Resumen de Unveiling the therapeutic potential of labdane derivatives against dyslipidemia in lung diseases using network pharmacology and experimental validation
Andrea Pérez Montero, Alfonso Luque, Diego Megias Vazquez, Beatriz de las Heras Polo, Ana Estévez Braun, Paloma Acebo Pais, Sonsoles Hortelano Blanco
Lipid metabolism disturbance or dyslipidemia is common to several lung diseases. Characteristic lipid-laden alveolar macrophages emerge as a hallmark for these pathologies and constitute a new challenge for therapeutic development. In this study, we used an integrated strategy based on a combination of experimental studies and network pharmacology, to characterize a cell model of intracellular lipid accumulation based on lipid droplets (LDs) formation induced by oleic acid (OA)-treatment. This model allowed exploring the protective effects of two labdane derivatives: dehydroisohispanolone (DIH) and 8,9-dehydrohispanolone-15,16-lactol (DHHL). Initial viability assays determined non-cytotoxic concentrations for OA, 100 μM; DIH, 1 and 10 μM, or DHHL, 1 μM, which were selected for further experiments. Exposure of alveolar macrophages (MH-S cell line) to OA resulted in an increase in LDs generation and triglyceride (TG) accumulation. Cell treatment with DIH or DHHL resulted in inhibition against LDs formation in OA-treated MH-S cells. Furthermore, DIH showed higher efficient repression properties by preventing TG storage and decreasing the number and size of LDs in OA-treated MH-S cells. Next, potential targets of DIH were predicted through network pharmacology. Pathway enrichment analysis indicated that lipid and fatty acid metabolism as well as inflammatory response were the core pathway of DIH. Protein–protein interaction network analysis revealed that peroxisome proliferator-activated receptor-alpha (PPARα) might play critical roles due to its function as lipid sensor. Expression analysis confirmed that the protective effects of DIH against lipid accumulation were associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of genes involved in lipogenesis. Our work describes a novel methodology, OA-treated MH-S cells combined with bioinformatics tools, useful in preclinical research searching for new drugs against lipid-related lung diseases. Moreover, we also demonstrate that the labdane derivative DIH might be a potential therapeutic candidate for managing lipid homeostasis of dysfunctional alveolar macrophages.
