Cyclophosphamide (CP) is one of the most potent alkylating agents and is widely used in the treatment of numerous neoplastic conditions, autoimmune diseases and following organ transplantation. Due to its ability to induce oxidative stress and subsequent apoptosis, CP is affiliated with many adverse effects with special emphasis on the highly prevalent hepatotoxicity. Dipeptidyl peptidase 4 (DDP-IV) inhibitors are being rediscovered for new biological effects due to their ability to target multiple pathways, among which is the phosphoinositide 3–kinase (PI3K) and protein kinase B (Akt) axis. This could offer protection to multiple organs against reactive oxygen species (ROS) through modulating sirtuin 1 (SIRT1) expression and, in turn, inactivation of forkhead box transcription factor of the O class 1 (FoxO1), thus inhibiting apoptosis. Accordingly, the current study aimed to investigate the potential therapeutic benefit of alogliptin (Alo), a DPP-IV inhibitor, against CP-induced hepatotoxicity through enhancing PI3K/Akt/SIRT1 pathway. Forty male Wistar rats were randomly divided into four groups. The CP-treated group received a single dose of CP (200 mg/kg; i.p.). The Alo-treated group received Alo (20 mg/kg; p.o.) for 7 days with single CP injection on Day 2. Alo successfully reduced hepatic injury as witnessed through decreased liver function enzymes, increased phospho (p)-PI3K, p-Akt, superoxide dismutase (SOD) levels, SIRT1 expression, p-FoxO1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2). This resulted in decreased apoptosis, as witnessed through decreased caspase-3 levels and improved histopathological picture. In conclusion, the current study succeeded to elaborate, for the first time, the promising impact of Alo in ameliorating chemotherapy-induced liver injury.

中文翻译：

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阿格列汀：一种通过调节 SIRT1/FoxO1 通路对抗环磷酰胺诱导的肝损伤的新方法。

环磷酰胺 (CP) 是最有效的烷化剂之一，广泛用于治疗多种肿瘤疾病、自身免疫性疾病和器官移植后。由于其能够诱导氧化应激和随后的细胞凋亡，CP 与许多不良反应有关，特别强调高度普遍的肝毒性。由于二肽基肽酶 4 (DDP-IV) 抑制剂能够靶向多种途径，其中包括磷酸肌醇 3-激酶 (PI3K) 和蛋白激酶 B (Akt) 轴，因此重新发现其具有新的生物学效应。这可以通过调节沉默调节蛋白 1 (SIRT1) 的表达，进而使 O 类 1 (FoxO1) 的叉头盒转录因子失活，从而为多个器官提供针对活性氧 (ROS) 的保护，从而抑制细胞凋亡。因此，目前的研究旨在通过增强 PI3K/Akt/SIRT1 通路来研究 DPP-IV 抑制剂阿格列汀 (Alo) 对 CP 诱导的肝毒性的潜在治疗益处。40 只雄性 Wistar 大鼠随机分为四组。CP 治疗组接受单剂量的 CP (200 mg/kg; ip)。Alo 治疗组接受 Alo (20 mg/kg; po) 7 天，第 2 天单次注射 CP。 Alo 成功减少了肝损伤，如肝功能酶降低、磷酸 (p)-PI3K、p-Akt 增加所见证的、超氧化物歧化酶 (SOD) 水平、SIRT1 表达、p-FoxO1 和抗凋亡 B 细胞淋巴瘤 2 (Bcl-2)。这导致细胞凋亡减少，正如通过降低 caspase-3 水平和改善组织病理学图片所证明的那样。总之，目前的研究成功地阐述了，