School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
Guangdong Food Green Processing and Nutrition Regulation Technologies Research Center, Guangzhou 510650, China.
J Agric Food Chem. 2024 Mar 27;72(12):6189-6202. doi: 10.1021/acs.jafc.3c05718. Epub 2024 Mar 19.
The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABA and 5-HT receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.
我们之前已经证明，六肽 YPVEPF 在大鼠脑内具有很强的促睡眠作用，单次口服给药后可检测到。在这项研究中，首次研究了 YPVEPF 在靶向应激诱导焦虑小鼠中的作用机制和分子效应，并进一步探讨了其关键的活性结构。结果表明，YPVEPF 可显著延长睡眠时间，改善焦虑指标，包括延长开放臂和中央停留时间。同时，YPVEPF 通过显著增加脑和血清中 GABA/Glu 比、5-HT 和多巴胺的水平，以及调节多个靶点的代谢，表现出很强的促睡眠作用，但这些作用可被 BIC 和 WAY100135 阻断。此外，分子模拟结果表明，YPVEPF 由于 Tyr-Pro-Xaa-Xaa-Pro- 的关键结构，能够稳定地与重要的 GABA 和 5-HT 受体结合，静电和范德华能在稳定构象中起主导作用。因此，YPVEPF 通过调节 GABA-Glu 代谢途径和 5-羟色胺能系统，显示出促睡眠和抗焦虑作用，这依赖于具有 Tyr 和两个 Pro 重复的独特自折叠结构。
