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E F Khaziev, D V Samigullin, A N Tsentsevitsky, E A Bukharaeva, E E Nikolsky
At neuromuscular junctions, ATP inhibits both the evoked and spontaneous acetylcholine release and inward calcium current operating via presynaptic P2Y receptors. It was shown in the experiments with the frog neuromuscular synapse using specific calcium-sensitive dye Oregon Green Bapta 1 that exogenous ATP reduces the amplitude of calcium transient, which reflects the changes in the entry of calcium ions in response to the nerve pulse. The depressing effect of ATP on the transient was prevented by suramin, the blocker of P2 receptors...
April 2018: Acta Naturae
Pierre-Eric Juif, Margaux Boehler, Michael Dobrow, Mike Ufer, Jasper Dingemanse
ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively...
August 8, 2018: Journal of Clinical Pharmacology
Seema Ali, Jeremy Turner, Samuel J Fountain
Adipose tissue contains self-renewing multipotent cells termed mesenchymal stromal cells. In situ, these cells serve to expand adipose tissue by adipogenesis, but their multipotency has gained interest for use in tissue regeneration. Little is known regarding the repertoire of receptors expressed by adipose-derived mesenchymal stromal cells (AD-MSCs). The purpose of this study was to undertake a comprehensive analysis of purinergic receptor expression. Mesenchymal stromal cells were isolated from human subcutaneous adipose tissue and confirmed by flow cytometry...
August 7, 2018: Purinergic Signalling
Jingjing Guo, Xuan Sheng, Yu Dan, Yurong Xu, Yuanruohan Zhang, Huihong Ji, Jiayue Wang, Zixi Xu, Hongyu Che, Guodong Li, Shangdong Liang, Guilin Li
Diabetes as a chronic epidemic disease with obvious symptom of hyperglycemia is seriously affecting human health globally due to the diverse diabetic complications. Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of both type 1 and type 2 diabetes and incurs high morbidity and mortality. However, the underlying mechanism for DCAN is unclear. It is well known that purinergic signaling is involved in the regulation of cardiovascular function. In this study, we examined whether the P2Y12 receptor could mediate DCAN-induced sympathetic reflexes...
August 6, 2018: Purinergic Signalling
Pei Y Ng, Kathryn A McIntosh, Gillian Hargrave, Ka H Ho, Andrew Paul, Robin Plevin
Previous research from our laboratory has demonstrated a novel phenomenon whereby GPCRs play a role in inhibiting cytokine-mediated c-Jun N-terminal kinase (JNK) signalling. So far this novel phenomenon seems to have been vastly overlooked, with little research in the area. Therefore, in this study we explored this further; by assessing the potential of P2YRs to mediate inhibition of cytokine-mediated JNK signalling and related functional outcomes in human endothelial cells. We utilised primary endothelial cells, and employed the use of endogenous activators of P2YRs and well characterised pharmacological inhibitors, to assess signalling parameters mediated by P2YRs, Interleukin-1β (IL-1β), TNFα and JNK...
August 1, 2018: Cellular Signalling
Nadia Cattane, Cristina Mora, Nicola Lopizzo, Alessandra Borsini, Carlo Maj, Laura Pedrini, Roberta Rossi, Marco Andrea Riva, Carmine Maria Pariante, Annamaria Cattaneo
Epidemiological and clinical studies have provided evidence for a role of both genetic and environmental factors, such as stressful experiences early in life, in the pathogenesis of Schizophrenia (SZ) and microRNAs (miRNAs) have been suggested to play a key role in the interplay between the environment and our genome. In this study, we conducted a miRNOme analysis in different samples (blood of adult subjects exposed to childhood trauma, brain (hippocampus) of rats exposed to prenatal stress and human hippocampal progenitor cells treated with cortisol) and we identified miR-125b-1-3p as a down-regulated miRNA in all the three datasets...
July 26, 2018: Schizophrenia Research
Younis Baqi, Thanigaimalai Pillaiyar, Aliaa Abdelrahman, Olesja Kaufmann, Samer Alshaibani, Muhammad Rafehi, Saman Ghasimi, Rhalid Akkari, Kirsten Ritter, Katharina Simon, Andreas Spinrath, Evi Kostenis, Qiang Zhao, Meryem Köse, Vigneshwaran Namasivayam, Christa E Müller
The orphan receptor GPR17 may be a novel drug target for inflammatory diseases. 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid (MDL29,951, 1) was previously identified as a moderately potent GPR17 agonist. In the present study we investigated the structure-activity relationships (SARs) of 1. Substitution of the indole 1-, 5-, or 7-position was detrimental. Only small substituents were tolerated in the 4-position while the 6-position accommodated large lipophilic residues. Among the most potent compounds were 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives containing the following substituents: 6-phenoxy (26, PSB-1737, EC50 270 nM), 4-fluoro-6-bromo (33, PSB-18422, EC50 27...
July 26, 2018: Journal of Medicinal Chemistry
Dujuan Huang, Junna Yang, XiaoHong Liu, Li He, Xiaomei Luo, Hong Tian, Tao Xu, Junwei Zeng
Purinergic signaling in spinal cord microglia plays an important role in the pathogenesis of neuropathic pain. Among all P2 receptors, P2Y6 receptor is expressed in rat dorsal spinal cord. However, it's not clear that the role of P2Y6 receptor in the chronic constriction injury (CCI) model of neuropathic pain rats. We evaluated the effect of repeated intrathecal administration of MRS2578 (selective P2Y6 receptor antagonist) on CCI-induced nociceptive behaviors in rats. After CCI, MRS2578 (10-11 -10-4  M) was administration...
July 23, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Maria Luiza Thorstenberg, Marcos Vinícius Rangel Ferreira, Natália Amorim, Claudio Canetti, Fernanda B Morrone, José Carlos Alves Filho, Robson Coutinho-Silva
The release of damage-associated molecular patterns, including uridine triphosphate (UTP) and adenosine triphosphate (ATP) to the extracellular milieu is a key component of innate immune response to infection. Previously, we showed that macrophage infection by the protozoan parasite Leishmania amazonensis -the etiological agent of cutaneous leishmaniasis-can be controlled by ATP- and UTP-mediated activation of P2Y and P2X7 receptors (activated by UTP/ATP and ATP, respectively), which provided comparable immune responses against the parasite...
2018: Frontiers in Immunology
Xuyang Liu, Zhan-Guo Gao, Yiran Wu, Raymond C Stevens, Kenneth A Jacobson, Suwen Zhao
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
July 24, 2018: Scientific Reports
Narongrit Thongon, Siriporn Chamniansawat
The mechanism of proton pump inhibitors (PPIs) suppressing intestinal Mg2+ uptake is unknown. The present study aimed to investigate the role of purinergic P2Y receptors in the regulation of Mg2+ absorption in normal and omeprazole-treated intestinal epithelium-like Caco-2 monolayers. Omeprazole suppressed Mg2+ transport across Caco-2 monolayers. An agonist of the P2Y2 receptor, but not the P2Y4 or P2Y6 receptor, suppressed Mg2+ transport across control and omeprazole-treated monolayers. Omeprazole enhanced P2Y2 receptor expression in Caco-2 cells...
July 21, 2018: Journal of Physiological Sciences: JPS
Shuo Li, Jiafang Li, Nan Wang, Gaixiang Hao, Jinsheng Sun
Uridine 5'-diphosphate (UDP)-activated purinergic receptor P2Y₆ is a member of a G-protein-coupled purinergic receptor family that plays an important role in mammalian innate immunity. However, the role of the P2Y₆ receptor (P2Y₆R) in fish immunity has not been investigated. In this report, we characterized a P2Y₆R gene from Japanese flounder ( Paralichthys olivaceus ) and examined its role in fish innate immunity. Sequence analysis reveals that the Japanese flounder P2Y₆R protein is conserved and possesses four potential glycosylation sites...
July 19, 2018: International Journal of Molecular Sciences
Jonathon P Audia, Xi-Ming Yang, Edward S Crockett, Nicole Housley, Ehtesham Ul Haq, Kristen O'Donnell, Michael V Cohen, James M Downey, Diego F Alvarez
Patients with acute myocardial infarction receive a P2Y12 receptor antagonist prior to reperfusion, a treatment that has reduced, but not eliminated, mortality, or heart failure. We tested whether the caspase-1 inhibitor VX-765 given at reperfusion (a requirement for clinical use) can provide sustained reduction of infarction and long-term preservation of ventricular function in a pre-clinical model of ischemia/reperfusion that had been treated with a P2Y12 receptor antagonist. To address, the hypothesis open-chest rats were subjected to 60-min left coronary artery branch occlusion/120-min reperfusion...
July 10, 2018: Basic Research in Cardiology
Jianfeng Wu, Bing Han, Vito Fanelli, Xiaoyan Wen, Yongbo Huang, Alice Luo, Mirna Ghazarian, Dingyan Wang, Julie Khang, Florence Morriello, Patricia C Liaw, John Marshall, Nanshan Zhong, Xiangdong Guan, Arthur S Slutsky, Yimin Li, Haibo Zhang
OBJECTIVES: To examine the effects and mechanisms of human neutrophil peptides in systemic infection and noninfectious inflammatory lung injury. DESIGN: Prospective experimental study. SETTING: University hospital-based research laboratory. SUBJECTS: In vitro human cells and in vivo mouse models. INTERVENTIONS: Wild-type (Friend virus B-type) and conditional leukocyte human neutrophil peptides transgenic mice were subjected to either sepsis induced by cecal ligation and puncture or acute lung injury by intratracheal instillation of hydrochloric acid followed by mechanical ventilation...
July 2, 2018: Critical Care Medicine
Karin Dreisig, Louise Sund, Maja Wallentin Dommer, Nikolaj Pagh Kristensen, Kim Boddum, Rannveig Viste, Simon Fredholm, Niels Odum, Marja Jäättelä, Søren Skov, Birgitte R Kornum
Adenosine triphosphate (ATP) is known to induce cell death in T lymphocytes at high extracellular concentrations. CD4+ and CD8+ T lymphocytes have a differential response to ATP, which in mice is due to differences in the P2X7 receptor expression levels. By contrast, we observed that the difference in human CD4+ and CD8+ T lymphocyte response toward the synthetic ATP-analog BzATP is not explained by a difference in human P2X7 receptor expression. Rather, the BzATP-induced human P2X7 receptor response in naïve and immune-activated lymphocyte subtypes correlated with the expression of another ATP-binding receptor: the human P2Y11 receptor...
2018: Frontiers in Immunology
Virginie Bondu, Casey Bitting, Valerie L Poland, Joshua A Hanson, Michelle S Harkins, Sarah Lathrop, Kurt B Nolte, Daniel A Lawrence, Tione Buranda
Sin Nombre virus (SNV) causes hantavirus cardiopulmonary pulmonary syndrome (HCPS) with the loss of pulmonary vascular endothelial integrity, and pulmonary edema without causing cytopathic effects on the vascular endothelium. HCPS is associated primarily with a dysregulated immune response. We previously found occult signs of hemostatic imbalance in the form of a sharp >30-100 fold increase in the expression of plasminogen activator inhibitor type 1 (PAI-1), in serial blood plasma draws of terminal stage-patients...
2018: Frontiers in Cellular and Infection Microbiology
Renee Koski, Blake Kennedy
Current practice guidelines recommend dual antiplatelet therapy comprised of aspirin and a purinergic signaling receptor Y12 (P2Y12 ) for patients following acute coronary syndrome. This article compares the efficacy, safety, and other characteristics of the three available oral P2Y12 inhibitors-clopidogrel, prasugrel, and ticagrelor.
June 2018: P & T: a Peer-reviewed Journal for Formulary Management
Tanya M Laidlaw, Katherine N Cahill, Juan Carlos Cardet, Katherine Murphy, Jing Cui, Brittney Dioneda, Parul Kothari, Benjamin A Raby, Elliot Israel, Joshua A Boyce
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions. OBJECTIVE: We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12 ) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD...
June 8, 2018: Journal of Allergy and Clinical Immunology
S Janapati, J Wurtzel, C Dangelmaier, B K Manne, D Bhavanasi, J C Kostyak, S Kim, M Holinstat, S P Kunapuli, L E Goldfinger
Essentials RAS proteins are expressed in platelets but their functions are largely uncharacterized. TC21/RRas2 is required for glycoprotein VI-induced platelet responses and for thrombus stability in vivo. TC21 regulates platelet aggregation by control of αIIb β3 integrin activation, via crosstalk with Rap1b. This is the first indication of functional importance of a proto-oncogenic RAS protein in platelets. SUMMARY: Background Many RAS family small GTPases are expressed in platelets, including RAC, RHOA, RAP, and HRAS/NRAS/RRAS1, but most of their signaling and cellular functions remain poorly understood...
June 8, 2018: Journal of Thrombosis and Haemostasis: JTH
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