Titanium nanostructure mitigating doxorubicin–induced testicular toxicity in rats via regulating major autophagy signaling pathways

Q1 Environmental Science
Rehab M. Abdel-Megeed, Abdel-Hamid Z. Abdel-Hamid, Mai O. Kadry
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引用次数: 0

Abstract

Doxorubicin (DOX) is a powerful antineoplastic FDA-approved anthracycline-derived antibiotic and is considered as the most suitable intervention for solid tumors and hematological cancers therapy. However, its therapeutic application is highly limited due to acute and chronic renal, hematological and testicular toxicity. Oxidative stress, lipid peroxidation and apoptosis in germ cells as well as low sperm count, motility and disturbing steroidogenesis are the principal machineries of DOX-induced testicular toxicity. Nevertheless, the comprehensive molecular pathways responsible for DOX-induced testicular damage are not yet fully understood. The current study aims to clarify the role of autophagy and apoptotic signaling pathways in testicular toxicity induced by DOX in the rat model. The study also investigates the potential role of both titanium dioxide nanoparticles (TiO2NP) loaded with DOX and Lactoferrin in combination with DOX in mitigating testicular toxicity induced by DOX the standard antitumor drug. In the present study, male Wister albino rats were intoxicated with a total cumulative dose of DOX (18 mg/kg) via intra-peritoneal injection and served as positive control group. The other two groups administered either TiO2NP-DOX or lactoferrin-DOX. Furthermore, biochemical and molecular analyses were then performed. DOX intoxication induced testicular toxicity, revealing mineral imbalance as indicated by an increase in both calcium and magnesium concentrations. Administration of either TiO2NP-DOX or lactoferrin-DOX resulted in a significant modulation of disrupted mineral concentrations, with TiO2NP-DOX showing superiority in modulating both magnesium and calcium concentrations. Acid Phosphatase level significantly increased upon DOX-induced testicular damage. Molecular analysis of EGFR and K-RAS gene expression showed significant overexpression, while p53 and JAK-2 gene expression was significantly reduced post-DOX intoxication. Protein expression of both AKT and PI3K significantly increased upon DOX administration. Results showed a remarkable modulation of all disrupted gene and protein expressions upon treatment with TiO2NP-DOX or Lactoferrin-DOX with the superiority of TiO2NP-DOX in modulating these parameters. In conclusion, TiO2NP-DOX could be a promising drug delivery system to improve bioavailability and drug release, as well as reducing DOX's adverse effects particularly on testicular function.
钛纳米结构通过调节主要自噬信号通路减轻阿霉素诱导的大鼠睾丸毒性。
多柔比星(DOX)是fda批准的一种强大的抗肿瘤蒽环类抗生素,被认为是实体肿瘤和血液学癌症治疗的最合适干预手段。然而,由于急性和慢性肾、血液和睾丸毒性,其治疗应用受到高度限制。生殖细胞的氧化应激、脂质过氧化和凋亡以及精子数量低、活力和类固醇生成紊乱是dox诱导睾丸毒性的主要机制。然而,dox诱导睾丸损伤的综合分子途径尚未完全了解。本研究旨在阐明自噬和凋亡信号通路在大鼠DOX致睾丸毒性模型中的作用。该研究还探讨了负载DOX和乳铁蛋白的二氧化钛纳米颗粒(TiO2NP)与DOX联合减轻标准抗肿瘤药物DOX诱导的睾丸毒性的潜在作用。本研究以雄性白化Wister大鼠腹腔注射DOX总累积剂量(18 mg/kg),作为阳性对照组。另外两组给予TiO2NP-DOX或乳铁蛋白- dox。然后进行生化和分子分析。DOX中毒引起睾丸毒性,显示钙和镁浓度增加所表明的矿物质失衡。服用TiO2NP-DOX或乳铁蛋白- dox均可显著调节被破坏的矿物质浓度,其中TiO2NP-DOX在调节镁和钙浓度方面表现出优势。dox致睾丸损伤后,酸性磷酸酶水平显著升高。分子分析显示EGFR和K-RAS基因表达明显过表达,而p53和JAK-2基因表达在dox中毒后显著降低。DOX处理后AKT和PI3K蛋白表达均显著升高。结果表明,用TiO2NP-DOX或乳铁蛋白- dox处理后,所有被破坏的基因和蛋白质的表达都有显著的调节,TiO2NP-DOX在调节这些参数方面具有优势。综上所述,TiO2NP-DOX可能是一种有前景的药物递送系统,可以提高生物利用度和药物释放,并减少DOX的不良反应,特别是对睾丸功能的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Toxicology Reports
Toxicology Reports Environmental Science-Health, Toxicology and Mutagenesis
CiteScore
7.60
自引率
0.00%
发文量
228
审稿时长
11 weeks
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