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Article ; Online: GAT107-mediated α7 nicotinic acetylcholine receptor signaling attenuates inflammatory lung injury and mortality in a mouse model of ventilator-associated pneumonia by alleviating macrophage mitochondrial oxidative stress via reducing MnSOD-S-glutathionylation.

Gauthier, Alex G / Lin, Mosi / Zefi, Sidorela / Kulkarni, Abhijit / Thakur, Ganesh A / Ashby, Charles R / Mantell, Lin L

Redox biology

2023 Volume 60, Page(s) 102614

Abstract: Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). Compromised host defense and inflammatory lung injury are ... ...

Abstract	Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial and viral infections, causing ventilator-associated pneumonia (VAP). Compromised host defense and inflammatory lung injury are mediated, in part, by high extracellular concentrations of HMGB1, which can be decreased by GTS-21, a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). Here, we report that a novel α7nAChR agonistic positive allosteric modulator (ago-PAM), GAT107, at 3.3 mg/kg, i.p., significantly decreased animal mortality and markers of inflammatory injury in mice exposed to hyperoxia and subsequently infected with Pseudomonas aeruginosa. The incubation of macrophages with 3.3 μM of GAT107 significantly decreased hyperoxia-induced extracellular HMGB1 accumulation and HMGB1-induced macrophage phagocytic dysfunction. Hyperoxia-compromised macrophage function was correlated with impaired mitochondrial membrane integrity, increased superoxide levels, and decreased manganese superoxide dismutase (MnSOD) activity. This compromised MnSOD activity is due to a significant increase in its level of glutathionylation. The incubation of hyperoxic macrophages with 3.3 μM of GAT107 significantly decreases the levels of glutathionylated MnSOD, and restores MnSOD activity and mitochondrial membrane integrity. Thus, GAT107 restored hyperoxia-compromised phagocytic functions by decreasing HMGB1 release, most likely via a mitochondrial-directed pathway. Overall, our results suggest that GAT107 may be a potential treatment to decrease acute inflammatory lung injury by increasing host defense in patients with VAP.
MeSH term(s)	Animals ; Mice ; Pneumonia, Ventilator-Associated/drug therapy ; Pneumonia, Ventilator-Associated/metabolism ; Pneumonia, Ventilator-Associated/microbiology ; alpha7 Nicotinic Acetylcholine Receptor ; HMGB1 Protein/metabolism ; Hyperoxia/metabolism ; Macrophages/metabolism ; Acute Lung Injury/metabolism ; Superoxide Dismutase/metabolism ; Oxidative Stress
Chemical Substances	alpha7 Nicotinic Acetylcholine Receptor ; 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinoline-8-sulfonamide ; HMGB1 Protein ; Superoxide Dismutase (EC 1.15.1.1)
Language	English
Publishing date	2023-01-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2023.102614
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Article ; Online: Correction to: GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

Sitapara, Ravikumar A / Gauthier, Alex G / Patel, Vivek S / Lin, Mosi / Zur, Michelle / Ashby, Charles R / Mantell, Lin L

Molecular medicine (Cambridge, Mass.)

2021 Volume 27, Issue 1, Page(s) 93

Language	English
Publishing date	2021-08-23
Publishing country	England
Document type	Published Erratum
ZDB-ID	1283676-x
ISSN	1528-3658 ; 1076-1551
ISSN (online)	1528-3658
ISSN	1076-1551
DOI	10.1186/s10020-021-00357-5
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Article ; Online: Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy.

White, Tomas L / Deshpande, Neha / Kumar, Varun / Gauthier, Alex G / Jurkunas, Ula V

Free radical biology & medicine

2021 Volume 164, Page(s) 34–43

Abstract: Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, ... ...

Abstract	Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, with both genetic and environmental factors. In this study, we have provided further insights into the pathogenesis of the disease, showing a causal relationship between senescence and endothelial-mesenchymal transition (EMT) using in vitro and in vivo models. Ultraviolet A (UVA) light induced EMT and senescence in CEnCs. Senescent cells were arrested in G2/M phase of the cell cycle and responsible for the resulting profibrotic phenotype. Inhibiting ATR signaling and subsequently preventing G2/M arrest attenuated EMT. In vivo, UVA irradiation induced cell cycle re-entry in post mitotic CEnCs, resulting in senescence and fibrosis at 1- and 2-weeks post-UVA. Selectively eliminating senescent cells using the senolytic cocktail of dasatinib and quercetin attenuated UVA-induced fibrosis, highlighting the potential for a new therapeutic intervention for FECD.
MeSH term(s)	Apoptosis ; Cell Division ; Cell Line, Tumor ; Endothelial Cells ; Endothelium, Corneal/metabolism ; Fibrosis ; Fuchs' Endothelial Dystrophy/genetics ; G2 Phase Cell Cycle Checkpoints ; Humans ; Oxidative Stress
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2020.12.445
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Zs.A 2109: Show issues

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Article ; Online: From nicotine to the cholinergic anti-inflammatory reflex - Can nicotine alleviate the dysregulated inflammation in COVID-19?

Gauthier, Alex G / Lin, Mosi / Wu, Jiaqi / Kennedy, Thomas P / Daley, Lee-Anne / Ashby, Charles R / Mantell, Lin L

Journal of immunotoxicology

2021 Volume 18, Issue 1, Page(s) 23–29

Abstract: The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury ...

Abstract	The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.
MeSH term(s)	Antibodies, Monoclonal, Humanized/therapeutic use ; Benzylidene Compounds/pharmacology ; COVID-19/drug therapy ; Cholinergic Agents/pharmacology ; Cigarette Smoking/adverse effects ; Dexamethasone/therapeutic use ; HMGB1 Protein/blood ; Humans ; Inflammation/drug therapy ; Nicotine/metabolism ; Pandemics ; Pyridines/pharmacology ; SARS-CoV-2/physiology ; Tobacco Use Disorder/drug therapy ; alpha7 Nicotinic Acetylcholine Receptor/agonists
Chemical Substances	Antibodies, Monoclonal, Humanized ; Benzylidene Compounds ; Cholinergic Agents ; HMGB1 Protein ; Pyridines ; alpha7 Nicotinic Acetylcholine Receptor ; Nicotine (6M3C89ZY6R) ; Dexamethasone (7S5I7G3JQL) ; 3-(2,4-dimethoxybenzylidene)anabaseine (8S399XDN2K) ; tocilizumab (I031V2H011)
Language	English
Publishing date	2021-04-16
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2021.1875085
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Zs.A 6167: Show issues

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Article ; Online: Inadequate Coping Strategies of Men who Have Committed Sexual Aggression Against Women: A Study of Their Developmental Antecedents.

Gauthier, Alexandre / Deli, Caroline / Garant, Etienne / Proulx, Jean

Sexual abuse : a journal of research and treatment

2023 , Page(s) 10790632231210534

Abstract: ... strategies (e.g., paraphilic sexual fantasies, substance abuse). However, very few researchers have ... and drug use) mediated by internalized psychological problems (e.g., anxiety, depression ...

Abstract	Several researchers have found that men who have committed sexual aggression have inadequate coping strategies (e.g., paraphilic sexual fantasies, substance abuse). However, very few researchers have empirically examined the factors potentially associated with the development of these strategies. In 2011, Maniglio hypothesized that the inadequate coping strategies of men who have committed sexual aggression are the result of childhood victimization, mediated by internalized psychological problems. The present study therefore empirically tested this hypothesis in a Canadian sample of 205 men who had committed sexual aggression against women, of whom 37 committed sexual murder. Structural equation modeling (SEM) resulted in the identification of several direct and indirect trajectories leading from childhood victimization (psychological, physical, sexual) to the development of inadequate coping strategies (paraphilic sexual fantasies, alcohol and drug use) mediated by internalized psychological problems (e.g., anxiety, depression, social isolation). The theoretical and clinical implications of these developmental trajectories are discussed.
Language	English
Publishing date	2023-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1283507-9
ISSN	1573-286X ; 1079-0632
ISSN (online)	1573-286X
ISSN	1079-0632
DOI	10.1177/10790632231210534
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Zs.A 3271: Show issues

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Article ; Online: Correction to: 2‑O, 3‑O desulfated heparin (ODSH) increases bacterial clearance and attenuates lung injury in cystic fibrosis by restoring HMGB1‑compromised macrophage function.

Wang, Mao / Gauthier, Alex G / Kennedy, Thomas P / Wang, Haichao / Velagapudi, Uday Kiran / Talele, Tanaji T / Lin, Mosi / Wu, Jiaqi / Daley, LeeAnne / Yang, Xiaojing / Patel, Vivek / Mun, Sung Soo / Ashby, Charles R / Mantell, Lin L

Molecular medicine (Cambridge, Mass.)

2021 Volume 27, Issue 1, Page(s) 98

Language	English
Publishing date	2021-09-03
Publishing country	England
Document type	Published Erratum
ZDB-ID	1283676-x
ISSN	1528-3658 ; 1076-1551
ISSN (online)	1528-3658
ISSN	1076-1551
DOI	10.1186/s10020-021-00354-8
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Article: 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

Antioxidants (Basel, Switzerland)

2021 Volume 10, Issue 1

Abstract: Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% ... ...

Abstract	Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O
Language	English
Publishing date	2021-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10010135
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Article: 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

Antioxidants. 2021 Jan. 19, v. 10, no. 1

2021

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 ... ...

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	Coronavirus infections ; actin ; antioxidants ; distress ; heme oxygenase (biliverdin-producing) ; hyperoxia ; lungs ; macrophages ; mice ; microbial load ; nicotinic receptors ; oxidation ; oxidative stress ; oxygen ; patients ; phagosomes ; superoxide dismutase ; therapeutics
Language	English
Dates of publication	2021-0119
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10010135
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.

Gore, Ashwini / Gauthier, Alex G / Lin, Mosi / Patel, Vivek / Thomas, Douglas D / Ashby, Charles R / Mantell, Lin L

Biochemical pharmacology

2020 Volume 176, Page(s) 113817

Abstract: Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia ( ... ...

Abstract	Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Hyperoxia/immunology ; Immunity, Innate/drug effects ; Macrophages/drug effects ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/immunology ; Nitric Oxide/metabolism ; Nitric Oxide Donors/pharmacology ; Nitroso Compounds/pharmacology ; Phagocytosis/drug effects ; Phagocytosis/immunology ; Pneumonia, Ventilator-Associated/drug therapy ; Pneumonia, Ventilator-Associated/immunology ; Pneumonia, Ventilator-Associated/microbiology ; Pseudomonas Infections/immunology ; Pseudomonas Infections/microbiology ; Pseudomonas Infections/prevention & control ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/immunology ; Pseudomonas aeruginosa/physiology ; RAW 264.7 Cells
Chemical Substances	Nitric Oxide Donors ; Nitroso Compounds ; 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (146724-94-9) ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2020-01-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2020.113817
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Zs.A 19: Show issues

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Article ; Online: The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

Sitapara, Ravikumar A / Gauthier, Alex G / Patel, Vivek S / Lin, Mosi / Zur, Michelle / Ashby, Charles R / Mantell, Lin L

Molecular medicine (Cambridge, Mass.)

2020 Volume 26, Issue 1, Page(s) 98

Abstract: Background: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises ... ...

Abstract	Background: Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. Method: GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O Results: The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O Conclusions: Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.
MeSH term(s)	Animals ; Benzylidene Compounds/pharmacology ; Disease Models, Animal ; HMGB1 Protein/metabolism ; Hyperoxia/diet therapy ; Hyperoxia/immunology ; Macrophages, Alveolar/drug effects ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Phagocytosis/drug effects ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa ; Pyridines/pharmacology ; RAW 264.7 Cells ; Ventilator-Induced Lung Injury/drug therapy ; alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors
Chemical Substances	Benzylidene Compounds ; HMGB1 Protein ; HMGB1 protein, mouse ; Pyridines ; alpha7 Nicotinic Acetylcholine Receptor ; 3-(2,4-dimethoxybenzylidene)anabaseine (8S399XDN2K)
Keywords	covid19
Language	English
Publishing date	2020-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1283676-x
ISSN	1528-3658 ; 1076-1551
ISSN (online)	1528-3658
ISSN	1076-1551
DOI	10.1186/s10020-020-00224-9
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