通过ROS介导的未折叠蛋白质反应激活在梅萨康尼丁诱导的肝损伤中驱动肝细胞亡
Jin Tian1, Yubin Zhuang2, Yinuo Liu1
1Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
Toxics
|March 26, 2025
概括
梅萨康尼丁 (MA) 通过增加氧化应激,炎症和内分泌网膜应激导致斑马鱼胚胎的剂量依赖性肝损伤,导致亡. 这项研究澄清了MA的MA.
科学领域:
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
- 发展生物学 发展生物学
背景情况:
- 梅萨康尼丁 (MA) 是一种来自Aconitum物种的类化合物,具有药理用途,但具有毒理风险,特别是肝毒性.
- 由于MA诱导的肝损伤的确切机制尚不清楚,因此需要进一步调查.
研究的目的:
- 使用斑马鱼胚胎阐明梅萨康尼丁 (MA) 诱导的肝毒性分子机制.
- 研究MA暴露对肝脏发育,氧化应激,炎症和亡的影响.
主要方法:
- 斑马鱼胚胎暴露于不同剂量的MA.
- 分析包括肝脏形态,基因表达 (肝脏特异性,炎症性,亡性,UPR相关),活性氧物种 (ROS) 水平和中性粒细胞透.
- 进行了全球转录组分析.
主要成果:
- MA诱导剂量依赖性肝毒性,减少肝脏大小和降低肝脏特异性基因 (tfa,cp,hhex,fabp10a) 的调节.
- 增加的ROS水平和中性粒细胞透表明氧化应激和炎症 (il1b,tnfa上调).
- 转录组分析显示,未展开的蛋白质反应 (UPR) 基因 (hsp90b1,hspa5,hspb9) 的上调,表明ER压力,导致了亡 (casp3a,casp3b,baxa上调).
结论:
- MA诱导的肝毒性包括氧化应激,内质网膜 (ER) 应激,UPR激活和随后的肝细胞亡.
- 这些发现为MA的毒理机制提供了洞察力,并建议Aconitum类化合物相关的肝损伤的潜在治疗点.
更多相关视频
10:50Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
933
08:04Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
Published on: October 23, 2018
18.7K
相关概念视频
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
01:37The Unfolded Protein Response
4.3K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.3K
01:32Export of Misfolded Proteins out of the ER
3.4K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.4K
01:16Necrosis
3.8K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
3.8K
01:46Electron Transport Chain: Complex I and II
9.8K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
9.8K
01:31The Intrinsic Apoptotic Pathway
5.8K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
5.8K