RESUMO
Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch's membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Calcinose/genética , Calcinose/patologia , Fibrose/genética , Fibrose/patologia , Proteínas de Peixe-Zebra/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Olho/metabolismo , Olho/patologia , Predisposição Genética para Doença , Mutação , Miocárdio/metabolismo , Miocárdio/patologia , Vitamina K/metabolismo , Vitamina K/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
As a part of our ongoing search for plant-derived compounds that inhibit nitric oxide production, the methanol extract of the roots of Vladimiria souliei was found to show significant inhibitory effects on INF-γ-induced nitric oxide production in murine macrophage RAW264.7 cells. Bioactivity-guided isolation of the extract yielded two most active sesquiterpenes, including a new compound, named souliene A (1) and alismol (2). Their structures were elucidated by spectroscopic methods (IR, ESIMS, HRESIMS, 1D and 2D NMR). Two isolates showed promising inhibitory effects on INF-γ-induced nitric oxide production in murine macrophage RAW264.7 cells.