Key result
Bufalin and lycorine were identified as effective antifibrotic molecules in vitro and in vivo, leading to improvement in diastolic function in rodent models of cardiac fibrosis.
Why the study?
No clinical therapeutic strategy specifically attenuates maladaptive responses of cardiac fibroblasts, prompting the aim to develop novel antifibrotic therapeutics from naturally derived substance library screens.
Do bufalin and lycorine reduce cardiac fibrosis and improve diastolic function in preclinical models?
Do bufalin and lycorine reduce cardiac fibrosis and improve diastolic function in preclinical models?
Bufalin and lycorine are promising natural compound candidates that attenuate cardiac fibrosis and improve diastolic function in preclinical models via microRNA 671-5p and selenoprotein P1.
Bufalin and lycorine merit translation studies in larger models; hypothesis-generating for antifibrotic therapy in diastolic dysfunction pending human trials.
BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. METHODS: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. RESULTS: species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. CONCLUSIONS: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.
No takes yet. Share an insight, caveat, or question.
Schimmel et al. (2020) studied Cardiac fibrosis and diastolic dysfunction. Bufalin and lycorine was evaluated on Inhibition of proliferation, modulation of apoptosis, extracellular matrix expression, and improvement in diastolic function. Bufalin and lycorine were identified as effective antifibrotic molecules in vitro and in vivo, leading to improvement in diastolic function in rodent models of cardiac fibrosis.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: