Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt.
Department of Biochemistry, Faculty of Medicine, Minia University, Minia, Egypt.
Hum Exp Toxicol. 2020 Sep;39(9):1224-1234. doi: 10.1177/0960327120914977. Epub 2020 Mar 31.
Endometrial hyperplasia (EH) is a medical condition that affects many females as it increases their uterine carcinogenic potential. EH results from entangling hormonal imbalance and inflammatory response. The study examined the role of a xanthine oxidase inhibitor, febuxostat, in a rat model of EH. Adult female Wistar albino rats were subjected to estradiol valerate (EV) 2 mg/kg for 10 days to induce EH. Another group was treated concomitantly with febuxostat 10 mg/kg for the same period. The uterine malondialdehyde, reduced glutathione (GSH), and superoxide dismutase (SOD) were assessed by chemical methods. Gene expressions of phosphatidylinositol-3-kinase (PI3K), Akt, and hypoxia-inducible factor 1 alpha were assessed by the quantitative real-time polymerase chain reaction. Moreover, the vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. Histopathology and immunohistochemical techniques were used for the detection of phosphatase and tensin homolog (PTEN). The results revealed that EV administration induced complex EH with focal atypia and loss of PTEN expression by the histological examination. Uteri of the EV group showed a significant drop in GSH content and SOD activity and rise in the expressions of PI3K, Akt, VEGF, and IL-6. Febuxostat administration significantly improved the uterine GSH and SOD levels. It decreased the expressions of PI3K, Akt, VEGF, and IL-6. The endometrium showed a regression of the proliferative epithelium with the restoration of PTEN expression and the absence of the atypical features. In conclusion, febuxostat protected the endometrium against estrogen-induced EH and may be beneficial in the management along with the hormonal therapy.
子宫内膜增生症（EH）是一种影响许多女性的疾病，因为它增加了她们的子宫致癌潜力。EH 是由激素失衡和炎症反应引起的。本研究探讨了黄嘌呤氧化酶抑制剂非布司他在 EH 大鼠模型中的作用。成年雌性 Wistar 白化大鼠用戊酸雌二醇（EV）2mg/kg 处理 10 天以诱导 EH。另一组同时用非布司他 10mg/kg 治疗相同时间。通过化学方法评估子宫丙二醛、还原型谷胱甘肽（GSH）和超氧化物歧化酶（SOD）。通过定量实时聚合酶链反应评估磷脂酰肌醇-3-激酶（PI3K）、Akt 和缺氧诱导因子 1α的基因表达。此外，通过酶联免疫吸附试验测量血管内皮生长因子（VEGF）和白细胞介素 6（IL-6）。组织病理学和免疫组织化学技术用于检测磷酸酶和张力蛋白同源物（PTEN）。结果表明，EV 给药诱导了具有局灶性非典型性的复杂 EH，并通过组织学检查导致 PTEN 表达缺失。EV 组的子宫显示 GSH 含量和 SOD 活性显著下降，PI3K、Akt、VEGF 和 IL-6 的表达增加。非布司他给药可显著改善子宫 GSH 和 SOD 水平。它降低了 PI3K、Akt、VEGF 和 IL-6 的表达。子宫内膜显示增生上皮的退化，PTEN 表达恢复，无非典型特征。总之，非布司他可保护子宫内膜免受雌激素诱导的 EH 影响，并且可能对激素治疗有益。
