作者: Angelo, Ana Luiza Pessoa Mendonça ; Cassali, Geovanni D. ; Miller, Leigh M ; de Gaetano, Monica ; Duray, Alexis M ; Alcorn, John F ; Rago, Flavia ; Batista Felix, Franciel ; Godson, Catherine ; Owen, Benjamin ; Teixeira, Mauro Martins ; Alcorn, John F. ; Miller, Leigh M. ; Vago, Juliana Priscila ; Duray, Alexis M. ; de Faria Gonçalves, Ana Paula ; Melo, Eliza Mathias ; Cassali, Geovanni D ; Brennan, Eoin ; Guiry, Patrick

INTRODUCTIONInfluenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming.OBJECTIVEHere, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.METHODMice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 μg/kg/day, i.p.) at day 3 post-infection.RESULTSAT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 ^-/- animals. In mice treated with LXA₄ (50 μg/kg/day, i.p., days 3-6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice.CONCLUSIONTherefore, treatment with a lipoxin A₄ analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.

2024-10-08·Current Medicinal Chemistry

Lipidomics in Periodontal Disease Research: A Systematic Review

Article

作者: Dias, Isabel ; Domingues, Rosário ; Peixoto, Francisco ; Viegas, Carlos ; Silva, Carolina

Introduction/Objective:Periodontal disease is a highly prevalent oral pathology in the human population, which has a significant local and systemic impact. Currently, multi-omics analyses, including lipidomics, are fundamental to obtaining an in-depth molecular understanding of the individual. Lipidomics is dedicated to the study of lipid species and their interactions in various health contexts. This specific multi-omics analysis is important for understanding the alteration of metabolism and signaling in disease, identifying biochemical markers, and potential therapeutic targets. This study aimed to carry out a systematic review of the existing scientific literature on lipidomics in periodontal disease and thus determine which molecules have already been analyzed and their potential in this specific disease.Methods:This study followed the recommendations of the PRISMA 2020 methodology. The inclusion criteria used were articles published in indexed journals between 2000 and 2023, written in English, and establishing an exclusive relationship about lipidomics in human periodontal disease. The articles were searched in three different databases.Results:Considering the criteria defined, only six articles were selected and zed individually in detail. In four of the six studies, differences in the lipidome of individuals with periodontal disease were identified. Furthermore, phosphoethanolamine ceramide was found to have potential as a diagnostic biomarker. Finally, the therapeutic potential of a lipoxin A4 analogue was also identified.Conclusion:These results reinforce the need for future research in this area so that the consequences of this disease on the lipidome can be identified.

2024-10-01·Experimental Cell Research

Lipoxin A4 modulates the PKA/CREB and NF-κB signaling pathway to mitigate chondrocyte catabolism and apoptosis in temporomandibular joint osteoarthritis

Article

作者: Sun, Jiadong ; Zhao, Ke ; Ou, Farong ; Tuerxun, Palati ; Jia, Xiaoshi ; Ng, Takkun ; Zhu, Ping

Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by the degradation of the extracellular matrix (ECM) in cartilage and the apoptosis of chondrocytes, which is caused by inflammation and disruptions of chondrocyte metabolism and inflammation. Lipoxin A4 (LXA4), a specialized pro-resolving mediator, has been shown to inhibit inflammation and regulate the balance between ECM synthesis and degradation. However, the therapeutic effects of LXA4 on TMJ-OA and its underlying mechanisms remain unclear. Interleukin-1 beta (IL-1β)-induced chondrocyte and surgically induced TMJ-OA rat models were established in this study. The viability of chondrocytes treated with LXA4 was evaluated with the cell counting kit-8 (CCK-8) assay, while protein levels were assessed by western blot analysis, and the apoptosis rate was evaluated with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Histological analysis was conducted to evaluate the impact of LXA4 on cartilage degradation in TMJ-OA rat models. In vitro, the qRT-PCR and western blot analysis demonstrated that LXA4 facilitated the upregulation of collagen proteins (Collagen II) and decreased expression of matrix metalloproteinases (MMP-3, and MMP-13) associated with ECM modulation. LXA4 enhanced the TMJ-OA chondrocyte viability and decreased apoptotic rate. In vivo, histology and immunohistochemistry (IHC) analysis revealed that intraperitoneal injection of LXA4 contributed to the amelioration of chondrocyte injuries and deceleration of TMJ-OA. Transcriptomic sequencing revealed that cAMP signaling pathway was up-regulated and NF-κB signaling pathway was down-regulated in LXA4 treated group. LXA4 inhibited the phosphorylation of P65 and inhibitor of nuclear factor kappa B (IκBα) proteins while enhancing the phosphorylation PKA and CREB. This study demonstrates the potential of LXA4 as a therapeutic agent for suppressing chondrocyte catabolism and apoptosis by increasing PKA/CREB activity and decreasing NF-κB signaling.

100 项与 Lipoxin A4 analogs 相关的药物交易

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