The Experts below are selected from a list of 8343 Experts worldwide ranked by ideXlab platform
John J. Castellot - One of the best experts on this subject based on the ideXlab platform.
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A Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma.
Journal of asthma and allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P
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a Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation remodeling and hyperreactivity in a mouse model of asthma
Journal of Asthma and Allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P<0.05). GC021109 prevented these changes. HDM-exposed mice had elevated inflammatory cell and total protein levels in LLF which were prevented by GC021109 (P<0.05). HDM mice also had elevated LLF levels of interleukin (IL)-4, IL-5, IL-12, granulocyte colony stimulating factor, chemokine (C-X-C) motif ligand 1, and leukemia inhibitory factor that were reduced by GC021109 with a dose-dependent pattern. HDM mice had increased peribronchial and perivascular inflammatory cell infiltration and increased α-SMA; these changes were absent with GC021109. Airway wall thickness measured on micro-CT images was increased after HDM exposure and significantly reduced by GC021109 treatment. Conclusion The P2Y6R prodrug GC021109 inhibited allergen-induced changes in pulmonary function, inflammatory responses, and airway and vascular smooth muscle mass. P2Y6R activation may be an effective therapeutic maintenance strategy in asthma.
Anne Chetty - One of the best experts on this subject based on the ideXlab platform.
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A Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma.
Journal of asthma and allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P
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a Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation remodeling and hyperreactivity in a mouse model of asthma
Journal of Asthma and Allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P<0.05). GC021109 prevented these changes. HDM-exposed mice had elevated inflammatory cell and total protein levels in LLF which were prevented by GC021109 (P<0.05). HDM mice also had elevated LLF levels of interleukin (IL)-4, IL-5, IL-12, granulocyte colony stimulating factor, chemokine (C-X-C) motif ligand 1, and leukemia inhibitory factor that were reduced by GC021109 with a dose-dependent pattern. HDM mice had increased peribronchial and perivascular inflammatory cell infiltration and increased α-SMA; these changes were absent with GC021109. Airway wall thickness measured on micro-CT images was increased after HDM exposure and significantly reduced by GC021109 treatment. Conclusion The P2Y6R prodrug GC021109 inhibited allergen-induced changes in pulmonary function, inflammatory responses, and airway and vascular smooth muscle mass. P2Y6R activation may be an effective therapeutic maintenance strategy in asthma.
Balazs Rada - One of the best experts on this subject based on the ideXlab platform.
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P2Y6 Receptor antagonist mrs2578 inhibits neutrophil activation and aggregated neutrophil extracellular trap formation induced by gout associated monosodium urate crystals
Journal of Immunology, 2017Co-Authors: Craig P Hayes, Barbara J Reaves, Patrick Breen, Shannon Quinn, Jeremy Sokolove, Balazs RadaAbstract:Human neutrophils (polymorphonuclear leukocytes [PMNs]) generate inflammatory responses within the joints of gout patients upon encountering monosodium urate (MSU) crystals. Neutrophil extracellular traps (NETs) are found abundantly in the synovial fluid of gout patients. The detailed mechanism of MSU crystal–induced NET formation remains unknown. Our goal was to shed light on possible roles of Purinergic signaling and neutrophil migration in mediating NET formation induced by MSU crystals. Interaction of human neutrophils with MSU crystals was evaluated by high-throughput live imaging using confocal microscopy. We quantitated NET levels in gout synovial fluid supernatants and detected enzymatically active neutrophil primary granule enzymes, myeloperoxidase, and human neutrophil elastase. Suramin and PPADS, general P2Y Receptor blockers, and MRS2578, an inhibitor of the Purinergic P2Y6 Receptor, blocked NET formation triggered by MSU crystals. AR-C25118925XX (P2Y2 antagonist) did not inhibit MSU crystal–stimulated NET release. Live imaging of PMNs showed that MRS2578 represses neutrophil migration and blocked characteristic formation of MSU crystal–NET aggregates called aggregated NETs. Interestingly, the store-operated calcium entry channel inhibitor (SK&F96365) also reduced MSU crystal–induced NET release. Our results indicate that the P2Y6/store-operated calcium entry/IL-8 axis is involved in MSU crystal–induced aggregated NET formation, but MRS2578 could have additional effects affecting PMN migration. The work presented in the present study could lead to a better understanding of gouty joint inflammation and help improve the treatment and care of gout patients.
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NET formation induced by gout-associated monosodium urate crystals requires IL-8-mediated neutrophil migration and is inhibited by the P2Y6 Receptor antagonist MRS2578.
Journal of Immunology, 2016Co-Authors: Payel Sil, Craig P Hayes, Barbara J Reaves, Jeremy Sokolove, Balazs RadaAbstract:Human neutrophils generate inflammatory responses within the joints of gout patients upon encountering Monosodium Urate (MSU) crystals. Studies (including ours) show that neutrophil extracellular traps (NETs) are found abundantly in the synovial fluid (SF) of gout patients and are crucial for the onset of the autoinflammatory cascade. Our goal is to shed light on possible roles of Purinergic signaling and neutrophil migration in mediating in vitro NET formation induced by MSU crystals. Our data show that gout SF supernatants have significantly higher levels of the neutrophil granule markers, myeloperoxidase (MPO) and human neutrophil elastase (HNE), and NETs than SF specimens from MSU-negative osteoarthritis patients. MSU crystal-triggered NETs in human neutrophils contain active DNA-bound MPO and HNE. MRS2578, a Purinergic P2Y6 Receptor antagonist, reduces the release of extracellular DNA, MPO and HNE in MSU crystal-stimulated neutrophils. Releases of MPO, HNE and NETs were measured by commercial ELISA and our proprietary NET-DNA ELISA assays. We found that MRS2578 reduces MSU crystal-induced IL-8 release, neutrophil chemotaxis and characteristic formation of DNA aggregates. The store operated calcium entry (SOCE) channel inhibitor (SK96365) blocked MSU crystal-induced NET release. Our results indicating that the P2Y6-SOCE-IL-8 axis is involved in MSU crystal-induced NET formation provide a novel mechanism potentially relevant in gout inflammation. Our work on the role of the P2Y6-SOCE-IL-8 axis in MSU crystal-triggered NET formation could potentially lead to a better understanding of the mechanism of gout joint inflammation and, thereby, help in improving the care of gout patients.
Azeem Sharda - One of the best experts on this subject based on the ideXlab platform.
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A Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma.
Journal of asthma and allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P
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a Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation remodeling and hyperreactivity in a mouse model of asthma
Journal of Asthma and Allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P<0.05). GC021109 prevented these changes. HDM-exposed mice had elevated inflammatory cell and total protein levels in LLF which were prevented by GC021109 (P<0.05). HDM mice also had elevated LLF levels of interleukin (IL)-4, IL-5, IL-12, granulocyte colony stimulating factor, chemokine (C-X-C) motif ligand 1, and leukemia inhibitory factor that were reduced by GC021109 with a dose-dependent pattern. HDM mice had increased peribronchial and perivascular inflammatory cell infiltration and increased α-SMA; these changes were absent with GC021109. Airway wall thickness measured on micro-CT images was increased after HDM exposure and significantly reduced by GC021109 treatment. Conclusion The P2Y6R prodrug GC021109 inhibited allergen-induced changes in pulmonary function, inflammatory responses, and airway and vascular smooth muscle mass. P2Y6R activation may be an effective therapeutic maintenance strategy in asthma.
Ellen O. Weinberg - One of the best experts on this subject based on the ideXlab platform.
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A Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma.
Journal of asthma and allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P
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a Purinergic P2Y6 Receptor agonist prodrug modulates airway inflammation remodeling and hyperreactivity in a mouse model of asthma
Journal of Asthma and Allergy, 2018Co-Authors: Anne Chetty, Azeem Sharda, Rod R. Warburton, Ellen O. Weinberg, Jinghui Dong, Min Fang, G. Gary Sahagian, Tiangmeng Chen, Chang Xue, John J. CastellotAbstract:Background Purinergic Receptors control cell proliferation, apoptosis, migration, inflammation, and cytokine secretion. Increased expression of specific Purinergic Receptors is reported in asthma. The role of Purinergic P2Y6 Receptors (P2Y6R) in asthma is controversial. Hypothesis P2Y6R activation in asthma improves pulmonary function and reduces inflammation and smooth muscle amount. Methods Female mice (C57/BL6, age 30 days) were randomly assigned to receive intranasal house dust mite (HDM) antigen (40 or 80 µg) or saline, 5 days/week, for 6 weeks. Randomly selected subgroups received intraperitoneal P2Y6R agonist prodrug (GC021109; 10 or 100 µg/kg weight/dose) simultaneously with HDM. After 6 weeks, lung function was measured. Lung lavage fluid (LLF) was used to measure total cell count, total protein, and cytokines. Immunohistochemistry for alpha smooth muscle actin (α-SMA) was done. Airway wall thickness was measured on micro-computed tomography (micro-CT) images. Results Pulmonary function testing revealed a HDM dose-dependent airway hyperresponsiveness. Airway resistance was increased 2-fold while compliance was decreased by 50% at the higher HDM dose (P<0.05). GC021109 prevented these changes. HDM-exposed mice had elevated inflammatory cell and total protein levels in LLF which were prevented by GC021109 (P<0.05). HDM mice also had elevated LLF levels of interleukin (IL)-4, IL-5, IL-12, granulocyte colony stimulating factor, chemokine (C-X-C) motif ligand 1, and leukemia inhibitory factor that were reduced by GC021109 with a dose-dependent pattern. HDM mice had increased peribronchial and perivascular inflammatory cell infiltration and increased α-SMA; these changes were absent with GC021109. Airway wall thickness measured on micro-CT images was increased after HDM exposure and significantly reduced by GC021109 treatment. Conclusion The P2Y6R prodrug GC021109 inhibited allergen-induced changes in pulmonary function, inflammatory responses, and airway and vascular smooth muscle mass. P2Y6R activation may be an effective therapeutic maintenance strategy in asthma.
