The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abd El-Fattah E.E.; Saber S.; Mourad A.A.E.; El-Ahwany E.; Amin N.A.; Cavalu S.; Yahya G.; Saad A.S.; Alsharidah M.; Shata A.; Sami H.M.; Kaddah M.M.Y.; Ghanim A.M.H.

Journal: Biomedicine and Pharmacotherapy

Publisher: Elsevier Masson s.r.l.

Publication Date: March 2022

Volume / Issue: Volume 147

Article No.: 112628

ISSN: 7533322

DOI: 10.1016/j.biopha.2022.112628

Scopus: View on Scopus

PubMed: 35032769

Document Type: Article

Access: All Open Access; Gold Open Access

Authors and Affiliations

Abd El-Fattah E.E., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Mourad A.A.E., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt; Cavalu S., Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, Oradea, 410087, Romania; Yahya G., Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, Egypt; Saad A.S., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt; Alsharidah M., Department of Physiology, College of Medicine, Qassim University, Qassim, 51452, Saudi Arabia; Shata A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Sami H.M., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Kaddah M.M.Y., Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Alexandria, 21934, Egypt; Ghanim A.M.H., Department of Biochemistry, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt

Abstract

Acute lung injury (ALI) is one the most common causes of morbidity and mortality in critically ill patients. In this study, we examined for first time the role of dapagliflozin (DPGZ) in lipopolysaccharide (LPS)-induced ALI in rats and determined the underlying molecular mechanisms by evaluating the effects of DPGZ on adenosine monophosphate kinase (AMPK), nuclear transcription factor kappa B, nucleotide-binding and oligomerization domain-like receptor 3 inflammasome activation. Treatment of acute lung injured rats with either low dose (5 mg/kg) or high dose (10 mg/kg) DPGZ significantly decreased oxidative stress by decreasing malondialdehyde and nitric oxide tissue levels with a significant increase in spectrophotometric measurements of superoxide dismutase, catalase, and reduced glutathione levels. DPGZ treatment resulted in a significant anti-inflammatory effect as indicated by suppression in myeloperoxidase activity, MCP-1, IL-1β, IL-18, and TNF-α levels. DPGZ treatment also increased p-AMPK/t-AMPK with a significant reduction in NF-kB P65 binding activity and NFĸB p65 (pSer536) levels. These effects of DPGZ were accompanied by a significant reduction in NLRP3 levels and NLRP3 gene expression and a significant decrease in caspase-1 activity, which were also confirmed by histopathological examinations. We conclude that DPGZ antioxidant and anti-inflammatory activity may occur through regulation of AMPK/NFĸB pathway and inhibition of NLRP3 activation. These results suggest that DPGZ represents a promising intervention for the treatment of ALI, particularly in patients with type 2 diabetes. © 2022 The Authors

Keywords

AMPK; Dapagliflozin; LPS; Lung injury; NFκB; NLRP3; Acute Lung Injury; AMP-Activated Protein Kinases; Animals; Benzhydryl Compounds; Disease Models, Animal; Glucosides; Inflammation; Lipopolysaccharides; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; adenosine kinase; adenosine mono phosphate kinase; C reactive protein; catalase; cryopyrin; glutathione; interleukin 18; interleukin 1beta; lipopolysaccharide; malonaldehyde; myeloperoxidase; nitric oxide; nuclear transcription factor kappa B; oligomerization domain like receptor 3 inflammasome; peptides and proteins; superoxide dismutase; tumor necrosis factor; unclassified drug; benzhydryl derivative; glucoside; hydroxymethylglutaryl coenzyme A reductase kinase; immunoglobulin enhancer binding protein; AMPK signaling; animal cell; animal experiment; animal model; animal tissue; antidiabetic activity; Article; binding affinity; bronchoalveolar lavage fluid; colorimetry; controlled study; drug megadose; enzyme linked immunosorbent assay; histopathology; lipopolysaccharide-induced acute lung injury; low drug dose; non insulin dependent diabetes mellitus; nonhuman; oligomerization; oxidative stress; protein blood level; reverse transcription polymerase chain reaction; animal; chemistry; disease model; drug effect; metabolism; pharmacology; rat; Sprague Dawley rat

Citation Information

Scopus Citations: 89

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