Naringenin Against Cadmium Toxicity in Fibroblast Cells: An Integrated Network Pharmacology and In Vitro Metabolomics Approach

IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Environmental Toxicology Pub Date : 2024-08-06 DOI:10.1002/tox.24388
Komal Priya, Ashim Chandra Roy, Abhinav Prasad, Prabhat Kumar, Ilora Ghosh
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Abstract

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 (CdCl2) 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 CdCl2-induced oxidative stress by reducing altered intracellular ROS, mitochondrial mass, and membrane potential. Also, NG reversed CdCl2-mediated nuclear damage, G2/M phase arrest, and apoptosis. GC/MS-based metabolomics of F111 cells revealed CdCl2 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 CdCl2 toxicity by mitigating oxidative stress and metabolic pathway alterations, providing a comprehensive understanding of its protective mechanisms against cadmium-induced toxicity.

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柚皮苷对抗成纤维细胞的镉毒性:综合网络药理学和体外代谢组学方法。
镉是一种重金属,会破坏细胞的稳态,具有很强的毒性,目前还没有针对其毒性的有效治疗方法。研究表明,植物化学物质为减轻镉毒性提供了一种有前景的策略。柚皮苷(NG)是一种主要存在于柑橘类水果中的强效抗氧化剂,对大鼠的镉毒性具有保护作用。然而,镉对成纤维细胞细胞毒性的确切机制仍不清楚。本研究利用网络药理学和硅学分子对接评估了 NG 对镉(CdCl2)毒性的作用,并在大鼠成纤维细胞 F111 中进行了进一步的实验验证。通过网络药理学,确定了 25 个可能的靶点,包括 NG 抗镉的前 10 个靶点。白细胞介素6(IL6)是NG的头号潜在靶点,其与NG的分子对接显示出强大的结合力,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 "对小分子代谢过程的负调控 "是 NG 针对镉的最主要通路。体外分析表明,NG(10 μM)通过减少细胞内 ROS、线粒体质量和膜电位的改变,减轻了 CdCl2 诱导的氧化应激。此外,NG 还能逆转 CdCl2-介导的核损伤、G2/M 期停滞和细胞凋亡。基于 GC/MS 的 F111 细胞代谢组学显示,氯化镉降低了胆固醇水平,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。总之,结合硅学和体外分析表明,NG 可通过减轻氧化应激和代谢途径的改变来保护细胞免受氯化镉毒性的伤害,从而提供了对镉诱导毒性的保护机制的全面了解。
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来源期刊
Environmental Toxicology
Environmental Toxicology 环境科学-毒理学
CiteScore
7.10
自引率
8.90%
发文量
261
审稿时长
4.5 months
期刊介绍: The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.
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