Pevonedistat (MLN4924) is a specific NEDD8-activating enzyme inhibitor that inactivates cullin–RING ligases involved in ubiquitylation and turnover of different signaling molecules. In the current study, we evaluated the effect of pevonedistat on cisplatin (CIS)-induced nephrotoxicity in mice. Serum creatinine and urea levels were analyzed in different groups. Histopathological examination of renal tissue was done using hematoxylin and eosin staining. In addition, renal IL-6 and TNF-α expressions were analyzed using the enzyme-linked immunosorbent assay technique, and IL-1β and NF-κB expressions were analyzed by immunohistochemical staining of renal tissue. Caspase-3, A20, β-catenin, and Nrf2 gene expressions in renal tissue were analyzed using the reverse-transcription polymerase chain reaction technique. Western blot analysis was adopted to assess cleaved caspase-3 and β-catenin expressions in renal tissue. Pevonedistat coadministration with CIS improved kidney functions and attenuated CIS-induced nephrotoxicity as indicated by the significant decrease in serum creatinine and urea levels. In addition, pevonedistat coadministration with CIS showed a significant decrease in caspase-3 and a significant increase in A20, β-catenin, and Nrf2 gene expressions. Also, pevonedistat decreased caspase-3 cleavage to p19 in mice treated with CIS. Moreover, pevonedistat decreased CIS-induced upregulation of IL-6, TNF-α, IL-1β, and NF-κB protein expressions in renal tissue. Thus, pevonedistat alleviated CIS-induced nephrotoxicity that might be attributed to suppression of the inflammation induced in renal tissue.

中文翻译：

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Pevonedistat 通过下调炎症介质的释放来减轻顺铂诱导的小鼠肾毒性

Pevonedistat (MLN4924) 是一种特异性 NEDD8 激活酶抑制剂，可灭活参与不同信号分子泛素化和周转的 cullin-RING 连接酶。在目前的研究中，我们评估了 pevonedistat 对顺铂 (CIS) 诱导的小鼠肾毒性的影响。分析不同组的血清肌酐和尿素水平。使用苏木精和伊红染色对肾组织进行组织病理学检查。此外，采用酶联免疫吸附测定技术分析肾IL-6和TNF- α的表达，通过肾组织的免疫组化染色分析IL- 1β和NF-κB的表达。Caspase-3、A20、β使用逆转录聚合酶链反应技术分析肾组织中β-catenin和Nrf2基因的表达。采用蛋白质印迹分析评估肾组织中切割的 caspase-3 和β -catenin 的表达。血清肌酐和尿素水平显着降低表明，Pevonedistat 与 CIS 联合使用可改善肾功能并减轻 CIS 诱导的肾毒性。此外，pevonedistat 与 CIS 联合给药显示 caspase-3 显着降低，A20、β-连环蛋白和 Nrf2 基因表达显着增加。此外，在接受 CIS 治疗的小鼠中，pevonedistat 降低了 caspase-3 对 p19 的切割。此外，pevonedistat 降低了 CIS 诱导的 IL-6、TNF - α、IL- 1β的上调, 和肾组织中 NF-κB蛋白的表达。因此，pevonedistat 减轻了 CIS 诱导的肾毒性，这可能归因于抑制肾组织中诱导的炎症。