Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil.
Curr Med Chem. 2011;18(22):3351-60. doi: 10.2174/092986711796504600.
Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2⁻/⁻ mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2⁺/⁺ cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.
噻唑烷二酮类（TZDs）是一类用于治疗 2 型糖尿病的药物。然而，目前可用的 TZDs（如罗格列酮）的治疗与重要的副作用相关，如水肿和体重增加，这表明有必要研究具有更好药理学特性的替代 TZDs。在这项研究中，我们研究了一种新型化学修饰的 TZD，即芳基烯噻唑烷二酮 5-（4-甲磺酰基-苄基）-3-（4-硝基苄基）-噻唑烷-2,4-二酮（SF23）的抗炎和抗氧化特性，并将结果与罗格列酮进行了比较。我们发现，我们的 SF23 对 PPARγ 的亲和力较弱，与罗格列酮相比，它以更低的幅度上调 PPARγ 和 CD36 的表达。在脂多糖（LPS）刺激的巨噬细胞中，SF23 减少亚硝酸盐的产生，并减弱 iNOS 和 COX-2 的 mRNA 表达。这些抗炎作用与罗格列酮相当。有趣的是，SF23 可以防止 LPS 诱导的线粒体膜超极化、凋亡、活性氧（ROS）生成和 NADPH 氧化酶亚基 Nox1 和 Nox2 的表达，而罗格列酮则不能防止 LPS 诱导的 Nrf2-/-巨噬细胞死亡和 ROS 生成。此外，在 Nrf2-/-小鼠的巨噬细胞中，SF23 可防止 LPS 诱导的细胞死亡和 ROS 生成，而罗格列酮仅能保护正常的 Nrf2+/+细胞免受氧化损伤，这表明与罗格列酮不同，SF23 的抗氧化活性可能与 Nrf2 无关。最后，在暴露于高浓度葡萄糖的巨噬细胞中，SF23 诱导葡萄糖转运体、胰岛素受体底物和 mitoNEET 的 mRNA 表达显著增加。总之，我们的数据表明，我们新的化学修饰的 TZD 显示出与罗格列酮相似的抗炎特性，但在 LPS 刺激的巨噬细胞中具有更好的抗氧化作用。
