Understanding the Dosage-Dependent Role of in Thyroid Tumorigenesis.

Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. has been found to be altered in papillary thyroid cancer (PTC).

Targeting the P2Y Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.

The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. To determine whether P2Y-R (P2Y receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma.

NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female.

Nucleotides released by smooth muscle cells (SMCs) and by innervating nerve terminals activate specific P2 receptors and modulate bladder contraction. We hypothesized that cell surface enzymes regulate SMC contraction in mice bladder by controlling the concentration of nucleotides. We showed by immunohistochemistry, enzymatic histochemistry, and biochemical activities that nucleoside triphosphate diphosphohydrolase-1 (NTPDase1) and ecto-5'-nucleotidase were the major ectonucleotidases expressed by SMCs in the bladder.

NTPDase8 protects mice from intestinal inflammation by limiting P2Y receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD.

Objective: Nucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation.

Lack of adipocyte purinergic P2Y receptor greatly improves whole body glucose homeostasis.

Uridine diphosphate (UDP)-activated purinergic receptor P2Y (P2YR) plays a crucial role in controlling energy balance through central mechanisms. However, P2YR's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2YR protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation.

P2Y receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release.

Microglia sense their environment using an array of membrane receptors. While P2Y receptors are known to play a key role in targeting directed motility of microglial processes to sites of damage where ATP/ADP is released, little is known about the role of P2Y , which transcriptome data suggest is the second most expressed neurotransmitter receptor in microglia. We show that, in patch-clamp recordings in acute brain slices from mice lacking P2Y receptors, the THIK-1 K current density evoked by ADP activating P2Y receptors was increased by ~50%.

Exacerbated intestinal inflammation in P2Y deficient mice is associated with Th17 activation.

Extracellular nucleotides are released as constitutive danger signals by various cell types and activate nucleotide (P2) receptors such as P2Y receptor. P2Y activation on monocytes induces the secretion of the chemokine CXCL8 which may propagate intestinal inflammation. Also, P2Y expression is increased in infiltrating T cells of Crohn's disease patients.

Validation of a LC/MSMS method for simultaneous quantification of 9 nucleotides in biological matrices.

Nucleotides play a role in inflammation processes: cAMP and cGMP in the endothelial barrier function, ADP in platelet aggregation, ATP and UTP in vasodilatation and/or vasoconstriction of blood vessels, UDP in macrophages activation. The aim of this study is to develop and validate a LC/MS-MS method able to quantify simultaneously nine nucleotides (AMP, cAMP, ADP, ATP, GMP, cGMP, UMP, UDP and UTP) in biological matrixes (cells and plasma). The method we developed, has lower LOQ's than others and has the main advantage to quantify all nucleotides within one single injection in less than 10 min.

Data on myeloperoxidase-oxidized low-density lipoproteins stimulation of cells to induce release of resolvin-D1.

This article present data related to the publication entitled "Native and myeloperoxidase-oxidized low-density lipoproteins act in synergy to induce release of resolvin-D1 from endothelial cells" (Dufour et al., 2018). The supporting materials include results obtained by Mox-LDLs stimulated macrophages and investigation performed on scavenger receptors.

Disruption of the Microglial ADP Receptor P2Y Enhances Adult Hippocampal Neurogenesis.

In mammalian species, including humans, the hippocampal dentate gyrus (DG) is a primary region of adult neurogenesis. Aberrant adult hippocampal neurogenesis is associated with neurological pathologies. Understanding the cellular mechanisms controlling adult hippocampal neurogenesis is expected to open new therapeutic strategies for mental disorders.

Mechanism underlying the contractile activity of UTP in the mammalian heart.

We previously reported that uridine 5'-triphosphate (UTP), a pyrimidine nucleoside triphosphate produced a concentration- and time-dependent increase in the contraction force in isolated right atrial preparations from patients undergoing cardiac bypass surgery due to angina pectoris. The stimulation of the force of contraction was sustained rather than transient. In the present study, we tried to elucidate the underlying receptor and signal transduction for this effect of UTP.

Native and myeloperoxidase-oxidized low-density lipoproteins act in synergy to induce release of resolvin-D1 from endothelial cells.

Background And Aims: Oxidation of native low-density lipoproteins (LDLs-nat) plays an important role in the development of atherosclerosis. A major player in LDL-nat oxidation is myeloperoxidase (MPO), a heme enzyme present in azurophil granules of neutrophils and monocytes. MPO produces oxidized LDLs called Mox-LDLs, which cause a pro-inflammatory response in human microvascular endothelial cells (HMEC), monocyte/macrophage activation and formation of foam cells.

P2Y Receptors Regulate CXCL10 Expression and Secretion in Mouse Intestinal Epithelial Cells.

In this study, we investigated the role of extracellular nucleotides in chemokine (KC, MIP-2, MCP-1, and CXCL10) expression and secretion by murine primary intestinal epithelial cells (IECs) with a focus on P2Y receptors. qRT-PCR experiments showed that P2Y was the dominant nucleotide receptor expressed in mouse IEC. In addition, the P2Y ligand UDP induced expression and secretion of CXCL10.

Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?

Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two-electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins.

Purinergic dysregulation causes hypertensive glaucoma-like optic neuropathy.

Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Although one of the highest risk factors for glaucoma is elevated intraocular pressure (IOP) and reduction in IOP is the only proven treatment, the mechanism of IOP regulation is poorly understood. We report that the P2Y6 receptor is critical for lowering IOP and that ablation of the P2Y6 gene in mice (P2Y6KO) results in hypertensive glaucoma-like optic neuropathy.

P2Y Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y and P2X in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury.

The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y2 in the context of fibrotic lung diseases.

Mouse P2Y Nucleotide Receptor Is a Negative Regulator of Cardiac Adipose-Derived Stem Cell Differentiation and Cardiac Fat Formation.

Cardiac adipose tissue-derived stem cells (cASCs) have the ability to differentiate into multiple cell lineages giving them a high potential for use in regenerative medicine. Cardiac fat tissue still raises many unsolved questions related to its formation and features. P2Y nucleotide receptors have already been described as regulators of differentiation of bone-marrow derived stem cells, but remain poorly investigated in cASCs.

Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone.

Objective: Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT.

New insights on pyrimidine signalling within the arterial vasculature - Different roles for P2Y2 and P2Y6 receptors in large and small coronary arteries of the mouse.

Extracellular pyrimidines activate P2Y receptors on both smooth muscle cells and endothelial cells, leading to vasoconstriction and relaxation respectively. The aim of this study was to utilize P2Y knock-out (KO) mice to determine which P2Y receptor subtype are responsible for the contraction and relaxation in the coronary circulation and to establish whether P2Y receptors have different functions along the mouse coronary vascular tree. We tested stable pyrimidine analogues on isolated coronary arteries from P2Y2 and P2Y6 receptor KO mice in a myograph setup.

Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension.

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR), promoted Ang II-induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II-induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction.

Müller cell-mediated neurite outgrowth of the retinal ganglion cells via P2Y receptor signals.

Müller cells, the primary macroglia of the retina, support various functions of retinal ganglion cells (RGCs). Here, we demonstrate a nucleotide-mediated communication between these two types of cells, by which Müller cells control neurite outgrowth of RGCs by activation of P2 receptors such as P2Y . Cultured mouse RGCs had significantly enhanced neurite outgrowth when cultured with either cultured mouse Müller cells or conditioned medium derived from Müller cells, and this was completely inhibited by the nucleotide-degrading enzyme, apyrase.

The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML.

Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation.

Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport.

Aims: High-density lipoproteins (HDLs) protect against atherosclerosis mainly due to their function in hepatobiliary reverse cholesterol transport (RCT). This is a process whereby excess cholesterol from peripheral tissues is transported by HDL particles to the liver for further metabolism and biliary excretion. Hepatic uptake of HDL holoparticles involves the P2Y13 receptor, independently of the selective cholesteryl ester uptake mediated by scavenger receptor class B, type I (SR-BI).

P2Y2R deficiency attenuates experimental autoimmune uveitis development.

We aimed to study the role of the nucleotide receptor P2Y2R in the development of experimental autoimmune uveitis (EAU). EAU was induced in P2Y2+/+ and P2Y2-/- mice by immunization with IRBP peptide or by adoptive transfer of in vitro restimulated semi-purified IRBP-specific enriched T lymphocytes from spleens and lymph nodes isolated from native C57Bl/6 or P2Y2+/+ and P2Y2-/- immunized mice. Clinical and histological scores were used to grade disease severity.