Institute of Cell Biophysics, the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 142290 Pushchino, Russia.
Prokhorov General Physics Institute, the Russian Academy of Sciences, 119991 Moscow, Russia.
Cells. 2023 Nov 28;12(23):2723. doi: 10.3390/cells12232723.
For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes caused by thioacetamide (TAA) injections and subsequent injections of selenium-containing nanoparticles and sorafenib have been proposed. We found that selenium nanoparticles of two types (doped with and without sorafenib) led to a significant decrease in almost all pro-fibrotic and pro-inflammatory genes. Sorafenib injections also reduced mRNA expression of pro-fibrotic and pro-inflammatory genes but less effectively than both types of nanoparticles. In addition, it was shown for the first time that TAA can be an inducer of ER-stress, most likely activating the IRE1α and PERK signaling pathways of the UPR, an inducer of apoptosis and pyroptosis. Sorafenib, despite a pronounced anti-apoptotic effect, still did not reduce the expression of caspase-3 and 12 or mitogen-activated kinase JNK1 to control values, which increases the risk of persistent apoptosis in liver cells. After injections of selenium-containing nanoparticles, the negative effects caused by TAA were leveled, causing an adaptive UPR signaling response through activation of the PERK signaling pathway. The advantages of selenium-containing nanoparticles over sorafenib, established in this work, once again emphasize the unique properties of this microelement and serve as an important factor for the further introduction of drugs based on it into clinical practice.
首次基于广泛的抗纤维化、抗炎和抗细胞凋亡基因以及内质网应激（ER-stress）的关键标志物的表达分析，提出了硫代乙酰胺（TAA）注射和随后注射含硒纳米粒子和索拉非尼的分子机制，调节纤维化和伴随的负过程。我们发现两种类型的硒纳米粒子（掺杂和不掺杂索拉非尼）导致几乎所有的促纤维化和促炎基因的表达显著下降。索拉非尼注射也降低了促纤维化和促炎基因的 mRNA 表达，但效果不如两种类型的纳米粒子。此外，首次表明 TAA 可以是 ER-stress 的诱导剂，很可能激活 UPR 的 IRE1α 和 PERK 信号通路，诱导细胞凋亡和细胞焦亡。尽管索拉非尼具有明显的抗细胞凋亡作用，但仍未能将 caspase-3 和 12 或丝裂原活化激酶 JNK1 的表达降低到对照值，从而增加了肝细胞持续凋亡的风险。注射含硒纳米粒子后，TAA 引起的负面影响得到了缓解，通过激活 PERK 信号通路引起适应性 UPR 信号反应。本研究中证实的含硒纳米粒子优于索拉非尼的优势，再次强调了这种微量元素的独特性质，并为进一步将基于该元素的药物引入临床实践提供了重要因素。
