Huang Yan, Wang Jianhui, Liu Feng, Wang Chenran, Xiao Zhiyong, Zhou Wenxia
Nanjing University of Chinese Medicine, Nanjing, China.
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Front Neurosci. 2023 Apr 20;17:1134176. doi: 10.3389/fnins.2023.1134176. eCollection 2023.
A substantial body of evidence has indicated that intracerebral O-linked N-acetyl-β-D-glucosamine (O-GlcNAc), a generalized post-translational modification, was emerging as an effective regulator of stress-induced emotional and cognitive impairments. Our previous studies showed that the Liuwei Dihuang formula (LW) significantly improved the emotional and cognitive dysfunctions in various types of stress mouse models. In the current study, we sought to determine the effects of LW on intracerebral O-GlcNAc levels in chronic unpredictable mild stress (CUMS) mice. The dynamic behavioral tests showed that anxiety- and depression-like behaviors and object recognition memory of CUMS mice were improved in a dose-dependent manner after LW treatment. Moreover, linear discriminate analysis (LEfSe) of genera abundance revealed a significant difference in microbiome among the study groups. LW showed a great impact on the relative abundance of these gut microbiota in CUMS mice and reinstated them to control mouse levels. We found that LW potentially altered the Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis process, and the abundance of O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in CUMS mice, which was inferred using PICRUSt analysis. We further verified advantageous changes in hippocampal O-GlcNAc modification of CUMS mice following LW administration, as well as changes in the levels of OGA and OGT. In summary, LW intervention increased the levels of hippocampal O-GlcNAc modification and ameliorated the emotional and cognitive impairments induced by chronic stress in CUMS mice. LW therefore could be considered a potential prophylactic and therapeutic agent for chronic stress.
大量证据表明，脑内O-连接的N-乙酰-β-D-葡萄糖胺（O-GlcNAc）作为一种普遍的翻译后修饰，正逐渐成为应激诱导的情绪和认知障碍的有效调节因子。我们之前的研究表明，六味地黄丸（LW）可显著改善各种应激小鼠模型中的情绪和认知功能障碍。在本研究中，我们试图确定LW对慢性不可预测轻度应激（CUMS）小鼠脑内O-GlcNAc水平的影响。动态行为测试表明，LW治疗后，CUMS小鼠的焦虑样和抑郁样行为以及物体识别记忆呈剂量依赖性改善。此外，属丰度的线性判别分析（LEfSe）显示，研究组之间的微生物群存在显著差异。LW对CUMS小鼠这些肠道微生物群的相对丰度有很大影响，并使其恢复到对照小鼠水平。我们发现，LW可能改变了尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）的生物合成过程，以及CUMS小鼠中O-连接的N-乙酰-β-D-氨基葡萄糖苷酶（OGA）和O-连接的N-乙酰葡糖胺转移酶（OGT）的丰度，这是通过PICRUSt分析推断出来的。我们进一步验证了LW给药后CUMS小鼠海马O-GlcNAc修饰的有利变化，以及OGA和OGT水平的变化。总之，LW干预增加了海马O-GlcNAc修饰水平，改善了CUMS小鼠慢性应激诱导的情绪和认知障碍。因此，LW可被认为是一种潜在的慢性应激预防和治疗药物。
