Nuamnaichati Narawat, Suriya Utid, Khine Hnin Ei Ei, Sungthong Rungroch, Suwannamai Poon, Sritularak Boonchoo, Prompetchara Eakachai, Laomeephol Chavee, Alduina Rosa, Chaotham Chatchai
Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Nutrients. 2025 Mar 21;17(7):1104. doi: 10.3390/nu17071104.
Phytochemicals possess diverse therapeutic potential; however, the impact of arene substitutions on the pharmacological properties of the bibenzyl compounds batatasin III and gigantol, derived from , remains unexplored.
This study examines how structural differences between these compounds affect cellular glucose uptake and lipid metabolism during adipocyte differentiation.
The effects of both bibenzyl compounds on cytotoxicity and glucose uptake were assessed in mouse and human pre-adipocytes and rat skeletal muscle myoblasts using colorimetric assays. Lipid metabolism was evaluated through Oil Red O staining and quantification of triglyceride and glycerol levels, while protein and gene expression during adipocyte differentiation were analyzed via western blotting and RT-qPCR.
At the highest non-cytotoxic concentration (25 µM), gigantol significantly enhanced glucose uptake (up to 2-fold) under both basal and insulin-stimulated conditions, whereas batatasin III showed a similar effect only under basal conditions. Gigantol upregulated GLUT1 and GLUT4 in myotubes but downregulated them in adipocytes, whereas batatasin III had minimal impact on these transporters. Both compounds suppressed lipid accumulation in mouse and human adipocytes by decreasing intracellular triglyceride content and promoting extracellular glycerol release. However, batatasin III did not affect extracellular glycerol release during early adipocyte differentiation, as evidenced by the marked downregulation of key lipogenic proteins (PLIN1, LPL, FABP4) observed only with gigantol. Molecular docking analyses suggest that gigantol's greater bioactivity may result from its higher number of arene substitutions.
This study provides the first evidence that differences in arene substitutions among orchid-derived bibenzyls influence their pharmacological properties. Our findings support the strategic modification of natural products as a potential approach for managing metabolic disorders.
植物化学物质具有多种治疗潜力；然而，源自[未提及具体来源]的联苄化合物甘薯黑檀素III和石斛酚的芳烃取代对其药理特性的影响尚未得到探索。
本研究考察这些化合物之间的结构差异如何影响脂肪细胞分化过程中的细胞葡萄糖摄取和脂质代谢。
使用比色法评估这两种联苄化合物对小鼠和人前脂肪细胞以及大鼠骨骼肌成肌细胞的细胞毒性和葡萄糖摄取的影响。通过油红O染色以及甘油三酯和甘油水平的定量来评估脂质代谢，同时通过蛋白质印迹法和逆转录定量聚合酶链反应分析脂肪细胞分化过程中的蛋白质和基因表达。
在最高非细胞毒性浓度（25μM）下，石斛酚在基础和胰岛素刺激条件下均显著增强葡萄糖摄取（高达2倍），而甘薯黑檀素III仅在基础条件下显示出类似效果。石斛酚上调肌管中的葡萄糖转运蛋白1（GLUT1）和葡萄糖转运蛋白4（GLUT4），但在脂肪细胞中下调它们，而甘薯黑檀素III对这些转运蛋白的影响最小。两种化合物均通过降低细胞内甘油三酯含量并促进细胞外甘油释放来抑制小鼠和人脂肪细胞中的脂质积累。然而，甘薯黑檀素III在脂肪细胞早期分化过程中不影响细胞外甘油释放，这通过仅在石斛酚处理时观察到的关键脂肪生成蛋白（ perilipin 1，PLIN1；脂蛋白脂肪酶，LPL；脂肪酸结合蛋白4，FABP4）的显著下调得以证明。分子对接分析表明，石斛酚更高的生物活性可能源于其更多的芳烃取代。
本研究提供了首个证据，即兰花来源的联苄类化合物之间的芳烃取代差异会影响其药理特性。我们的研究结果支持对天然产物进行策略性修饰作为管理代谢紊乱的一种潜在方法。
