FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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Like apelin (pE13F, K17F), Elabela/Toddler is an endogenous ligand of the apelin receptor playing a key role in cardiovascular development. Elabela/Toddler exists as peptide fragments of 32 (Q32P), 22 (K22P) and 11 (C11P) amino acids. In this study, we investigated the possible structural and functional similarities between these endogenous ligands. ⋯ We showed that Asp282 and Asp284 of rat and human apelin receptor, respectively, were not involved in Elabela/Toddler activity, whereas they are key residues for apelin binding and activity. We found that the structural features of Elabela/Toddler and apelin were different, resulting in different modes of binding of these endogenous ligands to the apelin receptor. These differences should be taken into account in the future development metabolically stable analogs of Elabela/Toddler and apelin as potential therapeutic tools for the treatment of cardiovascular diseases and water retention/hyponatremic disorders.
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Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. ⋯ Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.
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Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause that is characterized by progressive fibrotic lung remodeling. An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is often observed in IPF. However, the origin of this dysfunctional distal lung epithelium remains unknown due to a lack of suitable human model systems. ⋯ Stimulation with IPF-RC during differentiation increases secretion of IPF biomarkers and RNA sequencing (RNA-seq) of these cultures reveals significant overlap with human IPF patient data. IPF-RC treatment further impairs ATII differentiation by driving a shift toward an airway epithelial-like expression signature, providing evidence that a pro-fibrotic cytokine environment can influence the proximo-distal differentiation pattern of human lung epithelial cells. In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization of the lung epithelium in vitro.