Gao Mengmeng, Ling Hao, Guo Chengxiang, Hu Yinan, Zhu Jing, Wang Jicang
College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
J Appl Toxicol. 2025 Aug 14. doi: 10.1002/jat.4895.
Cadmium, a bluish-white metallic, possesses a prolonged half-life in organisms, causing damage to multiple tissues and organs. Naringenin, a natural flavonoid antioxidant, mitigates cadmium-induced damage in organisms. However, the mechanism by which naringenin attenuates Cd-associated hepatocellular damage has not been fully elucidated. The present investigation consequently aimed to elucidate the mechanistic involvement of autophagy in cadmium hepatotoxicity using the rat model, with parallel assessment of naringenin's hepatoprotective efficacy. In this experiment, 24 SD rats underwent randomization to four experimental groups: (1) control (intraperitoneal saline injection), (2) Cd (1 mg/kg b.w. CdCl₂ intraperitoneal injection), (3) Cd + Nar (1 mg/kg b.w. CdCl₂ injection + 50 mg/kg b.w. naringenin oral gavage), and (4) Nar (50 mg/kg b.w. naringenin oral gavage) groups. After the 14-day interventions, serum and liver tissues were collected post-euthanasia. Hepatic injury markers (AST and ALT) and antioxidant enzymes (CAT and SOD) were quantified. Histopathology utilized HE and TUNEL staining. RT-qPCR and western blot analyses determined mRNA and protein expression levels of autophagy-related factors (p62 and LC3) and apoptosis-related factor (Caspase-3). The results demonstrated that cadmium exposure significantly reduced body weight, increased relative liver weight, elevated serum AST/ALT levels, and diminished hepatic CAT/SOD activity. Cadmium significantly upregulated both mRNA and protein expression levels of p62 and Caspase-3 while suppressing LC3 expression. Naringenin co-administration attenuated cadmium-induced hepatic injury, oxidative stress, impaired autophagy, and enhanced apoptosis. These findings collectively demonstrate that cadmium exposure induces hepatic injury and oxidative stress in rats through autophagy inhibition and apoptotic activation, while naringenin exerts protective effects by modulating these pathological processes.
镉是一种蓝白色金属，在生物体内具有较长的半衰期，会对多个组织和器官造成损害。柚皮素是一种天然的黄酮类抗氧化剂，可减轻镉对生物体的损害。然而，柚皮素减轻镉相关肝细胞损伤的机制尚未完全阐明。因此，本研究旨在利用大鼠模型阐明自噬在镉肝毒性中的作用机制，并同时评估柚皮素的肝脏保护功效。在本实验中，24只SD大鼠被随机分为四个实验组：(1)对照组（腹腔注射生理盐水），(2)镉组（腹腔注射1 mg/kg体重的CdCl₂），(3)镉+柚皮素组（注射1 mg/kg体重的CdCl₂ + 口服灌胃50 mg/kg体重的柚皮素），以及(4)柚皮素组（口服灌胃50 mg/kg体重的柚皮素）。经过14天的干预后，安乐死后收集血清和肝脏组织。对肝损伤标志物（AST和ALT）和抗氧化酶（CAT和SOD）进行定量分析。组织病理学采用HE和TUNEL染色。RT-qPCR和蛋白质印迹分析确定自噬相关因子（p62和LC3）和凋亡相关因子（Caspase-3）的mRNA和蛋白质表达水平。结果表明，镉暴露显著降低体重、增加肝脏相对重量、升高血清AST/ALT水平，并降低肝脏CAT/SOD活性。镉显著上调p62和Caspase-3的mRNA和蛋白质表达水平，同时抑制LC3表达。联合给予柚皮素可减轻镉诱导的肝损伤、氧化应激、自噬受损和凋亡增强。这些研究结果共同表明，镉暴露通过抑制自噬和激活凋亡诱导大鼠肝损伤和氧化应激，而柚皮素通过调节这些病理过程发挥保护作用。
