Hispaglabridin B, a constituent of liquorice identified by a bioinformatics and machine learning approach, relieves protein-energy wasting by inhibiting forkhead box O1
Hispaglabridin B, a constituent of liquorice identified by a bioinformatics and machine learning approach, relieves protein-energy wasting by inhibiting forkhead box O1
复制标题
Hispaglabridin B 是通过生物信息学和机器学习方法鉴定出的甘草成分，通过抑制叉头盒 O1 来减少蛋白质能量浪费。
DOI：
10.1111/bph.14508
复制
发表时间：
2019-01-01
影响因子：
7.3
通讯作者：
Lu, Lu
中科院分区：
文献类型：
--
作者：
Huang, Zeng-Yan;Wang, Ling-Jun;Lu, Lu
背景与目的甘草是欧洲流行的食品光滑甘草的根，中国此前已证明其具有改善骨骼疲劳和营养新陈代谢的作用。然而，其作用机制和有效成分在很大程度上仍不清楚。本研究旨在探讨甘草消瘦肌肉的有效成分，并阐明其作用机制。采用实验法、RNA-Seq法和生物信息学分析方法对甘草的主要指标进行预测。使用机器学习模型和对接工具来预测活性成分。采用同位素标记实验、免疫染色、免疫印迹、定量逆转录聚合酶链式反应、芯片聚合酶链式反应和荧光素酶报告等方法进行体内外药理实验。通过基于重组的过度表达验证了逆转效果。关键结果甘草脂溶成分通过抑制蛋白质分解代谢和纤维萎缩改善肌肉萎缩。我们进一步确定FoxO1为甘草脂溶成分的靶标。此外，组胺结合蛋白B(HB)被预测为FoxO1的抑制剂。进一步的研究确定，HB通过抑制体内和体外的分解代谢来改善肌肉消耗。Hb还显著抑制FoxO1的转录活性，肌肉特异性E3泛素连接酶MuRF1和Atrogin-1的表达减少。结论和启示Hb可以作为一种新的天然食物提取物，用于预防慢性肾脏疾病和其他可能的分解代谢疾病中的肌肉萎缩。
Background and Purpose Liquorice is the root of Glycyrrhiza glabra, which is a popular food in Europe and China that has previously shown benefits for skeletal fatigue and nutrient metabolism. However, the mechanism and active ingredients remain largely unclear. The aim of this study was to investigate the active ingredients of liquorice for muscle wasting and elucidate the underlying mechanisms. Experimental Approach RNA-Seq and bioinformatics analysis were applied to predict the main target of liquorice. A machine learning model and a docking tool were used to predict active ingredients. Isotope labelling experiments, immunostaining, Western blots, qRT-PCR, ChIP-PCR and luciferase reporters were utilized to test the pharmacological effects in vitro and in vivo. The reverse effects were verified through recombination-based overexpression. Key Results The liposoluble constituents of liquorice improved muscle wasting by inhibiting protein catabolism and fibre atrophy. We further identified FoxO1 as the target of liposoluble constituents of liquorice. In addition, hispaglabridin B (HB) was predicted as an inhibitor of FoxO1. Further studies determined that HB improved muscle wasting by inhibiting catabolism in vivo and in vitro. HB also markedly suppressed the transcriptional activity of FoxO1, with decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. Conclusions and Implications HB can serve as a novel natural food extract for preventing muscle wasting in chronic kidney disease and possibly other catabolic conditions.