Benzbromarone mitigates cisplatin nephrotoxicity involving enhanced peroxisome proliferator-activated receptor-alpha (PPAR-α) expression
Benzbromarone mitigates cisplatin nephrotoxicity involving enhanced peroxisome proliferator-activated receptor-alpha (PPAR-α) expression
复制标题
DOI：
10.1016/j.lfs.2020.117272
复制
发表时间：
2020-02-15
期刊：
影响因子：
6.1
通讯作者：
Azouz, Amany A.
中科院分区：
文献类型：
--
作者：
Abdel-Razek, Esraa Abdel-Nassir;Abo-Youssef, Amira M.;Azouz, Amany A.
目的：尽管顺铂作为一种广泛使用的化疗药物具有很好的疗效，但其临床应用受到其严重副作用（肾毒性）的挑战的限制。在这项研究中，研究了苯溴马隆对过氧化物酶体增殖物激活受体-α（PPAR-a）对抗顺铂肾毒性的作用。持续14天，和顺铂（6.5mg/kg; i. p.）在第10天单次给药。收集血液和肾组织样品用于测定肾功能、生化和分子标志物以及组织病理学investigation.Key发现：苯溴马隆改善肾功能，这是由降低血清肌酐和血尿素氮证明了近一半，相比于单用顺铂的组。PPAR-alpha的蛋白表达随着苯溴马隆处理而增强，沿着氧化应激的显著抑制，因为苯溴马隆降低NADPH氧化酶的mRNA表达，同时增加与增强Nrf 2相关的抗氧化剂HO-1蛋白表达。此外，它还表现出明显的抗炎作用，其机制与抑制p38 MAPK/NF-κ B p65信号通路及其下游靶点有关。此外，苯溴马隆延迟凋亡与减少促凋亡（Bax）和增强抗凋亡（Bcl-2）蛋白的表达。benzbromarone的保护作用也证实了组织病理学结果。意义：我们的数据证实了PPAR-alpha之间的关系，顺铂诱导的有害影响。还可以表明，通过苯溴马隆增强PPAR-alpha表达是克服顺铂肾毒性的有前景的治疗方法，涉及调节不同的信号传导途径：Nrf 2/HO-1、p38 MAPK/NF-κ B p65和Bax/Bcl-2。
Aim: Despite the great efficacy reported for cisplatin as a widely used chemotherapeutic agent, its clinical use is limited by the challenge of facing its serious side effect; nephrotoxicity. In this study, the effect of the benzbromarone on peroxisome proliferator-activated receptor-alpha (PPAR-alpha) was investigated against cisplatin nephrotoxicity.Main methods: Rats were administered benzbromarone (10 mg/kg/day; p.o.) for 14 days, and cisplatin (6.5 mg/kg; i.p.) as a single dose on the 10th day. Blood and kidney tissue samples were collected for determination of kidney function, biochemical and molecular markers, as well as histopathological investigation.Key findings: Benzbromarone improved kidney function, that was evidenced by reduced serum creatinine and blood urea nitrogen to nearly the half, compared to the group administered cisplatin alone. The protein expression of PPAR-alpha was enhanced with benzbromarone treatment, along with a considerable suppression of oxidative stress as benzbromarone reduced mRNA expression of NADPH oxidase, while increased the anti-oxidant HO-1 protein expression associated with enhancing Nrf2. Besides, it displayed a marked anti-inflammatory effect involved suppression of p38 MAPK/NF-kappa B p65 signaling pathway and its downstream targets. Moreover, benzbromarone retarded apoptosis associated with reducing the pro-apoptotic (Bax) and enhancing the antiapoptotic (Bcl-2) protein expressions. The protective effects of benzbromarone were also confirmed by histopathological results.Significance: Our data confirm the relation between PPAR-alpha, and the deleterious effects induced by cisplatin. It can also be suggested that enhancing PPAR-alpha expression by benzbromarone is a promising therapeutic approach that overcomes cisplatin nephrotoxicity, involving regulation of different signaling pathways: Nrf2/HO-1, p38 MAPK/NF-kappa B p65, and Bax/Bcl-2.