PDF(Pubmed)
Abstract：
Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent antioxidant properties and a neuroprotective effect against oxidative stress. However, its impact on the liver is unclear. This study aimed to elucidate the antioxidative effects of MFA and their underlying mechanisms. We observed that MFA treatment upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Treatment with various anthranilic acid derivative-class NSAIDs, including MFA, increased the expression of sequestosome 1 (SQSTM1) in HepG2 cells. MFA disrupted the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, activating the Nrf2 signaling pathway. SQTM1 knockdown experiments revealed that the effect of MFA on the Nrf2 pathway was masked in the absence of SQSTM1. To assess the cytoprotective effect of MFA, we employed tert-Butyl hydroperoxide (tBHP) as a ROS inducer. Notably, MFA exhibited a protective effect against tBHP-induced cytotoxicity in HepG2 cells. This cytoprotective effect was abolished when SQSTM1 was knocked down, suggesting the involvement of SQSTM1 in mediating the protective effect of MFA against tBHP-induced toxicity. In conclusion, this study demonstrated that MFA exhibits cytoprotective effects by upregulating SQSTM1 and activating the Nrf2 pathway. These findings improve our understanding of the pharmacological actions of MFA and highlight its potential as a therapeutic agent for oxidative stress-related conditions.
摘要：
甲芬那酸（MFA）是一种常用的非甾体抗炎药（NSAID），具有抗炎和镇痛特性。已知MFA具有有效的抗氧化特性和抗氧化应激的神经保护作用。然而,其对肝脏的影响尚不清楚。本研究旨在阐明MFA的抗氧化作用及其潜在机制。我们观察到MFA治疗上调了核因子红系2相关因子2（Nrf2）途径。用各种邻氨基苯甲酸衍生物类NSAIDs治疗，包括MFA,增加了HepG2细胞中螯合体1（SQSTM1）的表达。MFA破坏了Kelch样ECH相关蛋白1（Keap1）和Nrf2之间的相互作用，激活了Nrf2信号通路。SQTM1敲低实验表明，在不存在SQSTM1的情况下，MFA对Nrf2途径的影响被掩盖。为了评估MFA的细胞保护作用，我们使用叔丁基过氧化氢(tBHP)作为ROS诱导剂。值得注意的是,MFA在HepG2细胞中表现出对tBHP诱导的细胞毒性的保护作用。当SQSTM1被击倒时，这种细胞保护作用被取消，表明SQSTM1参与介导MFA对tBHP诱导的毒性的保护作用。总之,这项研究表明，MFA通过上调SQSTM1和激活Nrf2途径而表现出细胞保护作用。这些发现提高了我们对MFA的药理作用的理解，并强调了其作为氧化应激相关疾病的治疗剂的潜力。
