Althunibat Osama Y, Abukhalil Mohammad H, Khwaldeh Alia, Abu-Zaiton Ahmed, Al-Fawaeir Saad
Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Jadara University, Irbid, 21110, Jordan.
Department of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an, 71111, Jordan.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 28. doi: 10.1007/s00210-025-04396-1.
Gentamicin (GEN), an antibiotic belonging to aminoglycosides, is commonly administered to treat gram-negative bacterial infections. However, GEN nephrotoxicity restricts its therapeutic applications. The study examined the nephroprotective efficiency of a plant flavonoid (Taxifolin, TX) against GEN-associated renal damage in mice. Oral administration of TX (25 or 50 mg/kg/day) in mice for 14 days was followed by intraperitoneal GEN (100 mg/kg/day) treatments from the 8th to 14th day. GEN-treated mice were characterized by higher creatinine and urea levels in the serum and significant renal histopathological modifications. They also presented elevated malondialdehyde (MDA) and protein carbonyl and decreased levels of reduced glutathione (GSH) and activities of catalase (CAT), and superoxide dismutase (SOD). TX effectively improved renal function and antioxidant potential while simultaneously lowering MDA and protein carbonyl levels in GEN-administered mice. Furthermore, TX suppressed the renal expressions of nuclear factor kappa B (NF-κB) p65 and decreased levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in GEN-treated mice. GEN treatment increased caspase-3 and Bcl-2 associated X (Bax) and reduced B-cell lymphoma-2 (Bcl-2) protein levels in mouse kidneys. These effects were significantly mitigated by TX treatment. GEN administration significantly suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein levels in mouse kidneys. Largely, TX restored renal Nrf2 and HO-1 protein levels, as evidenced by immunohistochemistry and ELISA analyses, respectively, in GEN-treated mice. Overall, TX provided nephroprotection against GEN-induced kidney damage via modulation of oxidative stress, inflammation, and apoptosis and restoration of Nrf2 signaling. Thus, TX could be a promising adjuvant candidate to prevent drug-linked organ injury.
庆大霉素（GEN）是一种氨基糖苷类抗生素，常用于治疗革兰氏阴性菌感染。然而，GEN的肾毒性限制了其治疗应用。本研究考察了一种植物类黄酮（紫杉叶素，TX）对小鼠GEN相关性肾损伤的肾保护效果。小鼠口服TX（25或50毫克/千克/天），持续14天，随后在第8天至第14天腹腔注射GEN（100毫克/千克/天）。GEN处理的小鼠血清肌酐和尿素水平较高，肾脏出现明显的组织病理学改变。它们还表现出丙二醛（MDA）和蛋白质羰基水平升高，还原型谷胱甘肽（GSH）水平和过氧化氢酶（CAT）及超氧化物歧化酶（SOD）活性降低。TX有效改善了GEN给药小鼠的肾功能和抗氧化能力，同时降低了MDA和蛋白质羰基水平。此外，TX抑制了GEN处理小鼠肾脏中核因子κB（NF-κB）p65的表达，降低了白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）水平。GEN处理增加了小鼠肾脏中半胱天冬酶-3和Bcl-2相关X蛋白（Bax）水平，降低了B细胞淋巴瘤-2（Bcl-2）蛋白水平。TX处理显著减轻了这些影响。GEN给药显著抑制了小鼠肾脏中核因子红细胞2相关因子2（Nrf2）和血红素加氧酶-1（HO-1）蛋白水平。在很大程度上，TX恢复了GEN处理小鼠肾脏中的Nrf2和HO-1蛋白水平，免疫组织化学和酶联免疫吸附测定分析分别证实了这一点。总体而言，TX通过调节氧化应激、炎症和细胞凋亡以及恢复Nrf2信号通路，对GEN诱导的肾损伤提供了肾保护作用。因此，TX可能是预防药物相关器官损伤的有前途的辅助候选药物。
