Erfan Omnia S, Sonpol Hany M A, Abd El-Kader Marwa
Anatomy and embryology department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Basic medical sciences department, College of Medicine, University of Bisha, Bisha, Saudi Arabia.
Anat Rec (Hoboken). 2021 Sep;304(9):1984-1998. doi: 10.1002/ar.24587. Epub 2021 Feb 2.
Acrylamide (ACRL) was demonstrated to induce hepatotoxicity and programmed cell death (PCD). Rapamycin (RAPA)-induced autophagy had been reported to limit the progression of hepatocellular injury in experimental models. This research was designed to study two death pathways involved in ACRL-induced hepatotoxicity and the modulating effect of RAPA on the resulting hepatic injury. Thirty-six adult male rats were divided into three groups: control group, ACRL-treated group (20 mg kg/day), and the last group co-treated with ACRL plus RAPA (0.5 mg kg/day). Drugs were administered for 21 days via oral gavage. Blood samples were collected to assess alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Livers were dissected; parts were used for detection of superoxide dismutase (SOD) and malondialdehyde (MDA) tissue levels. Other parts were processed for hematoxylin and eosin, Masson's trichrome staining, immunostaining for microtubule-associated proteins 1A/1B light chain 3B (LC3), ubiquitin-binding protein (p62), caspase-3, and receptor-interacting protein kinase 1 (RIPK1). ACRL induced a significant elevation in ALT, AST, MDA levels, and reduction in the SOD level. ACRL also induced hepatocellular injury, fibrosis, and defective autophagy indicated by elevation of LC3 and p62 and increased p62/LC3 ratio. Moreover, it increased the apoptotic (caspase-3) and necroptotic (RIPK1) markers expression. RAPA significantly reduced liver enzymes, oxidative stress, fibrosis, and improved liver histology. Moreover, RAPA decreased p62/LC3 ratio indicated enhanced autophagy, and significantly reduced caspase-3 and RIPK1 expression. In conclusion, RAPA maintained autophagic activity which may save the hepatocytes from PCD and enhance cell viability.
丙烯酰胺（ACRL）已被证明可诱导肝毒性和程序性细胞死亡（PCD）。据报道，雷帕霉素（RAPA）诱导的自噬可限制实验模型中肝细胞损伤的进展。本研究旨在探讨ACRL诱导肝毒性所涉及的两条死亡途径以及RAPA对由此导致的肝损伤的调节作用。将36只成年雄性大鼠分为三组：对照组、ACRL处理组（20毫克/千克/天）和最后一组ACRL与RAPA联合处理组（0.5毫克/千克/天）。通过灌胃给药21天。采集血样以评估丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）。解剖肝脏；部分用于检测超氧化物歧化酶（SOD）和丙二醛（MDA）的组织水平。其他部分进行苏木精和伊红染色、Masson三色染色、微管相关蛋白1A/1B轻链3B（LC3）、泛素结合蛋白（p62）、半胱天冬酶-3和受体相互作用蛋白激酶1（RIPK1）的免疫染色。ACRL导致ALT、AST、MDA水平显著升高，SOD水平降低。ACRL还诱导肝细胞损伤、纤维化和自噬缺陷，表现为LC3和p62升高以及p62/LC3比值增加。此外，它还增加了凋亡（半胱天冬酶-3）和坏死性凋亡（RIPK1）标志物的表达。RAPA显著降低了肝酶、氧化应激、纤维化，并改善了肝脏组织学。此外，RAPA降低了p62/LC3比值，表明自噬增强，并显著降低了半胱天冬酶-3和RIPK1的表达。总之，RAPA维持了自噬活性，这可能使肝细胞免受PCD并提高细胞活力。
