Ban Fangfang, Zhou Longjian, Yang Zhiyou, Liu Yayue, Zhang Yi
Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China.
Mar Drugs. 2025 Apr 23;23(5):181. doi: 10.3390/md23050181.
Natural products have extensive attractiveness as therapeutic agents due to their low toxicity and high efficiency. Our previous study has identified a depside-type Aspergillusidone G (Asp G) derived from DLEP2008001, which shows excellent neuroprotective activity for 1-methyl-4-phenylpyridinium (MPP)-induced primary cortical neurons and anti-neuroinflammatory property, promising to be a potential therapeutic agent for Parkinson's disease (PD). To further explore the anti-PD potential and mechanisms of Asp G, we employed network pharmacology, cellular experiments, and various biological techniques for analysis and validation. The analysis of network pharmacology suggested that Asp G's anti-PD potential might be attributed to its modulation of inflammation. The data from nitric oxide (NO) detection, qRT-PCR, and Western blot confirmed that Asp G dose-dependently inhibited lipopolysaccharide (LPS)-stimulated NO production, with 40 μM Asp G suppressing 90.54% of the NO burst compared to the LPS group, and suppressed the overproduction of inflammatory-related factors in LPS-induced BV2 cells. Further protein-protein interaction analysis indicated that matrix metalloproteinase 9 (MMP9), a promising target for PD intervention, was the most likely anti-PD target of Asp G, and the results of gelatin zymography, qRT-PCR, and Western blot validated that Asp G could inhibit the active and inactive forms of MMP9 directly and indirectly, respectively. Notably, the inhibition of 67 kDa-MMP9 by Asp G is expected to compensate for the inability of TIMP-1 to inhibit this form. Furthermore, a selective inhibitor of MMP9 (20 μM SB-3CT) further potentiated the anti-inflammatory effects of Asp G (20 μM), with inhibition rate on NO increasing from 27.57% to 63.50% compared to LPS group. In summary, our study revealed that Asp G exerts anti-neuroinflammatory effects by inhibiting MMP9, which provides a valuable lead compound for the development of anti-neuroinflammatory drugs and offers insights into the intervention of PD-associated neuroinflammation. Future studies will further investigate the upstream regulatory mechanisms of Asp G-mediated MMP9 inhibition and its effects in in vivo PD models.
天然产物因其低毒性和高效性而作为治疗药物具有广泛的吸引力。我们之前的研究从DLEP2008001中鉴定出一种缩酚酸型曲霉菌素G（Asp G），它对1-甲基-4-苯基吡啶鎓（MPP）诱导的原代皮层神经元显示出优异的神经保护活性以及抗神经炎症特性，有望成为帕金森病（PD）的潜在治疗药物。为了进一步探究Asp G的抗PD潜力及机制，我们采用网络药理学、细胞实验和各种生物学技术进行分析和验证。网络药理学分析表明，Asp G的抗PD潜力可能归因于其对炎症的调节作用。一氧化氮（NO）检测、qRT-PCR和蛋白质印迹的数据证实，Asp G剂量依赖性地抑制脂多糖（LPS）刺激的NO产生，与LPS组相比，40 μM的Asp G抑制了90.54%的NO爆发，并抑制了LPS诱导的BV2细胞中炎症相关因子的过量产生。进一步的蛋白质-蛋白质相互作用分析表明，基质金属蛋白酶9（MMP9）是PD干预的一个有前景的靶点，是Asp G最可能的抗PD靶点，明胶酶谱、qRT-PCR和蛋白质印迹的结果验证了Asp G可以分别直接和间接抑制MMP9的活性形式和非活性形式。值得注意的是，Asp G对67 kDa-MMP9的抑制有望弥补组织金属蛋白酶抑制因子-1（TIMP-1）无法抑制这种形式的不足。此外，MMP9的选择性抑制剂（20 μM SB-3CT）进一步增强了Asp G（20 μM）的抗炎作用，与LPS组相比，对NO的抑制率从27.57%提高到63.50%。总之，我们的研究表明Asp G通过抑制MMP9发挥抗神经炎症作用，这为抗神经炎症药物的开发提供了一种有价值的先导化合物，并为PD相关神经炎症的干预提供了见解。未来的研究将进一步探究Asp G介导的MMP9抑制的上游调控机制及其在体内PD模型中的作用。
