The Medical and Scientific Research Center, Guangxi Medical University, Nanning 530021, China; Research Center for Regenerative Medicine, Guangxi Medical University, Nanning 530021, China.
The Medical and Scientific Research Center, Guangxi Medical University, Nanning 530021, China.
Chem Biol Interact. 2014 Sep 25;221:127-38. doi: 10.1016/j.cbi.2014.08.002. Epub 2014 Aug 15.
The ideal therapeutic agent for treatment of osteoarthritis (OA) should have not only potent anti-inflammatory effect but also favorable biological properties to restore cartilage function. Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on OA (Singh et al., 2003) [1]. However, GA has much weaker antioxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel sulfonamido-based gallate named sodium salt of 3,4,5-trihydroxy-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-benzamide (SZNTC) and analyzed its chondro-protective and pharmacological effects. Comparison of SZNTC with GA and sulfathiazole sodium (ST-Na) was also performed. Results showed that SZNTC could effectively inhibit the Interleukin-1 (IL-1)-mediated induction of metalloproteinase-1 (MMP-1) and MMP-3 and could induce the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which demonstrated ability to reduce the progression of OA. SZNTC can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Expression of the collagen I gene was effectively down-regulated, revealing the inhibition of chondrocytes dedifferentiation by SZNTC. Hypertrophy that may lead to chondrocyte ossification was also undetectable in SZNTC groups. The recommended dose of SZNTC ranges from 3.91μg/ml to 15.64μg/ml, among which the most profound response was observed with 7.82μg/ml. In contrast, its source products of GA and ST-Na have a weak effect in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed SZNTC as a promising novel agent in the treatment of chondral and osteochondral lesions.
用于治疗骨关节炎 (OA) 的理想治疗剂不仅应具有有效的抗炎作用，而且还应具有恢复软骨功能的良好生物学特性。没食子酸 (GA) 及其衍生物是具有 OA 作用的抗炎剂（Singh 等人，2003 年）[1]。然而，与衍生物相比，GA 的抗氧化作用较弱，生物活性也较差。我们通过引入磺酰胺对 GA 进行修饰，合成了一种新型磺酰胺基没食子酸盐，命名为 3,4,5-三羟基-N-[4-(噻唑-2-基磺酰胺基)-苯基]-苯甲酰胺钠盐（SZNTC），并分析了其软骨保护和药理作用。还对 SZNTC 与 GA 和磺胺噻唑钠（ST-Na）进行了比较。结果表明，SZNTC 能有效抑制白细胞介素-1（IL-1）介导的基质金属蛋白酶-1（MMP-1）和 MMP-3 的诱导，并能诱导组织金属蛋白酶抑制剂-1（TIMP-1）的表达，从而具有减轻 OA 进展的能力。SZNTC 还可以通过促进细胞增殖和维持关节软骨细胞的表型来发挥软骨保护作用，表现为细胞生长改善，软骨特异性标志物如聚集蛋白聚糖、胶原 II 和 Sox9 的合成增强。胶原 I 基因的表达被有效下调，表明 SZNTC 抑制软骨细胞去分化。SZNTC 组也未检测到可能导致软骨细胞骨化的肥大。SZNTC 的推荐剂量范围为 3.91μg/ml 至 15.64μg/ml，其中 7.82μg/ml 时效果最显著。相比之下，其来源产物 GA 和 ST-Na 在软骨细胞的生物活性方面作用较弱，这表明这种修饰的重要性。这项研究揭示了 SZNTC 作为一种有前途的新型软骨和骨软骨病变治疗药物。
