蛋白质酶活性抑制调解了三类/脂聚糖类诱导的肝毒性中的内 плазма网膜应激-亡
Ruohan Cheng1, Yihan Jiang1, Yue Zhang1
1Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China.
Cell biology and toxicology
|July 29, 2024
概括
ptolide和脂聚糖因激活内分泌网膜应激和反应性氧物种而诱导肝损伤,由蛋白质酶抑制加剧. N-乙半氨酸和4-甲酸显示有保护作用.
科学领域:
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 三化物 (TP),是Tripterygium wilfordii的组成部分. F. (TWHF),具有生物活性,但引起显著的肝毒性.
- 以前的研究表明TP诱导的肝损伤涉及在脂多糖 (LPS) 刺激下肝过敏.
- 由于TP/LPS引起的肝过敏的精确分子机制尚不完全理解.
研究的目的:
- 阐明TP/LPS诱导的肝过敏症的机制.
- 为了研究蛋白酶体活动抑制,内细胞网膜应激 (ERS) 相关的亡以及反应性氧物种 (ROS) 积累的作用.
主要方法:
- 研究了一种ROS抑制剂N-乙半氨酸 (NAC) 对TP/LPS诱导的肝毒性的影响.
- 利用4 - 酸 (4-PBA),一种ERS抑制剂,以评估其对TP/LPS诱导的肝损伤的影响.
- 在TP/LPS暴露的背景下,使用抑制剂MG-132检查了蛋白质酶活性的作用.
主要成果:
- 纳克治疗降低了裂开的caspase-3和裂开的PARP表达,表明减少了亡.
- 4-PBA通过降低与ERS相关的亡标志物 (GRP78,p-eIF2α/eIF2α,ATF4,CHOP,分裂的酶-3,分裂的PARP) 和ROS水平来减轻TP/LPS诱导的肝毒性.
- 转录因子ATF4被确定为4-PBA保护作用中的关键调解者.
- MG-132加剧了与ERS相关的亡,突出显示了蛋白质酶抑制对肝损伤的贡献.
结论:
- 通过抑制蛋白酶体活性,TP/LPS可能会诱导肝脏过敏症,导致ROS产量增加和ERS相关的亡.
- 在调解观察到的细胞反应和潜在的治疗干预中,ATF4起着至关重要的作用.
- 针对ROS和ERS通路提供了一个潜在的策略,以减轻TP/LPS诱导的肝毒性.
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