Al-Rabia Mohammed W, Asfour Hani Z, Mansouri Rasha A, Abdulaal Wesam H, Choudhry Hani, El-Agamy Dina S, Alhakamy Nabil A, Alrabea Rakan Nasser, Mosaoa Rami M, Mohamed Gamal A, Ibrahim Sabrin R M, Elshal Mahmoud
Department of Clinical Microbiology and Immunology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Clinical and Molecular Microbiology Laboratory, King Abdulaziz University Hospital, Jeddah, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
Department of Clinical Microbiology and Immunology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
Food Chem Toxicol. 2025 Jan;195:115129. doi: 10.1016/j.fct.2024.115129. Epub 2024 Nov 22.
The clinical use of 5-fluorouracil (5-FU) in cancer patients has been associated with nephrotoxicity, which is greatly curbing its therapeutic application. The pathogenesis of 5-FU-induced nephrotoxicity is complex; however, oxidative stress-mediated inflammation is considered a central pathogenic factor. Urolithin B (UB), a product of ellagitannins, has recently been assigned diverse pharmacological activities due to its potent antioxidant and anti-inflammatory properties. Therefore, the current study explored the potential renoprotective effect of UB on 5-FU-induced nephrotoxicity in mice and illuminated its potential mechanistic pathways. In this study, administration of UB (50 and 100 mg/kg) mitigated 5-FU-induced elevated levels of kidney injury indices, including renal somatic index, serum creatinine, blood urea nitrogen, and serum cystatin C, that were concurrent with histopathological improvement. UB maintained renal oxidant/antioxidant balance and enhanced the nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) as well as the silent information regulator factor 2-related enzyme 1 (SIRT1)/forkhead box O 3 (FOXO3) antioxidant protective responses. On the other hand, 5-FU-driven activation of the NF-кB/TNF-α inflammatory signaling was opposed by UB administration. Conclusively, UB protected against 5-FU-induced nephrotoxicity through dose-dependent antioxidant and anti-inflammatory effects. These effects are mediated mainly through upregulating Nrf2/HO-1 and SIRT-1/FOXO3 antioxidant responses with subsequent suppression of NF-κB inflammatory signaling.
5-氟尿嘧啶（5-FU）在癌症患者中的临床应用与肾毒性有关，这极大地限制了其治疗应用。5-FU诱导的肾毒性发病机制复杂；然而，氧化应激介导的炎症被认为是一个核心致病因素。尿石素B（UB）是鞣花单宁的产物，由于其强大的抗氧化和抗炎特性，最近被赋予了多种药理活性。因此，本研究探讨了UB对5-FU诱导的小鼠肾毒性的潜在肾脏保护作用，并阐明了其潜在的作用机制途径。在本研究中，给予UB（50和100mg/kg）可减轻5-FU诱导的肾脏损伤指标升高，包括肾脏体指数、血清肌酐、血尿素氮和血清胱抑素C，同时伴有组织病理学改善。UB维持肾脏氧化/抗氧化平衡，并增强核因子红细胞2相关因子2（Nrf2）/血红素加氧酶1（HO-1）以及沉默信息调节因子2相关酶1（SIRT1）/叉头框O 3（FOXO3）抗氧化保护反应。另一方面，UB给药对抗了5-FU驱动的NF-кB/TNF-α炎症信号激活。总之，UB通过剂量依赖性的抗氧化和抗炎作用保护小鼠免受5-FU诱导的肾毒性。这些作用主要通过上调Nrf2/HO-1和SIRT-1/FOXO3抗氧化反应，随后抑制NF-κB炎症信号来介导。
