RESUMEN
Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.
Asunto(s)
Aneurisma de la Aorta Torácica , Técnicas Biosensibles , Humanos , Aneurisma de la Aorta Torácica/tratamiento farmacológico , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , 2-Metoxiestradiol/metabolismo , Evaluación Preclínica de Medicamentos , Dispositivos Laboratorio en un Chip , Aorta/metabolismo , Aorta/patología , Digoxina , Dimetilpolisiloxanos , Factor 1 Inducible por Hipoxia/metabolismo , Músculo Liso/metabolismo , Músculo Liso/patologíaRESUMEN
Although the quinolizidine alkaloids and flavonoids, the main active components of the traditional Chinese medicine Sophora flavescens, have been largely investigated, a new matrine alkaloid derivative 9alpha-hydroxy-7,11-dehydromatrine (1) and a rare 1,4-diazaindan-type alkaloid flavascensine (17), together with 15 known alkaloids, were isolated from S. flavescens. The structures were established on the basis of spectroscopic techniques.