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https://www.readbyqxmd.com/read/28935606/calcimycin-mediates-mycobacterial-killing-by-inducing-intracellular-calcium-regulated-autophagy-in-a-p2rx7-dependent-manner
#1
Shradha Mawatwal, Assirbad Behura, Abhirupa Ghosh, Saqib Kidwai, Abtar Mishra, Amar Deep, Sakshi Agarwal, Sudipto Saha, Ramandeep Singh, Rohan Dhiman
Phenotypic screening led to the identification of calcimycin as a potent inhibitor of Mycobacterium bovis BCG (M. bovis BCG) growth in vitro and in THP-1 cells. In the present study, we aim to decipher the mechanism of antimycobacterial activity of calcimycin. We noticed that treatment with calcimycin led to up-regulation of different autophagy markers like Beclin-1, autophagy-related gene (Atg) 7, Atg 3 and enhanced microtubule-associated protein 1A/1B-light chain 3-I (LC3-I) to LC3-II conversion in macrophages...
September 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28924009/site-specific-regulation-of-p2x7-receptor-function-in-microglia-gates-morphine-analgesic-tolerance
#2
Heather Leduc-Pessah, Nicholas L Weilinger, Churmy Y Fan, Nicole E Burma, Roger J Thompson, Tuan Trang
Tolerance to the analgesic effects of opioids is a major problem in chronic pain management. Microglia are implicated in opioid tolerance, but the core mechanisms regulating their response to opioids remain obscure. By selectively ablating microglia in the spinal cord using a saporin-conjugated antibody to Mac1, we demonstrate a causal role for microglia in the development, but not maintenance, of morphine tolerance in male rats. Increased P2X7 receptor (P2X7R) activity is a cardinal feature of microglial activation, and in this study we found that morphine potentiates P2X7R-mediated Ca(2+) responses in resident spinal microglia acutely isolated from morphine tolerant rats...
September 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28920575/the-p2x7-receptor-forms-a-dye-permeable-pore-independent-of-its-intracellular-domain-but-dependent-on-membrane-lipid-composition
#3
Akira Karasawa, Kevin Michalski, Polina Mikhelzon, Toshimitsu Kawate
The P2X7 receptor mediates extracellular-ATP signaling implicated in the development of devastating diseases such as chronic pain and cancer. Activation of the P2X7 receptor leads to opening of the characteristic dye-permeable membrane pore for molecules up to ~900 Da. However, it remains controversial what constitutes this peculiar pore and how it opens. Here we show that the panda P2X7 receptor, when purified and reconstituted into liposomes, forms an intrinsic dye-permeable pore in the absence of other cellular components...
September 18, 2017: ELife
https://www.readbyqxmd.com/read/28919433/the-p2x7-receptor-in-dorsal-root-ganglia-is-involved-in-hiv-gp120-associated-neuropathic-pain
#4
Bing Wu, Lichao Peng, Jinyan Xie, Lifang Zou, Qicheng Zhu, Huaide Jiang, Zhihua Yi, Shouyu Wang, Yun Xue, Yun Gao, Guilin Li, Shuangmei Liu, Chunping Zhang, Guodong Li, Shangdong Liang, Huangui Xiong
Human immunodeficiency virus (HIV)-associated neuropathic pain is common, and studies have shown that HIV envelope glycoprotein 120 (gp120) can directly stimulate primary sensory afferent neurons causing hyperalgesia. The P2X7 receptor in the dorsal root ganglia (DRG) is involved in pain transmission and is closely related to the inflammatory and immune response. In this study, we aimed to explore the role of the P2X7 receptor in gp120-induced neuropathic pain using a rat model specific for this type of pain...
September 14, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28905300/p2x7r-antagonism-after-subfailure-overstretch-injury-of-blood-vessels-reverses-vasomotor-dysfunction-and-prevents-apoptosis
#5
Weifeng Luo, Daniel Feldman, Reid McCallister, Colleen Brophy, Joyce Cheung-Flynn
Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban...
September 13, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28886985/pannexin-1-channels-in-epilepsy
#6
REVIEW
Mark S Aquilino, Paige Whyte-Fagundes, Georg Zoidl, Peter L Carlen
Pannexin-1 (Panx1) expression is raised in several animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy. Multiple factors that are characteristic of seizures are thought to regulate Panx1 channel opening, including elevated levels of extracellular K(+). Panx1, when open, 1) releases ATP, glutamate, and other metabolites into the extracellular medium, and 2) may depolarize the membrane due to a channel reversal potential around 0mV. Resultant ATP release from stimulated Panx1 can activate purinergic receptors, including P2X7 receptors...
September 5, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28884379/genetic-interaction-of-purinergic-p2x7-receptor-and-er-%C3%AE-polymorphisms-in-susceptibility-to-osteoporosis-in-chinese-postmenopausal-women
#7
Hui Wang, Chengxin Gong, Xingzi Liu, Shenqiang Rao, Tao Li, Luling He, Yijun Nie, Shuo Wang, Peipei Zhong, Yansong Xue, Jihong Wang, Jiani Zhao, Yuru Zhou, Lu Ding, Yunming Tu, Yuping Yang, Chaopeng Xiong, Shangdong Liang, Hong Xu
Osteoporosis (OP) is an increasing public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The aim of this study was to investigate the association of the purinergic P2X7 receptor (P2X7R) and estrogen receptor-α (ER-α) genes with OP risk, and the effect of the possible interaction between the two genes on predisposition to OP in Chinese postmenopausal women. A total of 596 subjects, including 350 OP patients and 246 controls, were recruited in this case-control study...
September 7, 2017: Journal of Bone and Mineral Metabolism
https://www.readbyqxmd.com/read/28878780/p2y6-receptor-activation-promotes-inflammation-and-tissue-remodeling-in-pulmonary-fibrosis
#8
Tobias Müller, Susanne Fay, Rodolfo Paula Vieira, Harry Karmouty-Quintana, Sanja Cicko, Cemil Korcan Ayata, Gernot Zissel, Torsten Goldmann, Giuseppe Lungarella, Davide Ferrari, Francesco Di Virgilio, Bernard Robaye, Jean-Marie Boeynaems, Eduardo R Lazarowski, Michael R Blackburn, Marco Idzko
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28878732/multiple-sclerosis-treatments-affect-monocyte-derived-microvesicle-production
#9
Maria Blonda, Antonella Amoruso, Roberta Grasso, Valeria Di Francescantonio, Carlo Avolio
Microvesicles (MVs) are released by immune cells especially of the myeloid lineage upon stimulation with ATP on its cognate receptor P2X7, both in physiological and pathological conditions. In multiple sclerosis (MS) the role of MVs remains little investigated. We aimed to compare the release of MVs in peripheral blood monocytes from MS patients with healthy donors (HDs) and to see how current MS treatment may affect such a production. We also assessed the treatment effect on M1 and M2 monocyte polarization and on the inflammasome components...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28871219/p2x7-receptor-activation-modulates-autophagy-in-sod1-g93a-mouse-microglia
#10
Paola Fabbrizio, Susanna Amadio, Savina Apolloni, Cinzia Volonté
Autophagy and inflammation play determinant roles in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), an adult-onset neurodegenerative disease characterized by deterioration and final loss of upper and lower motor neurons (MN) priming microglia to sustain neuroinflammation and a vicious cycle of neurodegeneration. Given that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS, and that P2X7 affects autophagy in immune cells, we have investigated if autophagy can be directly triggered by P2X7 activation in primary microglia from superoxide dismutase 1 (SOD1)-G93A mice...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28865468/brain-ureido-degenerative-protein-modifications-are-associated-with-neuroinflammation-and-proteinopathy-in-alzheimer-s-disease-with-cerebrovascular-disease
#11
Xavier Gallart-Palau, Aida Serra, Benjamin Sian Teck Lee, Xue Guo, Siu Kwan Sze
BACKGROUND: Brain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer's disease with cerebrovascular disease (AD + CVD) is the most prevalent form of dementia in the elder population. Thus, understanding the role(s) of brain DPMs in this dementia subtype may provide novel insight on the disease pathogenesis and may aid on the development of novel diagnostic and therapeutic tools. Two essential DPMs known to promote inflammation in several human diseases are the ureido DPMs (uDPMs) arginine citrullination and lysine carbamylation, although they have distinct enzymatic and non-enzymatic origins, respectively...
September 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28863817/regulation-of-p2x-purinergic-receptor-signaling-by-cholesterol
#12
Ruth D Murrell-Lagnado
P2X receptors are cation-selective channels that are activated by the binding of extracellular ATP. They have a high permeability to Ca(2+), Na(+), and K(+) and are expressed widely throughout the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems. Seven mammalian subtypes of P2X receptor subunits have been identified, P2X1-7, and those that function as homotrimeric receptors (P2X1, 2, 3, 4, and 7) are targeted to lipid rafts, although they show limited resistance to solubilization by Triton X-100...
2017: Current Topics in Membranes
https://www.readbyqxmd.com/read/28859168/p2x7-receptor-drives-th1-cell-differentiation-and-controls-the-follicular-helper-t-cell-population-to-protect-against-plasmodium-chabaudi-malaria
#13
Érika Machado de Salles, Maria Nogueira de Menezes, Renan Siqueira, Henrique Borges da Silva, Eduardo Pinheiro Amaral, Sheyla Inés Castillo-Méndez, Isabela Cunha, Alexandra Dos Anjos Cassado, Flávia Sarmento Vieira, David Nicholas Olivieri, Carlos Eduardo Tadokoro, José Maria Alvarez, Robson Coutinho-Silva, Maria Regina D'Império-Lima
A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28858765/1-aryl-1h-and-2-aryl-2h-1-2-3-triazole-derivatives-blockade-p2x7-receptor-in%C3%A2-vitro-and-inflammatory-response-in%C3%A2-vivo
#14
Daniel Tadeu Gomes Gonzaga, Leonardo Braga Gomes Ferreira, Thadeu Estevam Moreira Maramaldo Costa, Natalia Lidmar von Ranke, Paulo Anastácio Furtado Pacheco, Ana Paula Sposito Simões, Juliana Carvalho Arruda, Luiza Pereira Dantas, Hércules Rezende de Freitas, Ricardo Augusto de Melo Reis, Carmen Penido, Murilo Lamim Bello, Helena Carla Castro, Carlos Rangel Rodrigues, Vitor Francisco Ferreira, Robson Xavier Faria, Fernando de Carvalho da Silva
Fifty-one 1,2,3-triazole derivatives were synthesized and evaluated with respect to P2X7 receptor (P2X7R) activity and its associated pore. These triazoles were screened in vitro for dye uptake assay and its cytotoxicity against mammalian cell types. Seven 1,2,3-triazole derivatives (5e, 6e, 8h, 9d, 9i, 11, and 12) potently blocked P2X7 receptor pore formation in vitro (J774.G8 cells and peritoneal macrophages). All blockers displayed IC50 value inferior to 500 nM, and they have low toxicity in either cell types...
August 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28858048/2016-glenn-a-fry-award-lecture-mechanisms-and-potential-treatments-of-early-age-related-macular-degeneration
#15
Erica Lucy Fletcher
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in those older than 80 years. Understanding the mechanisms that cause this condition or its progression is critical for developing novel treatments. Here we summarize our studies evaluating the role of purine, adenosine triphosphate (ATP), in early AMD as well as photoreceptor loss and have also provided some insights to our investigations of a new laser treatment for those with early AMD. One of the receptors that are activated by ATP, P2X7, is expressed by neurons and immune cells and has a different function in each cell type...
August 25, 2017: Optometry and Vision Science: Official Publication of the American Academy of Optometry
https://www.readbyqxmd.com/read/28856625/inhibition-of-p2x7-receptor-ameliorates-nuclear-factor-kappa-b-mediated-neuroinflammation-induced-by-status-epilepticus-in-rat-hippocampus
#16
Cheng Huang, Xiao-Sa Chi, Rui Li, Xin Hu, Hai-Xia Xu, Jin-Mei Li, Dong Zhou
P2X7 receptor (P2X7R) has been reported participating in neuroinflammation in multiple neurological diseases. We explored the role of P2X7R in a rat status epilepticus (SE) model induced by coriaria lactone (CL) and its association with neuroinflammation. Thirty minutes after intracerebroventricular infusion with P2X7R antagonists Brilliant blue G (BBG), A-438079, A-740003, or agonists 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), SE was induced by intramuscular injection of CL in Sprague-Dawley rats...
August 30, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28842982/novel-therapeutic-targets-against-spreading-depression
#17
REVIEW
Shih-Pin Chen, Cenk Ayata
Migraine is among the most prevalent and disabling neurological diseases in the world. Cortical spreading depression (SD) is an intense wave of neuronal and glial depolarization underlying migraine aura, and a headache trigger, which has been used as an experimental platform for drug screening in migraine. Here, we provide an overview of novel therapeutic targets that show promise to suppress SD, such as acid-sensing ion channels, casein kinase Iδ, P2X7-pannexin 1 complex, and neuromodulation, and outline the experimental models and essential quality measures for rigorous and reproducible efficacy testing...
August 26, 2017: Headache
https://www.readbyqxmd.com/read/28841278/pharmacological-evaluation-of-novel-bioisosteres-of-an-adamantanyl-benzamide-p2x7-receptor-antagonist
#18
Shane M Wilkinson, Melissa L Barron, James O'Brien-Brown, Bieneke Janssen, Leanne Stokes, Eryn L Werry, Mansoor Chishty, Kristen K Skarratt, Jennifer A Ong, David E Hibbs, Danielle J Vugts, Stephen Fuller, Albert D Windhorst, Michael Kassiou
Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability...
August 25, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28840058/p2x7-receptor-and-apoe-polymorphisms-and-survival-from-heart-failure-a-prospective-study-in-frail-patients-in-a-geriatric-unit
#19
Giuseppe Pasqualetti, Marta Seghieri, Eleonora Santini, Chiara Rossi, Edoardo Vitolo, Livia Giannini, Maria Giovanna Malatesta, Valeria Calsolaro, Fabio Monzani, Anna Solini
Heart failure (HF) is one of the most frequent cause of hospitalization in elderly and often coexists with concurrent geriatric syndromes, like cognitive disturbances; various pathophysiological mechanisms are shared by HF and cognitive decline, notably a substrate of low-grade inflammation. We investigated whether SNPs in the purinergic receptor (P2X7R) and apolipoprotein (APO) E genes, both involved in a series of inflammatory responses, are associated to HF or cognitive impairment and are able to predict post-discharge mortality in the elderly...
July 2017: Aging and Disease
https://www.readbyqxmd.com/read/28836128/purinergic-antagonism-prevents-mitochondrial-dysfunction-and-behavioral-deficits-associated-with-dopaminergic-toxicity-induced-by-6-ohda-in-rats
#20
Saket Kumar, Akanksha Mishra, Sairam Krishnamurthy
Purinoceptors are present in neurons, microglia and oligodendrocytes and regulate dopamine (DA) release, striatal-related function and striatal neuronal and DA cells damage. Therefore, purinoceptors may be involved in the pathology of Parkinson's disease (PD) and purinergic antagonism may show neuroprotective effect. The study investigated the role of the non-selective purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2('), 4(')-disulfonic acid (PPADS) and a selective purinergic receptor P2X7 receptor antagonist Brilliant Blue G (BBG) against 6-OHDA induced dopaminergic neurotoxicity in rats; while adenosine triphosphate (ATP) was used as a P2X receptor agonist...
August 24, 2017: Neurochemical Research
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