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Jiae Kim, Su-Min Kim, Jung-Min Na, Hoh-Gyu Hahn, Sung-Woo Cho, Seung-Ju Yang
We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells. KHG26792 also reduced hypoxia-induced inducible nitric oxide synthase protein expression, which correlated with reduced nitric oxide accumulation...
October 19, 2016: BMB Reports
Andreas Reichenbach, Andreas Bringmann
Müller glia, the principal macroglia of the retina, express diverse subtypes of adenosine and metabotropic purinergic (P2Y) receptors. Müller cells of several species, including man, also express ionotropic P2X7 receptors. ATP is liberated from Müller cells after activation of metabotropic glutamate receptors and during osmotic and mechanical induction of membrane stretch; adenosine is released through equilibrative nucleoside transporters. Müller cell-derived purines modulate the neuronal activity and have autocrine effects, for example, induction of glial calcium waves and regulation of the cellular volume...
October 2016: Journal of Ocular Pharmacology and Therapeutics
Xuejing Cui, Bin Wan, Liang-Hong Guo, Yu Yang, Xiao-Min Ren
Co-existence of nanomaterials and environmental pollutants requires in-depth understanding of combined toxicity and underlying mechanism. In this work, we found that co-exposure to the mixture of non-cytotoxic level of single-walled carbon nanotubes (SWCNTs) (10 µg/mL) and Ni2+ (20 µM) induced significant cytotoxicity in macrophages. However, almost equal amount of intracellular Ni2+ was detected after Ni2+/SWCNT co-exposure or Ni2+ single exposure, indicating no enhanced cellular uptake of Ni2+ occurred...
October 17, 2016: Environmental Science & Technology
Hongbo Hu, Baohui Yang, Yumin Li, Subin Zhang, Zheng Li
P2X purinoceptor 7 (P2X7) receptor (P2X7R) is known to play a significant role in inflammation and pain-causing diseases, including osteoarthritis (OA). However, the mechanisms of action of P2X7R and its role in OA remain unclear. The articular cartilage is the crucial region in which pathological changes occur in OA, involving the dysregulation of degradation and maintenance mechanisms. In this study, we aimed to reveal the molecular mechanisms of action of P2X7R in articular cartilage in OA-induced pain and inflammation by using AZD9056, an antagonist of P2X7R...
October 13, 2016: International Journal of Molecular Medicine
Weifeng Luo, Christy M Guth, Olukemi Jolayemi, Craig L Duvall, Colleen Marie Brophy, Joyce Cheung-Flynn
Vascular stretch injury is associated with blunt trauma, vascular surgical procedures, and harvest of human saphenous vein for use in vascular bypass grafting. A model of subfailure overstretch in rat abdominal aorta was developed to characterize surgical vascular stretch injury. Longitudinal stretch of rat aorta was characterized ex vivo. Stretch to the haptic endpoint, where the tissues would no longer lengthen, occurred at twice the resting length. The stress produced at this length was greater than physiologic mechanical forces but well below the level of mechanical disruption...
2016: Frontiers in Bioengineering and Biotechnology
Ying Xue, Yuting Xie, Bo Xue, Nan Hu, Guowei Zhang, Huaijin Guan, Min Ji
P2X7 receptor (P2X7R), an ATP-gated ion channel, plays an important role in glaucomatous retinal ganglion cell (RGC) apoptotic death, in which activated retinal Müller glial cells may be involved by releasing ATP. In the present study, we investigated whether and how activated Müller cells may induce changes in P2X7R expression in RGCs by using immunohistochemistry and Western blot techniques. Intravitreal injection of DHPG, a group I metabotropic glutamate receptor (mGluR I) agonist, induced upregulation of GFAP expression, suggestive of Müller cell activation (gliosis), as we previously reported...
2016: BioMed Research International
Luiz Eduardo Baggio Savio, Mariana G Juste Andrade, Paola de Andrade Mello, Patrícia Teixeira Santana, Aline Cristina Abreu Moreira-Souza, Janaína Kolling, Aline Longoni, Linda Feldbrügge, Yan Wu, Angela T S Wyse, Simon C Robson, Robson Coutinho-Silva
Sepsis results in unfettered inflammation, tissue damage, and multiple organ failure. Diffuse brain dysfunction and neurological manifestations secondary to sepsis are termed sepsis-associated encephalopathy (SAE). Extracellular nucleotides, proinflammatory cytokines, and oxidative stress reactions are associated with delirium and brain injury, and might be linked to the pathophysiology of SAE. P2X7 receptor activation by extracellular ATP leads to maturation and release of IL-1β by immune cells, which stimulates the production of oxygen reactive species...
October 11, 2016: Molecular Neurobiology
Ryota Nakazato, Shogo Hotta, Daisuke Yamada, Miki Kou, Saki Nakamura, Yoshifumi Takahata, Hajime Tei, Rika Numano, Akiko Hida, Shigeki Shimba, Michihiro Mieda, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada
Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells...
October 11, 2016: Glia
Ryan L O'Hare Doig, Carole A Bartlett, Nicole M Smith, Stuart I Hodgetts, Sarah A Dunlop, Livia Hool, Melinda Fitzgerald
Combinations of Ca(2+) channel inhibitors have been proposed as an effective means to prevent excess Ca(2+) flux and death of neurons and glia following neurotrauma in vivo. However, it is not yet known if beneficial outcomes such as improved viability have been due to direct effects on intracellular Ca(2+) concentrations. Here, the effects of combinations of Lomerizine (Lom), YM872, memantine and/or oxATP to block voltage gated Ca(2+) channels, Ca(2+) permeable AMPA receptors, NMDA receptors and purinergic P2X7 receptors (P2X7R) respectively, on Ca(2+) concentration and viability of primary mixed cortical cultures exposed to hydrogen peroxide (H2O2) insult, were assessed...
October 7, 2016: Neuroscience
Jin-Hee Park, Yong-Chul Kim
The P2X7 receptor (P2X7R) is a unique subtype among the family of seven purinergic P2X receptors, which are ATP-gated non-selective cation channels. P2X7R has been reported to have pathological roles in various diseases, including autoimmune diseases such as arthritis and inflammatory bowel disease, neurodegenerative diseases, chronic pain, mood disorders and cancers. Therefore, many pharmaceutical companies have endeavored to develop a clinical candidate targeting P2X7R. Areas covered: This review provides a summary of various patents on chemicals and biologics and their clinical use published between 2010 and 2015...
October 10, 2016: Expert Opinion on Therapeutic Patents
Bo Xue, Yuting Xie, Ying Xue, Nan Hu, Guowei Zhang, Huaijin Guan, Min Ji
Müller cell reactivation (gliosis) is an early response in glaucomatous retina. Previous studies have demonstrated that activation of P2X7 receptors results in retinal ganglion cell (RGC) apoptosis. Here, the issues of whether and how activated Müller cells may contribute to RGC apoptosis through P2X7 receptors were investigated. Either intravitreal injection of (S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR I) agonist, in normal rat retinas, or DHPG treatment of purified cultured rat retinal Müller cells induced an increase in glial fibrillary acidic protein (GFAP) expression, indicative of Müller cell gliosis...
October 6, 2016: Experimental Eye Research
Soshi Seike, Masaya Takehara, Keiko Kobayashi, Masahiro Nagahama
BACKGROUND: Beta-toxin produced by Clostridium perfringens is a key virulence factor of fatal hemorrhagic enterocolitis and enterotoxemia. This toxin belongs to a family of β-pore-forming toxins (PFTs). We reported recently that the ATP-gated P2X7 receptor interacts with beta-toxin. The ATP-release channel pannexin 1 (Panx1) is an important contributor to P2X7 receptor signaling. Hence, we investigated the involvement of Panx1 in beta-toxin-caused cell death. METHODS: We examined the effect of Panx1 in beta-toxin-induced cell death utilizing selective antagonists, knockdown of Panx1, and binding using dot-blot analysis...
October 5, 2016: Biochimica et Biophysica Acta
Baochang Qi, Tiecheng Yu, Chengxue Wang, Tiejun Wang, Jihang Yao, Xiaomeng Zhang, Pengfei Deng, Yongning Xia, Wolfgang G Junger, Dahui Sun
BACKGROUND: Osteosarcoma is the most prevalent primary malignant bone tumor, but treatment is difficult and prognosis remains poor. Recently, large-dose chemotherapy has been shown to improve outcome but this approach can cause many side effects. Minimizing the dose of chemotherapeutic drugs and optimizing their curative effects is a current goal in the management of osteosarcoma patients. METHODS: In our study, trypan blue dye exclusion assay was performed to investigate the optimal conditions for the sensitization of osteosarcoma U2OS cells...
October 3, 2016: Journal of Experimental & Clinical Cancer Research: CR
Christopher J Davis, Ping Taishi, Kimberly A Honn, John N Koberstein, James M Krueger
The ionotropic purine type 2X7 receptor (P2X7R) is a non-specific cation channel implicated in sleep regulation and brain cytokine release. Many endogenous rhythms co-vary with sleep including locomotor activity and core body temperature. Further, brain-hypothalamic cytokines and purines play a role in the regulation of these physiological parameters as well as sleep. We hypothesized that these parameters are also affected by the absence of the P2X7 receptor. Herein we determine spontaneous expression of body temperature and locomotor activity in WT and P2X7R knockout (KO) mice and how they are affected by sleep deprivation (SD)...
October 5, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
B M Lee, H Jo, G Park, Y H Kim, C K Park, S J Jung, G Chung, S B Oh
Odontoblasts form dentin at the outermost surface of tooth pulp. An increasing level of evidence in recent years, along with their locational advantage, implicates odontoblasts as a secondary role as sensory or immune cells. Extracellular adenosine triphosphate (ATP) is a well-characterized signaling molecule in the neuronal and immune systems, and its potential involvement in interodontoblast communications was recently demonstrated. In an effort to elaborate the ATP-mediated signaling pathway in odontoblasts, the current study performed single-cell reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescent detection to investigate the expression of ATP receptors related to calcium signal in odontoblasts from incisal teeth of 8- to 10-wk-old rats, and demonstrated an in vitro response to ATP application via calcium imaging experiments...
September 30, 2016: Journal of Dental Research
Hiroki Koizumi, Shoji Ikezaki, Toyoaki Ohbuchi, Ba Hung Do, Nobusuke Hohchi, Rintaro Kawaguchi, Takuro Kitamura, Hideaki Suzuki
OBJECTIVE: The present study aimed at investigating ATP release in response to acetylcholine (Ach) and pharmacologically elucidating the intracellular signal transduction pathway of this reaction in an ex vivo experiment. METHODS: The inferior turbinate mucosa was collected from 21 patients with chronic hypertrophic rhinitis who underwent endoscopic turbinectomy. The mucosa was shaped into a filmy round piece, and incubated with chemical(s) in Hank's balanced salt solution for 10min...
September 27, 2016: Auris, Nasus, Larynx
Jian Li, Xiangnan Li, Xin Jiang, Mei Yang, Rui Yang, Geoffrey Burnstock, Zhenghua Xiang, Hongbin Yuan
Microglia are critical in the pathogenesis of neuropathic pain. In this study, we investigated the role of microvesicles (MVs) in neuropathic pain induced by spinal nerve ligation (SNL) in rats. First, we found that MVs shed from microglia were increased in the cerebrospinal fluid and dorsal horn of the spinal cord after SNL. Next, MVs significantly reduced paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). In addition, the P2X7-p38 pathway was related to the bleb of MVs after SNL. Interleukin (IL)-1β was found to be significantly upregulated in the package of MVs, and PWT and PWL increased following inhibition with shRNA-IL-1β...
September 28, 2016: Purinergic Signalling
N S Mohamad, A Sinadinos, D C Górecki, P Zioupos, J Tong
Duchenne muscular dystrophy (DMD) is an inherited, lethal disorder characterised by progressive muscle degeneration and associated bone abnormalities. We have previously demonstrated that P2RX7 purinergic receptors contribute to the pathogenesis of DMD, and found that P2RX7 ablation alleviated the severity of the disease. In this work we have used a dystrophic mdx mouse crossed with the global P2RX7 receptor to generate a knockout mouse (mdx/P2X7(-)(/)(-)), and compared its morphometric, mechanical and tissue properties against those of mdx, as well as the wild type (WT) and the P2RX7 knockout (P2X7(-)(/)(-))...
September 15, 2016: Journal of Biomechanics
K Barth, R Bläsche, A Neißer, S Bramke, J A Frank, M Kasper
The purinergic receptor P2X7 represents an ATP-gated ionotropic receptor with a selective localization in alveolar epithelial type I cells of the lung. Despite the involvement of the receptor in inflammatory processes of the lung, it is not established whether this receptor plays a specific role in the alveolar epithelial cell biology. There is evidence that P2X7 receptor influences Wnt/β-catenin signalling pathways in alveolar epithelial cells under conditions of injury. Here, we investigated the expression of GSK-3β, a potent protein kinase involved in alveolar epithelial barrier functions, and of tight junction molecules occludin, claudin-4 and claudin-18 in wild-type and P2X7(-/-) mice...
September 23, 2016: Histochemistry and Cell Biology
Xuejing Cui, Bin Wan, Yu Yang, Xiaomin Ren, Liang-Hong Guo, Hui Zhang
Exocytosis of single-walled carbon nanotubes (SWCNTs) determines therapeutic efficiency and toxicity of nanoproducts but its underlying mechanism remains elusive. In this study, it is found that the exocytosis mechanism of SWCNTs is mediated mainly through the activation of P2X7 receptor (P2X7 R), an ATP-gated membrane receptor highly expressed in macrophages. Inhibition of P2X7 R signaling by either a specific inhibitor (oxidized ATP) or small interfering RNA targeting P2X7 R largely prevents the exocytosis of SWCNTs from Raw264...
September 20, 2016: Small
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