Your browser doesn't support javascript.
The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages.
Gauthier, Alex G; Wu, Jiaqi; Lin, Mosi; Sitapara, Ravikumar; Kulkarni, Abhijit; Thakur, Ganesh A; Schmidt, Edward E; Perron, Jeanette C; Ashby, Charles R; Mantell, Lin L.
  • Gauthier AG; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Wu J; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Lin M; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Sitapara R; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Kulkarni A; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Thakur GA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Schmidt EE; Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
  • Perron JC; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Ashby CR; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
  • Mantell LL; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY 11439, USA.
Antioxidants (Basel) ; 10(1)2021 Jan 19.
Article in English | MEDLINE | ID: covidwho-1042079
Semantic information from SemMedBD (by NLM)
1. Pneumoni PROCESS_OF C0026809
Subject
Pneumoni
Predicate
PROCESS_OF
Object
C0026809
2. GAT107 INTERACTS_WITH alpha7 Nicotinic Acetylcholine Receptor
Subject
GAT107
Predicate
INTERACTS_WITH
Object
alpha7 Nicotinic Acetylcholine Receptor
3. Interventional procedure TREATS Respiratory distress
Subject
Interventional procedure
Predicate
TREATS
Object
Respiratory distress
4. Respiratory distress PROCESS_OF Patients
Subject
Respiratory distress
Predicate
PROCESS_OF
Object
Patients
5. Interventional procedure TREATS Patients
Subject
Interventional procedure
Predicate
TREATS
Object
Patients
6. Mouse Lung LOCATION_OF GAT107
Subject
Mouse Lung
Predicate
LOCATION_OF
Object
GAT107
7. Hyperoxia CAUSES Imbalance
Subject
Hyperoxia
Predicate
CAUSES
Object
Imbalance
8. GAT107 ADMINISTERED_TO RAW 264.7 Cells
Subject
GAT107
Predicate
ADMINISTERED_TO
Object
RAW 264.7 Cells
9. F-Actin PART_OF Phagosomes
Subject
F-Actin
Predicate
PART_OF
Object
Phagosomes
10. GAT107 TREATS Oxidative Stress
Subject
GAT107
Predicate
TREATS
Object
Oxidative Stress
11. macrophage LOCATION_OF Heme Oxygenase-1
Subject
macrophage
Predicate
LOCATION_OF
Object
Heme Oxygenase-1
12. GAT107 AFFECTS Host defense
Subject
GAT107
Predicate
AFFECTS
Object
Host defense
13. Patients LOCATION_OF alpha7 Nicotinic Acetylcholine Receptor
Subject
Patients
Predicate
LOCATION_OF
Object
alpha7 Nicotinic Acetylcholine Receptor
14. Pneumonia, Bacterial PROCESS_OF Mus
Subject
Pneumonia, Bacterial
Predicate
PROCESS_OF
Object
Mus
15. GAT107 INTERACTS_WITH alpha7 Nicotinic Acetylcholine Receptor
Subject
GAT107
Predicate
INTERACTS_WITH
Object
alpha7 Nicotinic Acetylcholine Receptor
16. Interventional procedure TREATS Respiratory distress
Subject
Interventional procedure
Predicate
TREATS
Object
Respiratory distress
17. Respiratory distress PROCESS_OF Patients
Subject
Respiratory distress
Predicate
PROCESS_OF
Object
Patients
18. Interventional procedure TREATS Patients
Subject
Interventional procedure
Predicate
TREATS
Object
Patients
19. Mouse Lung LOCATION_OF GAT107
Subject
Mouse Lung
Predicate
LOCATION_OF
Object
GAT107
20. Hyperoxia CAUSES Imbalance
Subject
Hyperoxia
Predicate
CAUSES
Object
Imbalance
21. GAT107 ADMINISTERED_TO RAW 264.7 Cells
Subject
GAT107
Predicate
ADMINISTERED_TO
Object
RAW 264.7 Cells
22. F-Actin PART_OF Phagosomes
Subject
F-Actin
Predicate
PART_OF
Object
Phagosomes
23. GAT107 TREATS Oxidative Stress
Subject
GAT107
Predicate
TREATS
Object
Oxidative Stress
24. macrophage LOCATION_OF Heme Oxygenase-1
Subject
macrophage
Predicate
LOCATION_OF
Object
Heme Oxygenase-1
25. GAT107 AFFECTS Host defense
Subject
GAT107
Predicate
AFFECTS
Object
Host defense
26. Patients LOCATION_OF alpha7 Nicotinic Acetylcholine Receptor
Subject
Patients
Predicate
LOCATION_OF
Object
alpha7 Nicotinic Acetylcholine Receptor
ABSTRACT
Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2021 Document Type: Article Affiliation country: Antiox10010135

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2021 Document Type: Article Affiliation country: Antiox10010135