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首页> 外文期刊>Scientific reports. >Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment
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Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

机译:天然产物衍生物生物通过心脏微环境的独特调节促进心肌梗死后的恢复

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摘要

The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2'Z,3'E)-6-Bromoindirubin-3'-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI.
机译:心脏微环境包括心肌细胞,成纤维细胞和巨噬细胞,其调节心肌梗死后的重塑(MI)。靶向这种微环境是MI的新疗法方法。我们发现天然化合物衍生物,生物((2'Z,3'e)-6-溴林素-3'-肟)调节心脏微环境以对MI发挥治疗作用。使用一系列共培养研究,生物血细胞生物诱导的心肌细胞增殖并抑制心脏成纤维细胞的增殖。生物产生心肌成纤维细胞的多种抗纤维化作用。在巨噬细胞中,生物抑制了促炎因子的表达。显着地,生物调节心脏成纤维细胞之间的分子串扰,分化巨噬细胞以诱导抗炎M2表型的偏振。在光学透明的斑马鱼心力衰竭模型中,生物诱导心肌细胞增殖并完全回收存活率。生物是一种已知的糖原合酶激酶-3β抑制剂,但不能使用经典抑制剂,氯化锂重新携带这些效果;表明生物的新疗效。我们鉴定了BIO作为P27蛋白表达的差异调节的机制,抗炎白细胞介素-10的效力诱导。在大鼠MI模型中,生物减少纤维化和改善的心脏能。组织学分析揭示了Bio的心脏微环境的调节,增加了抗炎M2巨噬细胞的存在。我们的结果表明,生物生物在心脏微观环境中产生了独特的效果,以促进MI的恢复。

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