Fan Xunjie, Zhang Yuanyuan, Song Yi, Zhao Yanyan, Xu Yanan, Guo Feng, Shao Mingwei, Ma Xiaojun, Zhang Wei, Wei Fangyi, Qin Guijun
Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Rd., Zhengzhou, Henan 450052, China; Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China.
Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Rd., Zhengzhou, Henan 450052, China.
Phytomedicine. 2023 Mar;111:154656. doi: 10.1016/j.phymed.2023.154656. Epub 2023 Jan 10.
Bidirectional communications between the gut microbiota and the brain may play a critical role in diabetes-related cognitive impairment. Compound Danshen Dripping Pills (CDDP) treatment has shown remarkable improvement in cognitive impairment in people with type 2 diabetes mellitus (T2DM) in clinical settings, but the underlying mechanisms remain unknown.
An extensive detailed strategy via in vivo functional experiments, transcriptomics, metabolomics, and network pharmacology was adopted to investigate the CDDP-treatment mechanism in diabetic cognitive dysfunction.
For 12 weeks, KK-Ay mice, a spontaneous T2DM model, were intragastrically administered various doses of CDDP solution or an equivalent volume of water, and the nootropic drug piracetam was orally administered as a positive control. At the 12th week, cognition was assessed using Morris water maze tests and brain magnetic resonance imaging (MRI). Furthermore, transcriptomics, metabolomics, and network pharmacology analyses were applied to reveal novel molecular mechanisms of CDDP-treatment in diabetic cognitive dysfunction of KK-Ay mice, which were then validated using quantitative real-time polymerase chain reaction and Western blot.
Here we verified that CDDP can suppress inflammatory response and alleviate the cognitive dysfunction in KK-Ay mice. Also, as demonstrated by 16S rRNA sequencing and short-chain fatty acids (SCFAs) analysis, CDDP attenuated intestinal flora disorder as well as increases of metabolites including butyric acid, hexanoic acid, and isohexic acid. Given the integrated analyses of network pharmacology, transcriptomic, metabolomic data, and molecular biology, the TLR4/MyD88/NF-κB signaling pathway was activated in diabetes, which could be reversed by CDDP.
Our findings demonstrate that CDDP restructures the gut microbiota composition and increased the intestinal SCFAs in KK-Ay mice, which might inhibit neuroinflammation, and thus improve diabetic mice cognitive disorder.
肠道微生物群与大脑之间的双向通信可能在糖尿病相关的认知障碍中起关键作用。复方丹参滴丸（CDDP）治疗在临床环境中已显示出对2型糖尿病（T2DM）患者认知障碍有显著改善，但潜在机制仍不清楚。
采用体内功能实验、转录组学、代谢组学和网络药理学等广泛详细的策略来研究CDDP治疗糖尿病认知功能障碍的机制。
将自发T2DM模型KK-Ay小鼠连续12周灌胃给予不同剂量的CDDP溶液或等体积的水，并口服促智药物吡拉西坦作为阳性对照。在第12周时，使用莫里斯水迷宫试验和脑磁共振成像（MRI）评估认知功能。此外，应用转录组学、代谢组学和网络药理学分析来揭示CDDP治疗KK-Ay小鼠糖尿病认知功能障碍的新分子机制，然后使用定量实时聚合酶链反应和蛋白质免疫印迹法进行验证。
在此我们证实CDDP可抑制KK-Ay小鼠的炎症反应并减轻其认知功能障碍。此外，如16S rRNA测序和短链脂肪酸（SCFAs）分析所示，CDDP减轻了肠道菌群紊乱以及包括丁酸、己酸和异己酸在内的代谢产物增加。综合网络药理学、转录组学、代谢组学数据和分子生物学分析，糖尿病中TLR4/MyD88/NF-κB信号通路被激活，而CDDP可使其逆转。
我们的研究结果表明，CDDP可重塑KK-Ay小鼠的肠道微生物群组成并增加肠道SCFAs，这可能抑制神经炎症，从而改善糖尿病小鼠的认知障碍。
Zotero 插件