基于比较毒基因组学数据库的新发现:肝脏YY1调解了药物诱导的肝损伤
Jin-Quan Zhao1, Yuan Sun1, Lu-Lu Yang1
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 639 Longmian Avenue, Nanjing 211198, China.
概括
转录因子YY1是药物诱导性肝损伤 (DILI) 的关键参与者,特别是在药物诱导的胆固醇酶中. 在肝脏中准YY1可能为管理DILI提供新的策略.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
背景情况:
- 转录因子YY1与肝脏疾病的发病有关.
- 它在药物诱导性肝损伤 (DILI) 中的特定作用被低估了.
- 了解YY1的功能对于解决DILI至关重要.
研究的目的:
- 阐明YY1在DILI发展中的作用.
- 研究YY1作为肝损伤的潜在治疗点.
主要方法:
- 查询了与YY1.1.交互的化合物的比较毒基因组学数据库 (CTD).
- 利用分子对接和表面等离子体共振 (SPR) 来评估结合亲和力.
- 研究了YY1在DILI中的作用,使用迪奥斯布尔B (DIOB) 和其他模型 (ANIT,LCA,APAP,CDDP).
- 采用转录基因分析和分子技术 (RT-qPCR,西部涂抹) 来发现机制.
主要成果:
- 在CTD中影响YY1表达的94种化合物中,59种是肝毒性,具有强烈的YY1.1结合.
- SPR证实了肝毒性化合物的强有力的结合,包括FDA批准的药物.
- 通过DIOB对YY1的上调抑制了FXR,BSEP和MRP2,导致胆固醇性肝损伤.
- 确定YY1是药物诱导胆固醇衰竭 (DIC) 和潜在的其他DILI类型的调解者.
结论:
- YY1在很大程度上介导了药物诱导胆固醇症 (DIC) 的发展.
- YY1也可能参与肝细胞和混合类型的DILI.
- 准肝脏YY1为管理DILI提供了一个新的治疗策略.
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