Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India.
Environ Toxicol. 2024 Nov;39(11):5124-5139. doi: 10.1002/tox.24388. Epub 2024 Aug 6.
Cadmium, a heavy metal, disrupts cellular homeostasis and is highly toxic, with no effective treatments currently available against its toxicity. According to studies, phytochemicals provide a promising strategy for mitigating cadmium toxicity. Naringenin (NG), a potent antioxidant found primarily in citrus fruits, showed protective properties against cadmium toxicity in rats. Nonetheless, the precise mechanism of cadmium cytotoxicity in fibroblasts remains unknown. This study evaluated NG against cadmium (CdCl) toxicity utilizing network pharmacology and in silico molecular docking, and was further validated experimentally in rat fibroblast F111 cells. Using network pharmacology, 25 possible targets, including the top 10 targets of NG against cadmium, were identified. Molecular docking of interleukin 6 (IL6), the top potential target with NG, showed robust binding with an inhibition constant (Ki) of 58.76 μM, supporting its potential therapeutic potential. Pathway enrichment analysis suggested that "response to reactive oxygen species" and "negative regulation of small molecules metabolic process" were the topmost pathways targeted by NG against cadmium. In vitro analysis showed that NG (10 μM) attenuated CdCl-induced oxidative stress by reducing altered intracellular ROS, mitochondrial mass, and membrane potential. Also, NG reversed CdCl-mediated nuclear damage, G2/M phase arrest, and apoptosis. GC/MS-based metabolomics of F111 cells revealed CdCl reduced cholesterol levels, which led to alterations in primary bile acid, steroid and steroid hormone biosynthesis pathways, whereas, NG restored these alterations. In summary, combined in silico and in vitro analysis suggested that NG protected cells from CdCl toxicity by mitigating oxidative stress and metabolic pathway alterations, providing a comprehensive understanding of its protective mechanisms against cadmium-induced toxicity.
镉是一种重金属，会破坏细胞内的稳态，具有高度毒性，目前尚无有效的解毒方法。根据研究，植物化学物质为减轻镉毒性提供了一种有前途的策略。柚皮素（NG）是一种主要存在于柑橘类水果中的强效抗氧化剂，已被证明对大鼠的镉毒性具有保护作用。然而，成纤维细胞中镉细胞毒性的确切机制尚不清楚。本研究利用网络药理学和计算机分子对接评估了 NG 对镉（CdCl）毒性的作用，并在大鼠成纤维细胞 F111 细胞中进行了实验验证。通过网络药理学，确定了 25 个可能的靶点，包括 NG 针对镉的前 10 个靶点。与 NG 结合的顶级潜在靶点白细胞介素 6（IL6）的分子对接显示与 NG 具有强大的结合能力，抑制常数（Ki）为 58.76 μM，支持其潜在的治疗潜力。通路富集分析表明，“对活性氧的反应”和“小分子代谢过程的负调控”是 NG 针对镉的最重要的通路。体外分析表明，NG（10 μM）通过降低细胞内 ROS、线粒体质量和膜电位的改变来减轻 CdCl 诱导的氧化应激。此外，NG 还逆转了 CdCl 介导的核损伤、G2/M 期阻滞和细胞凋亡。F111 细胞的 GC/MS 代谢组学分析表明，CdCl 降低了胆固醇水平，导致初级胆汁酸、类固醇和类固醇激素生物合成途径发生改变，而 NG 则恢复了这些改变。综上所述，体内和体外综合分析表明，NG 通过减轻氧化应激和代谢途径改变来保护细胞免受 CdCl 毒性，为其对镉诱导毒性的保护机制提供了全面的认识。
