The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury.
The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury.
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DOI：
10.1016/j.redox.2023.103022
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发表时间：
2024-04
期刊：
影响因子：
11.4
通讯作者：
Allen, Bryan G.
中科院分区：
文献类型：
--
作者：
Mapuskar, Kranti A.;Pulliam, Casey F.;Tomanek-Chalkley, Ann;Rastogi, Prerna;Wen, Hsiang;Dayal, Sanjana;Griffin, Benjamin R.;Zepeda-Orozco, Diana;Sindler, Amy L.;Anderson, Carryn M.;Beardsley, Robert;Kennedy, Eugene P.;Spitz, Douglas R.;Allen, Bryan G.
关键词：
顺铂导致急性肾损伤（阿基）和慢性肾脏疾病（CKD），在老年患者中发生的频率和严重程度更高。人成纤维细胞中顺铂相关的顺铂敏感性涉及老年供体细胞产生的线粒体超氧化物增加。用SOD模拟物avasopasem锰处理顺铂诱导的阿基和CKD的年轻和老年C57 BL/6 J小鼠模型，以研究潜在的抗氧化和抗炎作用。在接受顺铂和AVA治疗的患者中进行的II期和III期随机临床试验（NCT 02508389和NCT 03689712）的不良事件报告确定了阿基的发生率和严重程度。顺铂诱导的阿基和CKD发生在所有小鼠中，然而，在老年小鼠中更明显。AVA降低了年龄较大动物中顺铂诱导的死亡率、阿基和CKD。AVA还减轻了顺铂诱导的线粒体电子传递链（ETC）复合物活性和NADPH氧化酶4（NOX 4）的变化，并抑制炎症标志物TNFα、IL 1、ICAM-1和VCAM-1水平的升高。对临床试验（NCT 02508389、NCT 03689712）中接受顺铂治疗的年龄分层受试者的分析也支持阿基的发生率随年龄增加而增加，AVA减少了年龄相关的治疗诱导的不良事件（AE），包括低镁血症、肌酐升高和阿基。年龄较大的小鼠和人类更容易受到顺铂诱导的肾损伤，AVA治疗可减轻年龄相关的损伤。线粒体ETC和NOX 4活性代表了导致顺铂诱导的肾损伤的超氧化物产生的来源，并且促炎细胞因子产生和内皮功能障碍也可能通过超氧化物形成而增加。
Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.
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发表时间：
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期刊：
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影响因子：
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影响因子：
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