Abstract
Acute lung injury is characterized by alveolar-capillary barrier rupture, neutrophil-mediated airway inflammation, and tissue hypoxia. Since no effective pharmacotherapy is currently available, alternatives to improve its condition are mandatory. Recent studies demonstrated that curine, a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum (A.St.-Hil.) Miers, Menispermaceae, with anti-allergic and anti-inflammatory properties, inhibited lipopolysaccharide-mediated acute pulmonary response in mice. Therefore, this study aimed to investigate curine’s mechanism of action in a lipopolysaccharide-induced acute lung injury model. Curine inhibited the recruitment of inflammatory cells to the bronchoalveolar lavage fluid, mainly dependent on neutrophil migration, and restored the pulmonary architecture by reducing edema, vascular permeability, and the total protein content as well as the wet/dry ratio of the lung. Curine also decreased the TNF-α, IL-1β, and IL-6 production through downregulating the toll-like receptor 4 receptor expression and the nuclear factor-kappa B (p65) phosphorylation. In silico analysis demonstrated that curine made hydrophobic interactions with the Leu78, Ile80, Phe121, Ile124, Phe126, and Ile 152 amino acids of the hydrophobic cavity of the MD-2 receptor. This curine interaction presented stability during the simulation, remaining linked to the active site, indicating an antagonistic interaction with the molecular complex lipopolysaccharides/toll-likereceptor/4 myeloid differentiation factor 2.
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Funding
This study was sponsored by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES)- Finance Code 001 and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brasil).
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MRP, LAMPF, and LKDPF outlined and designed the experiments, wrote the original draft, and revised and edited the manuscript for submission. LAMPF and LKDPF performed the experimental model of ALI. LAMPF, LKDPF, and LML performed the ELISA protocol. LAMPF, LKDPF, and TMM performed the flow cytometry protocol. FAAFG performed the lung histology. MRP, LAMPF, and LKDPF analyzed the data. MSM and MTS performed the molecular docking and molecular dynamics simulations. JRF reviewed the manuscript. CSD was responsible for the alkaloid curine extraction and purification and made it available for the study. MRP was responsible for conceptualization, visualization, resources, funding acquisition, project administration, supervision, and writing—review and editing. All the authors have read the final manuscript and approved the submission.
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The authors declare that no experiments were performed on humans. All studies were conducted by following the guidelines of the National Animal Experimentation Control Council (CONCEA) and adhered strictly to the guidelines of the Brazilian Law (n°. 11.794/2008) which establishes rules for use and care of laboratory animals. The Committee on Ethics in Uses of Animals (CEUA/UFPB) approved the experimental procedures under certificate n° 7316150420. The used animals were purchased from the Animal Production Unit of the Institute for Research on Drugs and Medicines (IPeFarM) of the Federal University of Paraíba, João Pessoa, PB, Brazil.
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Paiva Ferreira, L.A.M., Paiva Ferreira, L.K.D., Monteiro, T.M. et al. Curine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Downregulating the TLR4/MD-2/NF-κB(p65) Signaling Pathway. Rev. Bras. Farmacogn. 32, 111–121 (2022). https://doi.org/10.1007/s43450-022-00230-4
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DOI: https://doi.org/10.1007/s43450-022-00230-4