The Sponge-Derived Brominated Compound Aeroplysinin-1 Impairs the Endothelial Inflammatory Response through Inhibition of the NF-κB Pathway.

(+)-Aeroplysinin-1 (Apl-1) is a brominated compound isolated from the marine sponge Aplysina aerophoba that exhibits pleiotropic bioactive effects, impairing cell growth in cancer cells, inhibiting angiogenesis in vitro and in vivo and modulating the redox status of different cell types, among other reported activities. In addition to the aforementioned effects, the anti-inflammatory potential of this natural compound was explored in previous work of our laboratory, but the mechanism of action underlying this effect was not described. In this work, we delve into the anti-inflammatory effect of Apl-1 in the context of vascular endothelial cells in vitro, providing new data regarding the molecular mechanism underlying this activity. The characterization of the mechanism of action points to an inhibitory effect of Apl-1 on the NF-κB pathway, one of the main axes involved in endothelial response during inflammatory events. Our results show that Apl-1 can inhibit the expression of pro-inflammatory genes in tumor necrosis factor alpha (TNF-α)- and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), targeting the nuclear factor kappa B subunit (NF-κB) pathway through a mechanism of action involving the inhibition of I kappa B kinase (IKK) complex phosphorylation and RelA/p65 nuclear import. In addition, Apl-1 prevented the phosphorylation of Akt induced by TNF-α in HUVECs, probably supporting the inhibitory effect of this compound in the NF-κB pathway. Experimental evidence reported in this work opens the door to the potential pharmacological use of this compound as an anti-inflammatory agent in diseases that course with a pathological endothelial response to inflammation, such as atherosclerosis.

From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates.

Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to "hit the mark".