El-Far Yousra M, El-Mesery Mohamed
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
J Biochem Mol Toxicol. 2021 Nov;35(11):e22908. doi: 10.1002/jbt.22908. Epub 2021 Sep 3.
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.
pevonedistat（MLN4924）是一种特异性NEDD8激活酶抑制剂，可使参与不同信号分子泛素化和周转的cullin-RING连接酶失活。在本研究中，我们评估了pevonedistat对顺铂（CIS）诱导的小鼠肾毒性的影响。分析了不同组小鼠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组织中IL-6和TNF-α的表达，并通过肾组织免疫组化染色分析IL-1β和NF-κB的表达。使用逆转录聚合酶链反应技术分析肾组织中Caspase-3、A20、β-连环蛋白和Nrf2基因的表达。采用蛋白质印迹分析评估肾组织中裂解的Caspase-3和β-连环蛋白的表达。与CIS联合使用pevonedistat可改善肾功能，并减轻CIS诱导的肾毒性，血清肌酐和尿素水平显著降低表明了这一点。此外，与CIS联合使用pevonedistat可使Caspase-3显著降低，A20、β-连环蛋白和Nrf2基因表达显著增加。此外，pevonedistat可降低CIS处理小鼠中Caspase-3裂解为p19的水平。此外，pevonedistat可降低CIS诱导的肾组织中IL-6、TNF-α、IL-1β和NF-κB蛋白表达上调。因此，pevonedistat减轻了CIS诱导的肾毒性，这可能归因于对肾组织中炎症的抑制。
