Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, United States.
Planta Med. 2023 Aug;89(10):964-978. doi: 10.1055/a-2058-3863. Epub 2023 Mar 20.
The low amount of metabolites isolated from natural products is one of the challenges preventing their biological evaluation. The modulation of biosynthetic pathways by stimulating stress-induced responses in plants was proven to be a valuable tool for diversification of already known natural products. Recently, we reported the dramatic effect of methyl jasmonate (MeJA) on alkaloids distribution. In this study, three compounds identified as 9-methoxyvincamine, minovincinine, and minovincine are successfully isolated in good yield and subjected to several bioassays based on a network pharmacology study. The extracts and isolated compounds show weak to moderate antimicrobial and cytotoxic activities. Also, they are found to significantly promote wound healing in scratch assay, and transforming growth factor- (TGF-) modulation is suggested to be the potential pathway based on bioinformatic analysis. Hence, Western blotting is used to assess the expression of several markers related to this pathway and wound healing. The extracts and isolated compounds are able to increase the expression of Smad3 and Phosphatidylinositol-3-kinase (PI3K), while downregulating the levels of cyclin D1 and the mammalian target of rapamycin (mTOR) except for minovincine, which increases the mTOR expression, inferring that it might act through a different mechanism. Molecular docking is used to give insights on the ability of isolated compounds to bind with different active sites in mTOR. Collectively, the integrated phytochemical, , and molecular biology approach reveal that and its metabolite could be repurposed for the management of dermatological disorders where these markers are dysregulated, which opens the gate to develop new therapeutics in the future.
从天然产物中分离得到的代谢产物含量低，是阻碍其生物评价的挑战之一。通过刺激植物中的应激诱导反应来调节生物合成途径，已被证明是一种多样化已有的天然产物的有效工具。最近，我们报道了甲基茉莉酮酸（MeJA）对生物碱分布的显著影响。在这项研究中，成功地从 3 种化合物中分离出 9-甲氧基长春胺、米诺福林和米诺环素，收率良好，并根据网络药理学研究进行了多种生物测定。提取物和分离得到的化合物表现出弱至中等的抗菌和细胞毒性活性。此外，它们在划痕实验中被发现能显著促进伤口愈合，并且基于生物信息学分析，推测转化生长因子-（TGF-）调节是潜在的途径。因此，使用 Western blot 来评估与该途径和伤口愈合相关的几个标志物的表达。提取物和分离得到的化合物能够增加 Smad3 和磷脂酰肌醇-3-激酶（PI3K）的表达，同时下调细胞周期蛋白 D1 和哺乳动物雷帕霉素靶蛋白（mTOR）的水平，但米诺福林除外，它能增加 mTOR 的表达，这表明它可能通过不同的机制发挥作用。分子对接用于研究分离得到的化合物与 mTOR 不同活性部位结合的能力。综上所述，综合的植物化学、生物化学和分子生物学方法揭示了 和其代谢产物可被重新用于管理这些标志物失调的皮肤病，为未来开发新的治疗方法开辟了道路。
