Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando 32827, USA.
Eur J Pharmacol. 2013 Jan 15;699(1-3):55-61. doi: 10.1016/j.ejphar.2012.11.051. Epub 2012 Dec 7.
Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter's redox reactions to yield hydrogen peroxide (H(2)O(2)), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H(2)O(2), a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O(2)(-.) and H(2)O(2). As Sirt1 and PGC-1α profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases.
基于乙酰水杨酸（ASA，阿司匹林）迅速水解为水杨酸（SA），SA 形成二羟基苯甲酸（DBA）的能力，以及后者的氧化还原反应生成过氧化氢（H2O2），我们预测 ASA 可能具有诱导 Sirtuin1（Sirt1）及其下游效应的潜力。我们观察到，用 ASA 处理培养的肝细胞导致 Sirt1、过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）和 NAD（P）H 醌氧化还原酶 1（Nqo1）基因的诱导。Paraoxonase 1（PON1）和 Aryl hydrocarbon receptor（AhR）siRNA 转染抑制了 ASA 诱导的基因表达，表明需要乙酰酯水解和羟化生成 DHBA。后者也诱导了 Sirt1，证实了所提出的途径。正如预测的那样，ASA 和 SA 处理导致 H2O2的产生，这是 Sirt1 的已知诱导剂，并在当前研究中得到证实。更重要的是，ASA 处理导致线粒体的增加，如通过追踪染料所见。我们认为，通过 Nqo1 介导的氧化/还原反应从 ASA 生成的 DHBA 可能参与了 O2-和 H2O2的产生。由于 Sirt1 和 PGC-1α 深刻影响线粒体代谢和能量利用，ASA 除了抑制环氧化酶的能力外，可能具有治疗潜力。
