黄素靶向FOXO3a、TLR2/MyD88/NF-κB级联和铁凋亡可改善铁诱导的肝毒性。

IF 3.6 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Trace Elements in Medicine and Biology Pub Date : 2025-09-16 DOI:10.1016/j.jtemb.2025.127758

Afnan Bakhsh , Samir A. Salama , Musaad M. Althobaiti , Shuruq E. Alsufyani , Abdullah M. Almalki , Samyah T. Alanazi

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引用次数: 0

摘要

背景：虽然微量铁是必需的，但铁含量过高会导致严重的健康问题。铁水平升高是血色素沉着症和贫血的继发性后果，需要频繁输血，导致器官毒性，特别是肝毒性。方法：本研究探讨了茶黄素对铁引起的肝毒性的潜在改善作用。建立雄性Wistar大鼠铁中毒模型，给予茶黄素10天。收集血液和肝脏标本，进行组织病理学、ELISA、生化和免疫印迹检测。结果：茶黄素抑制铁引起的肝损伤，表现为血清中肝细胞酶活性的显著降低和肝脏组织病理结构的改善。茶黄素激活抗氧化转录因子FOXO3a，上调其响应性抗氧化基因产物，包括硫氧还蛋白还原酶、超氧化物歧化酶和过氧化氢酶，同时减少DNA氧化修饰。同样重要的是，茶黄素抑制TLR2的炎症级联反应，这可以通过显著下调TLR2及其接头蛋白MyD88的蛋白表达，抑制其下游炎症转录因子NF-κB的磷酸化和核易位来证明。在相同的情况下，茶黄素显著降低NF-κ b反应性细胞因子TNF-α和IL-6的水平。有趣的是，茶黄素通过调节其生物标志物GPx4和COX-2蛋白表达、脂质氢过氧化物水平和肝细胞铁负荷来抑制铁诱导的肝细胞铁下垂。结论：这些发现强调了茶黄素对铁引起的肝毒性的改善作用，并揭示了FOXO3a、TLR2/MyD88/NF-κB级联和铁凋亡可能的分子靶点。

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Targeting FOXO3a, TLR2/MyD88/NF-κB cascade, and ferroptosis by theaflavin ameliorates iron-elicited liver toxicity

Background

While iron is essential in trace amounts, elevated level represents a serious health problem. Elevated iron level arises as a secondary consequence to hemochromatosis and anemias that necessitate frequent blood transfusions, leading to organ toxicity, particularly liver toxicity.

Methods

The current study investigated the potential ameliorating impact of theaflavin against the iron-elicited liver toxicity. A model of iron intoxication was established in male Wistar rats, and theaflavin was given over a 10-day period. Blood and liver specimens were collected and subjected to histopathological, ELISA, biochemical, and Western blotting investigations.

Results

Theaflavin suppressed the iron-evoked liver injury as indicated by a significant decrease in activity of the hepatocellular enzymes in sera and improved hepatic histopathological architecture. Theaflavin activated the antioxidant transcription factor FOXO3a with upregulation of its responsive antioxidant gene products including thioredoxin reductase, superoxide dismutase, and catalase, along with reduced DNA oxidative modification. Equally important, theaflavin suppressed TLR2 inflammatory cascade as evidenced by a significant downregulation in protein expression of TLR2 and its adaptor protein MyD88, and inhibition of phosphorylation and nuclear translocation of its downstream inflammatory transcription factor NF-κB. In the same context, theaflavin markedly reduced levels of NF-κB-responsive cytokines TNF-α and IL-6. Interestingly, theaflavin repressed the iron-elicited hepatocellular ferroptosis as indicated by modulation of its biomarkers GPx4 and COX-2 protein expression, and levels of lipid hydroperoxides and hepatocellular iron load.

Conclusion

These findings emphasize the ameliorating impact of theaflavin against the iron-elicited liver toxicity and shed light on FOXO3a, TLR2/MyD88/NF-κB cascade, and ferroptosis as possible molecular targets.

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来源期刊

Journal of Trace Elements in Medicine and Biology 医学-内分泌学与代谢

CiteScore

6.60

自引率

2.90%

发文量

202

审稿时长

85 days

期刊介绍： The journal provides the reader with a thorough description of theoretical and applied aspects of trace elements in medicine and biology and is devoted to the advancement of scientific knowledge about trace elements and trace element species. Trace elements play essential roles in the maintenance of physiological processes. During the last decades there has been a great deal of scientific investigation about the function and binding of trace elements. The Journal of Trace Elements in Medicine and Biology focuses on the description and dissemination of scientific results concerning the role of trace elements with respect to their mode of action in health and disease and nutritional importance. Progress in the knowledge of the biological role of trace elements depends, however, on advances in trace elements chemistry. Thus the Journal of Trace Elements in Medicine and Biology will include only those papers that base their results on proven analytical methods. Also, we only publish those articles in which the quality assurance regarding the execution of experiments and achievement of results is guaranteed.