Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, El Ismailia, Egypt; Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt.
Life Sci. 2021 Mar 15;269:119031. doi: 10.1016/j.lfs.2021.119031. Epub 2021 Jan 13.
Cadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways.
The testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks.
Sitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx.
Sitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways.
镉（Cd）是一种普遍存在的环境污染物，会对健康造成有害影响，包括睾丸损伤。西他列汀是一种选择性二肽基肽酶-4（DPP-4）抑制剂，已显示出明显的心脏、肝脏和肾脏保护作用，然而，其对 Cd 引起的睾丸功能障碍的影响尚未被研究。因此，本研究旨在探讨西他列汀对 Cd 诱发的睾丸损伤的可能有益影响，这可能增加其潜在的临床应用。探讨了睾丸自噬和凋亡平衡的潜在机制，包括 AMPK/mTOR 和 Nrf2/HO-1 途径。
使用组织病理学、免疫组织化学、Western blot 和 ELISA 检查睾丸组织。西他列汀（10mg/kg/天，灌胃）连续给药 4 周。
西他列汀通过改善相对睾丸重量、精子计数/活力、精子畸形和血清睾酮来减轻睾丸损伤。此外，西他列汀对抗 Cd 引起的组织学异常/破坏的生精作用。有趣的是，西他列汀通过上调 Beclin 1 蛋白表达和降低 p62 SQSTM1 蛋白积累来增强受损的自噬。这些作用是通过激活睾丸 AMPK/mTOR 途径介导的，如增加 p-AMPK（Ser485，Ser491）/总 AMPK 和减少 p-mTOR（Ser2448）/总 mTOR 蛋白表达所示。此外，西他列汀通过下调 Bax 和上调 Bcl-2 蛋白表达来抑制睾丸凋亡事件。同时，西他列汀通过降低脂质过氧化物和激活 Nrf2/HO-1 途径来抑制睾丸的氧化应激，通过上调 Nrf2、下游效应物 HO-1 和 GPx 的蛋白表达。
西他列汀通过激活 AMPK/mTOR 和 Nrf2/HO-1 途径，增强自噬/凋亡比值，减轻 Cd 诱导的睾丸损伤。
