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Xiaoran Yu, Jingjing Quan, Weilin Long, Huimin Chen, Ruoxun Wang, Jiaxin Guo, Xiaoxuan Lin, Sui Mai
Oral diseases, such as periapical periodontitis and periodontitis, are characterized by inflammation-induced bone loss. LL-37, a human antimicrobial peptide (AMP), has multiple biological functions and the potential to promote osteogenesis. Therefore, this study aimed to investigate the regulatory effects of LL-37 within normal and inflammatory microenvironments. The roles of P2X7 receptor (P2X7R) and mitogen-activated protein kinase (MAPK) signaling pathway were also demonstrated. The results showed that LL-37 promoted bone marrow stromal cell (BMSC) proliferation, migration and osteogenic differentiation...
October 1, 2018: Experimental Cell Research
Liangcai Gao, Zejie Lin, Guixiang Xie, Tian Zhou, Wenhao Hu, Chi Liu, Xinnan Liu, Xinyi Wang, Min Qian, Bing Ni
Neuroinflammation is one of the key factors contributing to depression. Recent studies have identified P2X7 receptor (P2X7r) as a major inflammatory regulator. However, the effects of P2X7r knockout (KO) on emotional conditions over the lifespan of mice are unknown. In this study, the effects of P2X7r deletion on emotional conditions over the lifespan of mice were investigated in young-aged (2 month old), middle-aged (10 month old), and old-aged (18 month old) female P2X7r KO mice and age-matched female C57BL/6 mice...
October 2, 2018: Neuroreport
Michel Koole, Mark Schmidt, Anja Hijzen, Paulien Ravenstijn, Corinne Vandermeulen, Donatienne Van Weehaeghe, Kim Serdons, Sofie Celen, Guy Bormans, Marc Ceusters, Wei Zhang, Luc Van Nueten, Hartmuth Kolb, Jan de Hoon, Koen Van Laere
The P2X7 receptor (P2X7R) is an adenosine triphosphate(ATP)-gated ion channel that is predominantly expressed on microglial cells in the central nervous system (CNS). Overactivation of microglia is hypothesized to play a role in the pathophysiology of several CNS disorders, including neurodegeneration and mood disorders. We report the clinical qualification of a P2X7 specific PET ligand 18 F-JNJ-64413739 in healthy volunteers including biodistribution and dosimetry, kinetic modelling and blocking by pharmacological doses of the clinical P2X7 antagonist JNJ-54175446...
September 27, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Erika Nuka, Kohta Ohnishi, Junji Terao, Yoshichika Kawai
Innate immune cells, such as macrophages, respond to pathogen-associated molecular patterns, such as a lipopolysaccharide (LPS), to secrete various inflammatory mediators. Recent studies have suggested that damage-associated molecular patterns (DAMPs), released extracellularly from damaged or immune cells, also play a role in the activation of inflammatory responses. In this study, to prevent excess inflammation, we focused on DAMPs-mediated signaling that promotes LPS-stimulated inflammatory responses, especially adenosine 5'-triphosphate (ATP)-triggered signaling through the ionotropic purinergic receptor 7 (P2X7R), as a potential new anti-inflammatory target of natural polyphenols...
2018: PloS One
Tomasz Grygorowicz, Lidia Strużyńska
Microglia-mediated neuroinflammation accompanies many central nervous system (CNS) diseases, including multiple sclerosis (MS), and is strongly dependent on the purinergic P2X7 receptor. The nature of the inflammatory response in MS is studied for decades indicating, that proinflammatory microgliosis is involved in advanced stages of MS and is associated with active tissue damage and neurological dysfunctions. Evidence on the role of microgliosis in initial stages of the disease is scarce. Thus, in the present study, we investigated the time course of microglial activation in rat brain subjected to experimental autoimmune encephalomyelitis (EAE) which is the animal model of MS...
September 12, 2018: Inflammopharmacology
Antonella Amoruso, Maria Blonda, Giulia D'Arrigo, Roberta Grasso, Valeria Di Francescantonio, Claudia Verderio, Carlo Avolio
Recently, microvesicles (MVs) were considered as important mediators of intercellular communication, especially in pathological conditions as Multiple Sclerosis (MS). In myeloid cells, MV shedding is induced by the receptor P2X7 with the involvement of acid sphingomyelinase (A-SMase) and release of the IL-1β. In this study we evaluate how Fingolimod affects MVs production by the monocytes, as well as P2X7R, IL-1β expression and A-SMase activity. Treatment decreased MVs production and IL-1β expression. This effect was associated with the inhibition of A-SMase activity in BzATP-stimulated monocytes from MS patients...
October 15, 2018: Journal of Neuroimmunology
Tetsuro Ishii, Eiji Warabi, Giovanni E Mann
Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains...
September 4, 2018: Free Radical Biology & Medicine
Jia-Piao Lin, Chao-Qin Chen, Ling-Er Huang, Na-Na Li, Yan Yang, Sheng-Mei Zhu, Yong-Xing Yao
α2-Adrenoceptor agonists attenuate hypersensitivity under neuropathic conditions. However, the mechanisms underlying this attenuation remain largely unknown. In the present study, we explored the potential roles of purinergic receptor 7 (P2X7R)/extracellular signal-regulated kinase (ERK) signaling in the anti-nociceptive effect of dexmedetomidine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. An animal model of CCI was adopted to mimic the clinical neuropathic pain state...
August 2018: Experimental Neurobiology
Qiu-Li Zhang, Wei Wang, Alatantuya, Dongmei, Zhan-Jun Lu, Lan-Lan Li, Tian-Zi Zhang
Several microRNAs (miRNAs) expressed in the retina were confirmed to involve in retinal cell apoptosis, which was closely linked with the development of retinal diseases. Our previous studies have confirmed a vital role of miR-187 in retinal cells apoptosis. The aim of this study was to further elucidate the precise role of miR-187 and its probable mechanisms in RGC-5 cells apoptosis. The cellular oxidative stress status was assessed by reactive oxygen species (ROS) production and malondialdehyde (MDA) level...
December 2018: International Journal of Biological Macromolecules
Rebecca Dalgarno, Heather Leduc-Pessah, Alexandra Pilapil, Charlie Ht Kwok, Tuan Trang
Pain hypersensitivity resulting from peripheral nerve injury depends on pathological microglial activation in the dorsal horn of the spinal cord. This microglial activity is critically modulated by P2X7 receptors (P2X7R) and ATP stimulation of these receptors produces mechanical allodynia, a defining feature of neuropathic pain. Peripheral nerve injury increases P2X7R expression and potentiates its cation channel function in spinal microglia. Here, we report a means to preferentially block the potentiation of P2X7R function by delivering a membrane permeant small interfering peptide that targets Y382-384 , a putative tyrosine phosphorylation site within the P2X7R intracellular C-terminal domain...
January 2018: Molecular Pain
Erica F Diezmos, Irit Markus, D S Perera, Steven Gan, Li Zhang, Shaun L Sandow, Paul P Bertrand, Lu Liu
Introduction: The pannexin-1 (Panx1) channels are found in many cell types, and ATP released from these channels can act on nearby cells activating purinergic P2X7 receptors (P2X7R) which lead to inflammation. Although Panx1 and P2X7R are implicated in the process of inflammation and cell death, few studies have looked at the role they play in inflammatory bowel disease in human. Hence, the aim of the present study was to investigate the function of Panx1 and P2X7R in an ex vivo colitis model developed from human colonic mucosal explants...
2018: Frontiers in Pharmacology
Weifeng Zhu, Yan Deng, Xiaodong Zhou
Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1β, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CD14, CARD8, P2X7R, EGF, A1CF, HNF4G and TRIM46, LRP2, GKRP, ADRB3, ADH1B, ALDH2, COMT, MAOA, PRKG2, WDR1, ALPK1, CARMIL (LRRC16A), RFX3, BCAS3, CNIH-2, FAM35A and MYL2-CUX2 ...
2018: Open Rheumatology Journal
Sara R Oliveira, Cláudia Figueiredo-Pereira, Carlos B Duarte, Helena L A Vieira
Carbon monoxide (CO) is an endogenous gasotransmitter that limits inflammation and prevents apoptosis in several tissues, including the brain. Low concentrations of CO are cytoprotective in astrocytes, neurons, and microglia, but the underlying molecular mechanisms remain poorly understood. This work aims at identification of alterations in gene expression conferred by CO in primary cultures of cortical astrocytes, for further disclosure of the molecular mechanism of action of the gasotransmitter. Astrocytes were treated with the CO-releasing molecule CORM-A1 for 40 min, and transcriptional changes were analyzed using RNASeq...
August 13, 2018: Molecular Neurobiology
Tobias Eckrich, Kerstin Blum, Ivan Milenkovic, Jutta Engel
Before the onset of hearing, which occurs around postnatal day 12 (P12) in mice, inner hair cells (IHCs) of the immature cochlea generate sound-independent Ca2+ action potentials (APs), which stimulate the auditory pathway and guide maturation of neuronal circuits. During these early postnatal days, intercellular propagating Ca2+ waves elicited by ATP-induced ATP release are found in inner supporting cells (ISCs). It is debated whether IHCs are able to fire Ca2+ APs independently or require a trigger by an ISC Ca2+ wave...
2018: Frontiers in Molecular Neuroscience
Michael Mousseau, Nicole E Burma, Kwan Yeop Lee, Heather Leduc-Pessah, Charlie H T Kwok, Allison R Reid, Melissa O'Brien, Boriss Sagalajev, Jo Anne Stratton, Natalya Patrick, Patrick L Stemkowski, Jeff Biernaskie, Gerald W Zamponi, Paul Salo, Jason J McDougall, Steven A Prescott, John R Matyas, Tuan Trang
Chronic joint pain such as mechanical allodynia is the most debilitating symptom of arthritis, yet effective therapies are lacking. We identify the pannexin-1 (Panx1) channel as a therapeutic target for alleviating mechanical allodynia, a cardinal sign of arthritis. In rats, joint pain caused by intra-articular injection of monosodium iodoacetate (MIA) was associated with spinal adenosine 5'-triphosphate (ATP) release and a microglia-specific up-regulation of P2X7 receptors (P2X7Rs). Blockade of P2X7R or ablation of spinal microglia prevented and reversed mechanical allodynia...
August 2018: Science Advances
Yue Shang, Xi-Feng Li, Ming-Ji Jin, Ying Li, Yan-Ling Wu, Quan Jin, Yu Zhang, Xia Li, Min Jiang, Ben-Wen Cui, Li-Hua Lian, Ji-Xing Nan
The current study was aimed to reveal that leucodin, a sesquiterpene lactone from Artemisia capillaris could inhibit the inflammatory response in macrophages and the lipid accumulation in hepatocytes via P2x7R-NLRP3 inflammasome activation. Several types of macrophages including mouse peritoneal macrophages, mouse bone marrow-derived macrophages and human macrophages THP-1 cells were pretreated with different concentrations of leucodin for 1 h and then stimulated with LPS and ATP. LPS plus ATP initiated IL-1β cleavage and release in mouse peritoneal macrophages and peaked at 4 h...
November 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Gergely Kovács, Zsuzsanna Környei, Krisztina Tóth, Mária Baranyi, János Brunner, Máté Neubrandt, Ádám Dénes, Beáta Sperlágh
The P2X7R protein, a P2 type purinergic receptor functioning as a non-selective cation channel, is expressed in different cell types of the central nervous system in several regions of the brain. The activation of the P2X7R protein by ATP modulates excitatory neurotransmission and contributes to microglial activation, apoptosis and neuron-glia communication. Zinc is an essential micronutrient that is highly concentrated in the synaptic vesicles of glutamatergic hippocampal neurons where free zinc ions released into the synaptic cleft alter glutamatergic signal transmission...
July 30, 2018: Cell Calcium
Ben J Gu, James S Wiley
The P2X7 receptor has been widely studied for its ATP-induced pro-inflammatory effect, but in the absence of a ligand, P2X7 has a second function as a scavenger receptor, which is active in the development of the human brain. The scavenger activity of P2X7 is only evident in the absence of serum but is fully active in cerebrospinal fluid. P2X7 on the cell surface is present as a membrane complex, and an attachment to non-muscle myosin of the cytoskeleton is required for particle engulfment. Selective antagonists of P2X7 pro-inflammatory function have little effect on phagocytosis, but inheritance of a variant haplotype spanning the P2RX7 and P2RX4 genes has been associated with loss of P2X7-mediated phagocytosis...
August 10, 2018: British Journal of Pharmacology
Sanja Cicko, Thomas Christian Köhler, Cemil Korcan Ayata, Tobias Müller, Nicolas Ehrat, Anja Meyer, Madelon Hossfeld, Andreas Zech, Francesco Di Virgilio, Marco Idzko
Acute respiratory distress syndrome (ARDS) is a life-threating lung condition resulting from a direct and indirect injury to the lungs [1, 2]. Pathophysiologically it is characterized by an acute alveolar damage, an increased permeability of the microvascular-barrier, leading to protein-rich pulmonary edema and subsequent impairment of arterial oxygenation and respiratory failure [1]. This study examined the role of extracellular ATP in recruiting inflammatory cells to the lung after induction of acute lung injury with lipopolysaccharide (LPS)...
July 17, 2018: Oncotarget
Jan M Deussing, Eduardo Arzt
Depression is a prime contributor to global disease burden with 300 million affected patients worldwide. The persistent lack of progress with regards to pharmacotherapy stands in stark contrast to the pandemic magnitude of the disease. Alterations of inflammatory pathways in depressed patients, including altered circulating pro-inflammatory cytokines, have been put forward as a potential pathophysiological mechanism. The P2X7 receptor (P2X7R) plays an important role regulating the release of interleukin-1β and other cytokines...
September 2018: Trends in Molecular Medicine
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