Life sciences · 2024
Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation.
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Pereira-Silva Gean C, Cornélio Cassia K C A, Pacheco Gabriella, Rochael Natalia C, Gomes Isaac A B, Cajado Aurilene G, Silva Katriane C, Gonçalves Barbara Simonson, Temerozo Jairo R, Bastos Ruan S, Rocha Jefferson A, Souza Leonardo P, Souza Marcellus H L P, Lima-Júnior Roberto C P, Medeiros Jand V R, Filgueiras Marcelo C, Bou-Habib Dumith Chequer, Saraiva Elvira M, Nicolau Lucas A D
Аннотация
AIMS: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE).
MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.