咖啡酸苯乙酯通过调节 FOXO1/Nrf2/Sirt1 轴改善多黏菌素诱导的大鼠肾毒性。

Caffeic acid phenethyl ester ameliorates colistin-induced nephrotoxicity in rats via modulation of FOXO1/Nrf2/Sirt1 axis.

机构信息

Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.

Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.

出版信息

Clin Exp Pharmacol Physiol. 2024 Dec;51(12):e70000. doi: 10.1111/1440-1681.70000.

DOI:10.1111/1440-1681.70000

PMID:39448197

Abstract

BACKGROUND

Colistin (Cst) is one of the antimicrobial peptides and is reserved for use against multi-drug-resistant Gram-negative bacteria. However, the clinical value of Cst is limited by its nephrotoxic adverse effects. Caffeic acid phenethyl ester (CAPE) is a honeybee propolis flavonoid recognised for its diverse pharmacological potential. It has demonstrated d antioxidant and anti-inflammatory properties, as well as protective effects against chemically induced toxicity in variuos biological systems. This study aimed to investigate the impact of CAPE on nephrotoxicity induced in rats by Cst.

METHODS

Animals were randomly divided into five groups. Group 1 served as control, group 2 received CAPE (10 mg/kg) orally, group 3 received Cst IP, group 4 received Cst + CAPE (5 mg/kg) and group 5 received Cst + CAPE (10 mg/kg). All treatments were given daily for 10 consecutive days.

RESULTS

CAPE notably attenuated Cst-inducednephrotoxicity as shown by reducing urea serum levels, creatinine, cystatin C, urinary protein contents and urinary N-acetyl-β-D-glucosaminidase (NAG). This was confirmed by histological investigations that indicated amelioration of histopathological changes in the kidney architecture as well as the deposition of collagen in renal tissues. CAPE exhibited antioxidant effects supported by the prevention of rise in Cst-induced lipid peroxidation and depletion of superoxide dismutase and catalase enzymatic activities. In addition, CAPE inhibited the expression of the inflammatory markers including tumour necrosis factor-α, nuclear factor kappa B and interleukin-6. These actions were associated with modulation of messenger ribonucleic acid (mRNA) expression of Bax and Bcl-2 in favour of anti-apoptosis. CAPE inhibited Cst-induced rise in forkhead box O1 (FOXO1) expression and downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sirtuin 1 (Sirt1) immune-expression.

CONCLUSION

CAPE protects against nephrotoxicity induced by Cst in ratsprimarily through its antioxidant, antiinflammatory and antiapoptotic activities. These pritective effects are mediated via modulation of FOXO1/Nrf2/Sirt1 axis.

摘要

背景

黏菌素（Cst）是一种抗菌肽，仅用于治疗多重耐药革兰氏阴性菌。然而，由于其肾毒性不良反应，Cst 的临床应用价值受到限制。咖啡酸苯乙酯（CAPE）是一种蜜蜂蜂胶中的类黄酮，具有多种药理学潜力。它具有抗氧化和抗炎特性，并且在各种生物系统中对化学诱导的毒性具有保护作用。本研究旨在探讨 CAPE 对 Cst 诱导的大鼠肾毒性的影响。

方法

动物随机分为五组。第 1 组为对照组，第 2 组给予 CAPE（10mg/kg）口服，第 3 组给予 Cst 腹腔注射，第 4 组给予 Cst+CAPE（5mg/kg），第 5 组给予 Cst+CAPE（10mg/kg）。所有治疗均连续 10 天每日给予。

结果

CAPE 显著减轻 Cst 诱导的肾毒性，表现为降低血清尿素水平、肌酐、胱抑素 C、尿蛋白含量和尿 N-乙酰-β-D-氨基葡萄糖苷酶（NAG）。组织学研究证实了这一点，表明肾组织结构的病理变化以及肾组织中胶原的沉积得到改善。CAPE 表现出抗氧化作用，可防止 Cst 诱导的脂质过氧化增加以及超氧化物歧化酶和过氧化氢酶酶活性的耗竭。此外，CAPE 抑制了肿瘤坏死因子-α、核因子 κB 和白细胞介素-6 等炎症标志物的表达。这些作用与 Bax 和 Bcl-2 的信使核糖核酸（mRNA）表达的调节有关，有利于抗细胞凋亡。CAPE 抑制 Cst 诱导的叉头框 O1（FOXO1）表达增加以及核因子红细胞 2 相关因子 2（Nrf2）和 Sirtuin 1（Sirt1）免疫表达的下调。