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<p>Oncofertility is an emergent discipline that combines many strategies to preserve fertility for cancer patients who are at risk of becoming infertile due to the gonadotoxicity of therapy. Although paclitaxel (PTX) is frequently used as an antineoplastic, testicular damage is regretfully linked to its use. Sitagliptin (SIT) and mangiferin (MAN) have promising antioxidant, anti-inflammatory, and anti-apoptotic actions. Thus, the goal of this study is to explore the ameliorative impact of SIT, MAN, and their combination on the PTX-provoked testicular toxicity model. Testicular toxicity is triggered by a single dose of PTX (8&#xa0;mg/kg). Adult male albino rats were randomly classified into 5 equal groups: control, PTX, and PTX groups treated with SIT, MAN, or their combination for 14 days. The testes and epididymides were gathered for biochemical assessments and sperm analysis, respectively. Histopathological, ultrastructural, and immunohistochemical examinations of caspase-3, cleaved caspase-3, NLRP3, Nrf2, and Keap1 were investigated. Treated groups with SIT, MAN, or their combination significantly increased serum testosterone, testicular LDH-C content, sperm count, and motility compared to PTX group. Testicular catalase activity, Nrf2, and sestrin2 levels were significantly elevated compared to the PTX group. The treated groups counteracted the increase in serum ALP, ACP, LDH-C, testicular MDA, caspase-1, IL-1ꞵ, and IL-18 contents, NLRP3, Keap1, caspase-3, and cleaved caspase-3 expressions induced by PTX. Such therapeutic effects were more pronounced in combination than monotherapy. In conclusion, our study found that combining SIT and MAN had a remarkably beneficial impact on PTX-induced testicular toxicity by mediating the Sestrin2/Keap1/Nrf2 signaling pathway.</p>

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Combination of sitagliptin and mangiferin mitigates testicular damage induced by paclitaxel via mediating Sestrin2/Keap1/Nrf2 signaling pathway

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Kareman M. El-Beheiry,
  • Nagla A. El-Shitany,
  • Magda El-Sayed El-Sayad,
  • Alaa E. Elsisi

摘要

Oncofertility is an emergent discipline that combines many strategies to preserve fertility for cancer patients who are at risk of becoming infertile due to the gonadotoxicity of therapy. Although paclitaxel (PTX) is frequently used as an antineoplastic, testicular damage is regretfully linked to its use. Sitagliptin (SIT) and mangiferin (MAN) have promising antioxidant, anti-inflammatory, and anti-apoptotic actions. Thus, the goal of this study is to explore the ameliorative impact of SIT, MAN, and their combination on the PTX-provoked testicular toxicity model. Testicular toxicity is triggered by a single dose of PTX (8 mg/kg). Adult male albino rats were randomly classified into 5 equal groups: control, PTX, and PTX groups treated with SIT, MAN, or their combination for 14 days. The testes and epididymides were gathered for biochemical assessments and sperm analysis, respectively. Histopathological, ultrastructural, and immunohistochemical examinations of caspase-3, cleaved caspase-3, NLRP3, Nrf2, and Keap1 were investigated. Treated groups with SIT, MAN, or their combination significantly increased serum testosterone, testicular LDH-C content, sperm count, and motility compared to PTX group. Testicular catalase activity, Nrf2, and sestrin2 levels were significantly elevated compared to the PTX group. The treated groups counteracted the increase in serum ALP, ACP, LDH-C, testicular MDA, caspase-1, IL-1ꞵ, and IL-18 contents, NLRP3, Keap1, caspase-3, and cleaved caspase-3 expressions induced by PTX. Such therapeutic effects were more pronounced in combination than monotherapy. In conclusion, our study found that combining SIT and MAN had a remarkably beneficial impact on PTX-induced testicular toxicity by mediating the Sestrin2/Keap1/Nrf2 signaling pathway.