moes, Eric Bombardier, A Russell Tupling, Ken D Stark, Robin E Duncan
Acylglycerophosphate acyltransferase 4 (AGPAT4)/lysophosphatidic acid acyltransferase delta (LPAATδ) catalyzes the formation of phosphatidic acid (PA), a precursor of triacylglycerol (TAG). We investigated the effect of Agpat4 gene ablation on white adipose tissue (WAT), after finding consistent expression across depots. Epididymal WAT mass was 40% larger in male Agpat4-/- mice than wildtype littermates, but unchanged in perirenal, retroperitoneal, and inguinal WAT and subscapular brown adipose tissue. Metabolic changes were identified in epididymal WAT that were not evident in perirenal WAT, which was analyzed for comparison...
August 16, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28814238/structural-insights-for-drugs-developed-for-phospholipase-d-enzymes
#3
Kimberly Stieglitz
BACKGROUND: In recent years human phospholipase D enzymes (PLD1 and PLD2 isozymes) have emerged as drug targets for various diseases such as cardiovascular disease, cancer, infectious diseases and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The interest in PLD as a drug target is due to the fact that PLD enzymes belong to a superfamily of phospholipases that are essential to intracellular and extracellular signaling. Many bioactive lipid signaling molecules are generated by these enzymes including phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG)...
August 15, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28807933/mice-deficient-in-lysophosphatidic-acid-acyltransferase-%C3%AE-lpaat%C3%AE-acylglycerophosphate-acyltransferase-4-agpat4-have-impairments-in-spatial-learning-and-memory-associated-with-reductions-in-nmda-and-ampa-receptors
#4
Ryan M Bradley, Emily B Mardian, Darin Bloemberg, Juan J Aristizabal Henao, Andrew S Mitchell, Phillip M Marvyn, Katherine A Moes, Ken D Stark, Joe Quadrilatero, Robin E Duncan
We previously characterized LPAATδ/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here we report that Lpaatδ (-/-) mice display impaired spatial learning and memory compared to wildtype littermates in the Morris Water Maze, and investigated potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged...
August 14, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28792932/structural-insights-into-ligand-recognition-by-the-lysophosphatidic-acid-receptor-lpa6
#5
Reiya Taniguchi, Asuka Inoue, Misa Sayama, Akiharu Uwamizu, Keitaro Yamashita, Kunio Hirata, Masahito Yoshida, Yoshiki Tanaka, Hideaki E Kato, Yoshiko Nakada-Nakura, Yuko Otani, Tomohiro Nishizawa, Takayuki Doi, Tomohiko Ohwada, Ryuichiro Ishitani, Junken Aoki, Osamu Nureki
Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6)...
August 9, 2017: Nature
https://www.readbyqxmd.com/read/28782946/synergistic-tailoring-of-electrostatic-and-hydrophobic-interactions-for-rapid-and-specific-recognition-of-lysophosphatidic-acid-an-early-stage-ovarian-cancer-biomarker
#6
Ying Wang, Hanwen Pei, Yan Jia, Jianhua Liu, Zelun Li, Kelong Ai, Zhongyuan Lu, Lehui Lu
Early detection of ovarian cancer, the most lethal type of gynecologic cancer, can dramatically improve the efficacy of available treatment strategies. However, few screening tools exist for rapidly and effectively diagnosing ovarian cancer in early stages. Here, we present a facile 'lock-key' strategy, based on rapid, specific detection of plasma lysophosphatidic acid (LPA, an early-stage biomarker) with polydiacetylenes (PDAs)-based probe, for the early diagnosis of ovarian cancer. This strategy relies on specifically inserting LPA 'key' into the PDAs 'lock' through the synergistic electrostatic and hydrophobic interactions between them, leading to conformation transition of the PDA backbone with a concomitant blue-to-red color change...
August 7, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28770493/measurement-of-lysophosphatidic-acid-and-sphingosine-1-phosphate-by-liquid-chromatography-coupled-electrospray-ionization-tandem-mass-spectrometry
#7
Maria P Kraemer, Suchismita Halder, Susan S Smyth, Andrew J Morris
Lysophosphatidic acids and sphingosine-1-phosphate are bioactive lipids that regulate diverse cellular and physiological processes through actions that are largely mediated by cell surface receptors. The roles played by these lipids in multiple disease processes make the enzymes and receptors involved in their synthesis, inactivation, and signaling attractive targets for pharmacological therapies. In this chapter we describe methods for sensitive accurate quantitation of LPA and S1P levels in biological fluids using liquid chromatography-coupled electrospray ionization tandem mass spectrometry...
August 3, 2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28766061/lysophosphatidic-acid-enhances-human-umbilical-cord-mesenchymal-stem-cell-viability-without-differentiation-via-lpa-receptor-mediating-manner
#8
Narengerile Li, Ya-Li Yan, Sachaofu Fu, Rui-Juan Li, Peng-Fei Zhao, Xi-Yuan Xu, Jing-Ping Yang, Alatangaole Damirin
Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential stromal cells which are regarded as the most feasible stem cell group in cell therapy. The maintenance of cell survival without differentiation is important in cell transplantation and stem cell therapy. However, negative factors exist in cell transplantation. Lysophosphatidic acid (LPA) is a non-antigenic small molecule phospholipid which induced several fundamental cellular responses, such as cell proliferation, apoptosis and migration. In this study we aimed to explore the effects of LPA on the survival and differentiation of MSCs and its availability in cell therapy...
August 1, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28765952/mtor-signaling-promotes-foam-cell-formation-and-inhibits-foam-cell-egress-through-suppressing-the-sirt1-signaling-pathway
#9
Haixiang Zheng, Yucai Fu, Yusheng Huang, Xinde Zheng, Wei Yu, Wei Wang
Atherosclerosis (AS) is a chronic immuno‑inflammatory disease accompanied by dyslipidemia. The authors previously demonstrated that sirtuin 1 (SIRT1) may prevent atherogenesis through influencing the liver X receptor/C‑C chemokine receptor type 7/nuclear factor‑κB (LXR‑CCR7/NF‑κB) signaling pathway. Previous studies have suggested a role for mammalian target of rapamycin (mTOR) signaling in the pathogenesis of cardiovascular diseases. The present study investigated the potential association between mTOR signaling and SIRT1‑LXR‑CCR7/NF‑κB signaling (SIRT1 signaling) in AS pathogenesis...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28765047/lysophosphatidic-acid-individually-induces-macrophage-derived-foam-cell-formation-by-blocking-the-expression-of-srbi
#10
Linmu Chen, Jun Zhang, Xiao Deng, Yan Liu, Xi Yang, Qiong Wu, Chao Yu
The leading cause of morbidity and mortality is the result of cardiovascular disease, mainly atherosclerosis. The formation of macrophage foam cells by ingesting ox-LDL and focal retention in the subendothelial space are the hallmarks of the early atherosclerotic lesion. Lysophosphatidic acid (LPA), which is a low-molecular weight lysophospholipid enriched in oxidized LDL, exerts a range of effects on the cardiovascular system. Previous reports show that LPA increases the uptake of ox-LDL to promote the formation of foam cells...
July 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28758906/activin-a-enhances-mtor-signaling-to-promote-aberrant-chondrogenesis-in-fibrodysplasia-ossificans-progressiva
#11
Kyosuke Hino, Kazuhiko Horigome, Megumi Nishio, Shingo Komura, Sanae Nagata, Chengzhu Zhao, Yonghui Jin, Koichi Kawakami, Yasuhiro Yamada, Akira Ohta, Junya Toguchida, Makoto Ikeya
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28739650/lysophosphatidic-acid-receptor-antagonism-protects-against-diabetic-nephropathy-in-a-type-2-diabetic-model
#12
Ming-Zhi Zhang, Xin Wang, Haichun Yang, Agnes B Fogo, Brian J Murphy, Robert Kaltenbach, Peter Cheng, Bradley Zinker, Raymond C Harris
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril)...
July 24, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28735625/free-fatty-acid-receptor-ffar-agonists-inhibit-proliferation-of-human-ovarian-cancer-cells
#13
Mandi M Hopkins, Kathryn E Meier
Many cellular actions of omega-3 fatty acids are mediated by two G protein-coupled receptors, FFA1 and FFA4, free fatty acid receptor (FFAR) family members that are activated by these dietary constituents. FFAR agonists inhibit proliferation of human prostate and breast cancer cells. Since omega-3 fatty acids can inhibit ovarian cancer cell growth, the current study tested the potential role of FFARs in the response. OVCAR3 and SKOV3 human ovarian cancer cell lines express mRNA for FFA1; FFA4 mRNA was detected at low levels in SKOV3 but not OVCAR3...
July 2017: Prostaglandins, Leukotrienes, and Essential Fatty Acids
https://www.readbyqxmd.com/read/28732508/lysophosphatidic-acid-plasma-concentrations-in-healthy-subjects-circadian-rhythm-and-associations-with-demographic-anthropometric-and-biochemical-parameters
#14
Anna Michalczyk, Marta Budkowska, Barbara Dołęgowska, Dariusz Chlubek, Krzysztof Safranow
BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive lipid with a wide biological activity. Previous studies have shown its potential usefulness as a diagnostic marker for ovarian cancer. The aim of the study was to investigate which factors may influence plasma LPA concentrations in healthy subjects and to propose reference values. METHODS: The study group consisted of 100 healthy subjects. From all of them the blood samples were taken at 7 a.m. (fasting state)...
July 21, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28731719/discovery-structure-activity-relationship-and-binding-mode-of-an-imidazo-1-2-a-pyridine-series-of-autotaxin-inhibitors
#15
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/28716732/lysophosphatidic-acid-signaling-regulates-the-klf9-ppar%C3%AE-axis-in-human-induced-pluripotent-stem-cell-derived-neurons
#16
Tamotsu Tsukahara, Shuhei Yamagishi, Yoshikazu Matsuda, Hisao Haniu
Lysophosphatidic acid (LPA) is a lipid signaling molecule that plays several significant roles in the nervous system during development and injury. In this study, we differentiated human induced pluripotent stem cells (iPSCs) into neurons as an in vitro model to examine the specific effects of LPA. We demonstrated that LPA activates peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated nuclear receptor, as well as its cognate receptor LPA1 on human iPSC-derived neurons to enhance proliferation and neurite outgrowth...
July 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28714993/a-two-helix-motif-positions-the-lysophosphatidic-acid-acyltransferase-active-site-for-catalysis-within-the-membrane-bilayer
#17
Rosanna M Robertson, Jiangwei Yao, Stefan Gajewski, Gyanendra Kumar, Erik W Martin, Charles O Rock, Stephen W White
Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3-phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase αβ-domain that contains the catalytic HX4D motif. PlsC dictates the acyl chain composition of the 2-position of phospholipids, and the acyl chain selectivity 'ruler' is an appropriately placed and closed hydrophobic tunnel...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28712726/sengers-syndrome-associated-mitochondrial-acylglycerol-kinase-is-a-subunit-of-the-human-tim22-protein-import-complex
#18
Yilin Kang, David A Stroud, Michael J Baker, David P De Souza, Ann E Frazier, Michael Liem, Dedreia Tull, Suresh Mathivanan, Malcolm J McConville, David R Thorburn, Michael T Ryan, Diana Stojanovski
Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins...
August 3, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28712724/acylglycerol-kinase-mutated-in-sengers-syndrome-is-a-subunit-of-the-tim22-protein-translocase-in-mitochondria
#19
Milena Vukotic, Hendrik Nolte, Tim König, Shotaro Saita, Maria Ananjew, Marcus Krüger, Takashi Tatsuta, Thomas Langer
Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane...
August 3, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28708504/study-of-lysophosphatidic-acid-receptors-lpars-in-buffalo-uterus-demonstrated-upregulation-of-lpar1-and-lpar6-in-early-pregnancy
#20
Abdul Sadam, Subhashree Parida, Amol R Padol, Ankita D Verma, Naseer Ahmad Baba, Wanta M Khuman, Vivek Srivastava, Manjit Panigrahi, Thakur Uttam Singh, Souvendra Nath Sarkar
Lysophosphatidic acid (LPA) is an important factor involved in embryo implantation and pregnancy establishment in humans and domestic livestock. LPA exerts its action through six G-protein-coupled receptors (LPA1-LPA6). We investigated the types of LPA receptors expressed in buffalo uterus and also their differential expression in the nonpregnant, and early-pregnant endometrium. The nonpregnant, and early-pregnant (<42 days) uteri were collected from the local slaughterhouse. RT-PCR experiments detected mRNAs of all the six LPA receptors (LPAR1-LPAR6) in both nonpregnant, and early-pregnant endometrial tissues...
May 27, 2017: Theriogenology
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