Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Korea.
Mar Drugs. 2013 Apr 23;11(4):1409-26. doi: 10.3390/md11041409.
Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1-3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE2, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1.
蛋白酪氨酸磷酸酶 1B（PTP1B）在胰岛素信号的负调节中起着主要作用，因此被认为是治疗糖尿病的有吸引力的治疗靶标。对海洋来源真菌青霉 JF-55 培养物的甲基乙基酮提取物进行基于生物测定的研究，提供了一种新的 PTP1B 抑制性 styrylpyrone 型代谢产物，命名为 penstyrylpyrone（1），以及两种已知代谢产物，anhydrofulvic acid（2）和 citromycetin（3）。化合物 1 和 2以剂量依赖的方式抑制 PTP1B 活性，并且对 PTP1B 抑制的动力学分析表明，这些化合物以竞争性方式抑制 PTP1B 活性。为了获得分离化合物的更多生物学潜力，还评估了化合物 1-3 的抗炎作用。在所测试的化合物中，只有化合物 1 由于抑制 iNOS 和 COX-2 的表达而抑制了 NO 和 PGE2 的产生。Penstyrylpyrone（1）还降低了 TNF-α和 IL-1β的产生，并且这些抗炎作用与抑制 IκB-α的磷酸化和降解、NF-κB 核易位和 NF-κB DNA 结合活性相关。此外，使用 HO-1 的抑制剂 tin protoporphyrin（SnPP）验证了 penstyrylpyrone（1）对促炎介质和 NF-κB DNA 结合活性的抑制作用与 HO-1 的表达有关。因此，这些结果表明，penstyrylpyrone（1）通过表达抗炎性 HO-1 抑制 PTP1B 活性以及通过 NF-κB 途径产生促炎介质。
