基于“郁结中焦”理论探讨越鞠丸通过胃mTORC1/S6K1信号通路调控GHR-脂稳态治疗抑郁症的作用机制

随着社会压力加大，抑郁症发病率与关注度逐年增高。朱丹溪指出“凡郁皆在中焦”，针对“六郁”创立了越鞠丸，具有良好的抗抑郁效果。我们前期研究发现：中焦脾胃功能异常影响机体脂代谢，越鞠丸明显改善了抑郁症状，并显著改善了抑郁大鼠血浆脂代谢紊乱。文献报道也表明脂质在抑郁症发病机理中至关重要。受胃X/A样细胞mTORC1/S6K1信号通路调控的Ghrelin（GHR,食欲素）是外周循环GHR的主要来源，参与整体脂代谢调节。因此，本课题提出“基于胃X/A样细胞mTORC1/S6K1信号通路研究越鞠丸调控GHR-脂稳态治疗抑郁症作用机制”的科学假说。拟在抑郁模型上，通过行为学、机体表型、作用机制三层次研究，在组织和细胞两水平，运用代谢组学、Western-blot、免疫组化、siRNA和信号通路特异阻断等技术，创新性地从中焦脾胃出发，阐述越鞠丸治疗抑郁症作用机制，为其临床使用与开发提供科学依据。

With the increasing pressure of work and social environment, the incidence and attention of depression are increasing year by year. Yueju Pill, as the representative prescription of “all depression is in middle-jiao”, has a good antidepressant effect, and “stagnation in middle-jiao” is an important basis for its antidepressant effect. Our previous research results showed that the abnormal function of spleen and stomach in middle-jiao affected lipid metabolism, Yueju pill significantly improved the symptoms of depression, and significantly improved the disorder of lipid metabolism in plasma of depressed rats. The literature also shows that lipids play an important role in the pathogenesis of depression. Ghrelin (GHR) (orexin), which is regulated by mTORC1/S6K1 signal pathway in gastric X/A like cell, is the main source of GHR in peripheral circulation, which participates in the regulation of overall lipid metabolism. In this study, we proposed a scientific hypothesis of “Yueju Pill regulating CHR- lipid homeostasis in the treatment of depression based on mTORC1/S6K1 signal pathway in gastric X/A like cell”. On the model of depression, through the study of neuroethology, body phenotype and action mechanism, at the tissue and cell levels, using metabonomics, Western-blot, immunohistochemistry, siRNA and signal pathway specific blocking techniques, the mechanism of Yueju pill in the treatment of depression is expounded innovatively from middle Jiao, so as to provide scientific basis for its clinical use and development. According to this, we can provide more references for the treatment of depression by multi-channel and multi-target of traditional Chinese medicine.