Comparative normal/failing rat myocardium cell membrane chromatographic analysis system for screening specific components that counteract doxorubicin-induced heart failure from Acontium carmichaeli.
Comparative normal/failing rat myocardium cell membrane chromatographic analysis system for screening specific components that counteract doxorubicin-induced heart failure from Acontium carmichaeli.
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DOI：
10.1021/ac500287e
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发表时间：
2014-05-20
影响因子：
7.4
通讯作者：
Chai, Yifeng
中科院分区：
文献类型：
--
作者：
Chen, Xiaofei;Cao, Yan;Zhang, Hai;Zhu, Zhenyu;Liu, Min;Liu, Haibin;Ding, Xuan;Hong, Zhanying;Li, Wuhong;Lv, Diya;Wang, Lirong;Zhuo, Xianyi;Zhang, Junping;Xie, Xiang-Qun;Chai, Yifeng
来源于病理组织的细胞膜色谱（CMC）是筛选复杂药物中作用于特定疾病的特定成分的理想方法，因为它最大限度地模拟了体内药物受体的相互作用。然而，目前还没有建立病理组织来源的CMC模型，也没有正常和病理CMC柱之间潜在活性成分的可视化亲和力比较。本研究基于在线选柱和综合二维色谱/整体柱/飞行时间质谱技术，建立了一种新型的正常/衰竭大鼠心肌CMC对比分析系统，以平行比较正常和病理CMC柱的色谱行为，并快速筛选乌头（Acontium carmichaeli, Fuzi）中抗阿霉素（DOX）诱导心力衰竭的特异性治疗药物。在正常和衰竭心肌CMC模型中，附子均保留了16种结构相似的潜在活性生物碱成分。除talatizamine （TALA）、14-乙酰TALA、hetisine、14-苯甲酰新碱4种成分外，其余各组对衰竭心肌CMC的亲和力均较正常CMC模型明显降低。分离出亲和力最高的一种化合物TALA，进一步进行体外药效学验证和靶标鉴定，验证筛选结果。电压依赖性K+通道被证实是TALA和14-乙酰-TALA的高亲和力结合靶点。在线高通量比较CMC分析方法可提高筛选结果的特异性，适用于草药中特定活性成分的筛选，也可应用于其他生物色谱模型。
Cell membrane chromatography (CMC) derived from pathological tissues is ideal for screening specific components acting on specific diseases from complex medicines owing to the maximum simulation of in vivo drug-receptor interactions. However, there are no pathological tissue-derived CMC models that have ever been developed, as well as no visualized affinity comparison of potential active components between normal and pathological CMC columns. In this study, a novel comparative normal/failing rat myocardium CMC analysis system based on online column selection and comprehensive two-dimensional (2D) chromatography/monolithic column/time-of-flight mass spectrometry was developed for parallel comparison of the chromatographic behaviors on both normal and pathological CMC columns, as well as rapid screening of the specific therapeutic agents that counteract doxorubicin (DOX)-induced heart failure from Acontium carmichaeli (Fuzi). In total, 16 potential active alkaloid components with similar structures in Fuzi were retained on both normal and failing myocardium CMC models. Most of them had obvious decreases of affinities on failing myocardium CMC compared with normal CMC model except for four components, talatizamine (TALA), 14-acetyl-TALA, hetisine, and 14-benzoylneoline. One compound TALA with the highest affinity was isolated for further in vitro pharmacodynamic validation and target identification to validate the screen results. Voltage-dependent K+ channel was confirmed as a binding target of TALA and 14-acetyl-TALA with high affinities. The online high throughput comparative CMC analysis method is suitable for screening specific active components from herbal medicines by increasing the specificity of screened results and can also be applied to other biological chromatography models.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
1.7
作者：
He, LC;Wang, SC;Geng, XD
通讯作者：
Geng, XD
影响因子：
2.2
作者：
Caballero, Norma Angelica;Melendez, Francisco Javier;Munoz-Caro, Camelia
通讯作者：
Munoz-Caro, Camelia
影响因子：
7.4
作者：
Adcock, Jacqui L.;Adams, Mike;Marriott, Philip J.
通讯作者：
Marriott, Philip J.
影响因子：
4.3
作者：
Du, Hui;Ren, Jing;He, Langchong
通讯作者：
He, Langchong