To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1 (IL-1 ), tumor necrosis factor (TNF-) and nuclear factor (NF-B). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.

中文翻译：

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非布索坦通过抑制 JAK/STAT 轴减轻睾酮诱导的大鼠良性前列腺增生


目的 研究非布索坦对大鼠睾酮诱导的良性前列腺增生 (BPH) 的可能调节作用，重点关注黄嘌呤氧化酶 (XO)/Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 轴。雄性Wistar大鼠用睾酮治疗，不加/不加非布索坦。通过组织病理学和前列腺重量/指数的测定，在结构水平上评估非布索坦对 BPH 的影响。通过免疫组织化学方法评估 Cyclin D1 蛋白表达，并通过实时聚合酶链式反应分析 (RT-PCR) 测定 Bax/Bcl-2 mRNA 表达的比率。此外，通过比色法测定血清尿酸水平。评估前列腺 XO 活性以及氧化应激和炎症标志物。此外，还进行了蛋白质印迹分析以确定组织中 JAK-1 和磷酸化形式的 STAT-3 的表达。结果显示，与睾酮治疗组相比，非布索坦抑制了前列腺重量和指数的增加。此外，非布索坦改善了睾酮诱导的组织病理学变化，阻止了细胞周期蛋白 D1 表达的上升并增强了 Bax/Bcl2 比率。非布索坦抑制睾酮诱导的前列腺 XO 活性和血清尿酸水平的增加。此外，它还调节氧化应激标志物，包括：丙二醛（MDA）、超氧化物歧化酶（SOD）活性和谷胱甘肽（GSH）含量。此外，它还能抑制前列腺中白细胞介素6（IL-6）、白细胞介素1（IL-1）、肿瘤坏死因子（TNF-）和核因子（NF-B）含量的增加。有趣的是，非布索坦显着降低了 JAK-1 和随后的 STAT-3 蛋白表达的磷酸化。 非布索坦通过抑制 XO/JAK/STAT 轴改善睾酮诱导的 BPH。这可能有助于重新调整 XO 抑制剂的用途。