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1.
Int J Biol Macromol ; 182: 743-749, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1163841

ABSTRACT

The development of high-end targeted drugs and vaccines against modern pandemic infections, such as COVID-19, can take a too long time that lets the epidemic spin up and harms society. However, the countermeasures must be applied against the infection in this period until the targeted drugs became available. In this regard, the non-specific, broad-spectrum anti-viral means could be considered as a compromise allowing overcoming the period of trial. One way to enhance the ability to resist the infection is to activate the nonspecific immunity using a suitable driving-up agent, such as plant polysaccharides, particularly our drug Panavir isolated from the potato shoots. Earlier, we have shown the noticeable anti-viral and anti-bacterial activity of Panavir. Here we demonstrate the pro-inflammation activity of Panavir, which four-to-eight times intensified the ATP and MIF secretion by HL-60 cells. This effect was mediated by the active phagocytosis of the Panavir particles by the cells. We hypothesized the physiological basis of the Panavir proinflammatory activity is mediated by the indol-containing compounds (auxins) present in Panavir and acting as a plant analog of serotonin.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Drug Carriers , Nanoparticles , Plants/chemistry , Polysaccharides , Probucol , Adolescent , Adult , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , HL-60 Cells , Humans , Male , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Phagocytosis/drug effects , Polysaccharides/chemistry , Polysaccharides/pharmacology , Probucol/chemistry , Probucol/pharmacokinetics , Probucol/pharmacology
2.
Mol Med ; 26(1): 98, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-894987

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% O2) and subsequently challenged with PA. 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% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. 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.


Subject(s)
Benzylidene Compounds/pharmacology , Hyperoxia/immunology , Macrophages, Alveolar/drug effects , Pseudomonas Infections/drug therapy , Pyridines/pharmacology , Ventilator-Induced Lung Injury/drug therapy , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors , Animals , Disease Models, Animal , HMGB1 Protein/metabolism , Hyperoxia/diet therapy , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Male , Mice , Mice, Inbred C57BL , Phagocytosis/drug effects , Pseudomonas aeruginosa , RAW 264.7 Cells
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