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Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

ABSTRACT: 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:High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae 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.

SUBMITTER: Schimmel K

PROVIDER: S-EPMC7050799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsDiastolic dysfunction is common in geriatric heart failure. A reliable parameter to predict myocardium stiffness and relaxation under similar end-diastolic pressure is being developed. We propose a material and mathematical model for calculating myocardium stiffness based on the concept of linear correlation between [Formula: see text] and wedge pressure.Methods and resultsWe enrolled 919 patients (male: [Formula: see text][Formula: see text]). Compared with the younger population of controls (mean age: [Formula: see text] years; [Formula: see text]; male: [Formula: see text] [Formula: see text]), the elderly (mean age: [Formula: see text]; [Formula: see text]; male: [Formula: see text] [Formula: see text]) had a greater prevalence of hypertension, diabetes mellitus, and coronary artery disease (all [Formula: see text]). We collected their M-mode and 2-D echocardiographic volumetric parameters, intraventricular filling pressure, and speckle tracking images to establish a mathematical model. The feasibility of this model was validated. The average early diastolic velocity of the mitral annulus assessed using tissue Doppler imaging was significantly attenuated in the elderly ([Formula: see text]: [Formula: see text] vs. [Formula: see text]; [Formula: see text]) and corresponded to the higher estimated wedge ([Formula: see text]) pressure ([Formula: see text] vs. [Formula: see text]; [Formula: see text]) in that cohort. E (Young's modulus) was calculated to describe the tensile elasticity of the myocardium. With the same intraventricular filling pressure, E was significantly higher in the elderly, especially those with [Formula: see text] values [Formula: see text]. Compared with diastolic dysfunction parameters, E also presented sentinel characteristics more sensitive for detecting early myocardial relaxation impairment, which indicates stiffer myocardium in aging hearts.ConclusionOur material and geometric mathematical model successfully described the stiffer myocardium in aging hearts with higher intraventricular pressure. Additional studies that compare individual differences, especially in health status, are needed to validate its application for detecting diastolic heart failure.

Project description:Health organizations worldwide have warned that we are on the cusp of a "post-antibiotic era," necessitating new approaches to combat antibiotic resistant infections. One such approach is the development of antibiotic adjuvants, which have little or no inherent antibiotic activity at their active concentrations but instead potentiate the activity of antibiotics against antibiotic-resistant bacteria. Recently, we demonstrated that meridianin D, a natural product originally reported to have activity against Staphylococcus aureus and Mycobacterium tuberculosis, possesses the ability to reverse colistin resistance in colistin resistant bacteria. As most natural product screens typically involve screening for only certain activities (anticancer, antiviral, and antimicrobial are typical), we posited that the meridianin D discovery was not unique and there are potentially many natural products that have adjuvant activity. To explore this, the National Cancer Institute (NCI) Natural Product Library Set IV was screened for adjuvant activity using four classes of antibiotics (β-lactams, aminoglycosides, macrolides, and polymyxins) against three bacterial pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae). Sixteen compounds suppressed β-lactam resistance in MRSA, five of which effected a 16-fold reduction in the oxacillin minimum inhibitory concentration (MIC). Two natural products effectively suppressed aminoglycoside resistance in both of the Gram-negative species tested, and no hits were observed with macrolides. In contrast, a larger number of natural product adjuvants were identified when screening against colistin-resistant strains of A. baumannii and K. pneumoniae. Nine compounds reduced the colistin MIC to its breakpoint or lower (up to a 1024-fold reduction). Clorobiocin, novobiocin, and prodigiosin were most effective, reducing the colistin MIC in K. pneumoniae strain B9 to 2 μg/mL at concentrations as low as 0.625, 2.5, and 1.25 μM, respectively. Restored sensitivity to colistin with these compounds does not appear to coincide with known mechanisms of colistin resistance.

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Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

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