Salah Tasneem M, Rabie Mostafa A, El Sayed Nesrine S
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt.
Food Chem Toxicol. 2025 Feb;196:115179. doi: 10.1016/j.fct.2024.115179. Epub 2024 Dec 5.
Cisplatin (Cisp) is a potent cancer drug, but its use is limited by acute kidney injury (AKI). Autophagy, a process that removes damaged proteins and maintains cellular homeostasis, has been shown to alleviate Cisp-induced AKI. The balance between autophagy and apoptosis is crucial to kidney protection. Treatment with Berberine, known for its antioxidant and anti-inflammatory effects in nephrotoxicity models, was studied for its potential to enhance autophagy in Cisp-induced AKI. Treatment with Berberine (Berb) upregulated Klotho gene expression, enhancing autophagy as indicated by elevated protein levels of pS486-AMPK, pS638-ULK1, and Beclin-1, accompanied by a decrease in pS248-mTOR protein expression. Also, Berb mitigated oxidative stress by reducing elevated MDA levels and boosting SOD activity, which in turn suppressed inflammation by down-regulating HMGB1 and RAGE gene expression, as well as reducing pS536-NF-κB and IL-6 protein contents. Additionally, Berb reduced apoptosis by increasing Bcl-2 and decreasing Bax. This coordinated action preserved kidney function, evidenced by reductions in early injury markers (cystatin C, KIM-1, NGAL) and late markers (creatinine, BUN), along with attenuation of histopathological alterations. The use 3-MA, autophagy inhibitor, nullified these protective effects, highlighting Berb's role in promoting autophagy, reducing oxidative stress, inflammation, and apoptosis, and preserving renal health in Cisp-induced AKI.
顺铂（Cisp）是一种有效的抗癌药物，但其应用受到急性肾损伤（AKI）的限制。自噬是一个清除受损蛋白质并维持细胞内稳态的过程，已被证明可减轻顺铂诱导的急性肾损伤。自噬与凋亡之间的平衡对于肾脏保护至关重要。黄连素在肾毒性模型中具有抗氧化和抗炎作用，本研究探讨了其在顺铂诱导的急性肾损伤中增强自噬的潜力。黄连素（Berb）治疗上调了Klotho基因表达，pS486-AMPK、pS638-ULK1和Beclin-1蛋白水平升高表明自噬增强，同时pS248-mTOR蛋白表达降低。此外，黄连素通过降低升高的丙二醛水平和提高超氧化物歧化酶活性减轻氧化应激，进而通过下调HMGB1和RAGE基因表达以及降低pS536-NF-κB和白细胞介素-6蛋白含量来抑制炎症。此外，黄连素通过增加Bcl-2和减少Bax来减少细胞凋亡。这种协同作用保护了肾功能，早期损伤标志物（胱抑素C、KIM-1、中性粒细胞明胶酶相关脂质运载蛋白）和晚期标志物（肌酐、尿素氮）降低以及组织病理学改变减轻证明了这一点。使用自噬抑制剂3-MA消除了这些保护作用，突出了黄连素在促进自噬、减少氧化应激、炎症和细胞凋亡以及保护顺铂诱导的急性肾损伤中的肾脏健康方面的作用。
