Apocynin abrogates methotrexate-induced nephrotoxicity: role of TLR4/NF-κB-p65/p38-MAPK, IL-6/STAT-3, PPAR-γ, and SIRT1/FOXO3 signaling pathways

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Emad H. M. Hassanein, Ahmed M. Sayed, Omnia A. M. Abd El-Ghafar, Zainab M. M. Omar, Eman K. Rashwan, Zuhair M. Mohammedsaleh, So Young Kyung, Jae Hyeon Park, Hyung Sik Kim, Fares E. M. Ali
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引用次数: 6

Abstract

The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC +MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-κB-p65, Ace-NF-κB-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IκBα, PPAR-γ, SIRT1, and FOXO3 expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities.

Abstract Image

罗布麻苷消除甲氨蝶呤诱导的肾毒性:TLR4/NF-κB-p65/p38-MAPK、IL-6/STAT-3、PPAR-γ和SIRT1/FOXO3信号通路的作用
本研究旨在评估罗布麻苷(APC)对甲氨蝶呤(MTX)引起的肾毒性的潜在保护作用。为了实现这一目标,大鼠被分为四组:对照组;APC (100 mg/kg/天;口头);甲氨蝶呤(20mg /kg;试验第5天末单次腹腔注射);APC +MTX(在MTX诱导肾毒性前5天和后5天口服APC)。第11天,收集样本以评估肾功能生物标志物、氧化应激、促炎细胞因子和其他分子靶标。与MTX对照组相比,APC治疗显著降低尿素、肌酐和KIM-1水平,改善肾脏组织学改变。此外,APC恢复了氧化/抗氧化平衡,MDA、GSH、SOD和MPO水平显著降低。iNOS、NO、p-NF-κB-p65、acenf -κB-p65、TLR4、p-p38-MAPK、p-JAK1、p-STAT-3表达降低,i -κ b α、PPAR-γ、SIRT1、FOXO3表达显著升高。在NRK-52E细胞中,APC以浓度依赖的方式保护mtx诱导的细胞毒性。此外,APC可降低mtx处理的NRK-52E细胞中p-STAT-3和p-JAK1/2表达水平的升高。体外实验显示,apc保护的mtx介导的肾小管上皮细胞通过抑制JAK/STAT3通路而受损。此外,通过分子对接和网络药理学分析预测计算药理学结果,验证了我们的体内和体外结果。综上所述,我们的研究结果表明,由于APC具有很强的抗氧化和抗炎生物活性,因此APC可能是mtx诱导的肾损伤的良好候选者。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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