基于代谢组学和转录组学分析的综合研究揭示补阳还五汤对帕金森病模型小鼠的作用
Integrated analysis of metabolomic and transcriptomic profiling reveals the effect of Buyang Huanwu decoction on Parkinson's disease in mice.
机构信息
Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China; Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China.
Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China.
出版信息
Phytomedicine. 2023 Jun;114:154755. doi: 10.1016/j.phymed.2023.154755. Epub 2023 Mar 13.
BACKGROUND
Parkinson's disease (PD) is a common, complex, and chronic neurodegenerative disorder involved in multi-system. At present, medicine for PD has many limitations. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicinal (TCM) formulae, is used in the treatment of PD clinically in China. However, the therapeutic mechanism is still unknown.
PURPOSE
We aimed to explore the pharmacological mechanism of BHD alleviating PD through an integrated liver metabolome and brain transcriptome analysis.
METHODS
The mice with PD were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests and immunohistochemistry were used to evaluate the neuroprotective effects of BHD. The non-targeted metabolomics analysis was conducted to profile differentially accumulated metabolites (DAMs) in the liver using a UHPLC-Q-Exactive MS/MS method. The differentially expressed genes (DEGs) in the brain were investigated by transcriptomic analysis on an Illumina sequencing platform. The correlations of DAMs and DEGs were investigated using an integrated metabolomic and transcriptomic approach.
RESULTS
The results of behavioral tests and immunohistochemistry proved the alleviated effects of BHD on PD symptoms. A total of 14 and 36 DAMs were detected in the groups treated with low- (L group) and high-dose (H group) BHD respectively under the positive ion mode. Compared with the PD model group (M group), three enriched pathways including metabolic pathways, ABC transporters, and biosynthesis of amino acids were common in the L and H group. Transcriptomic analysis proved that BHD could regulate the expression of numerous genes, some of which were targeted by Ben-Ldopa such as Creb5, Gm45623, Ccer2, Cd180, Fosl2, Crip3, and Noxred1. Based on the integrated metabolomic and transcriptomic analysis, 7 metabolite-gene pairs were found in four comparisons, including C vs M, M vs P, M vs L, and M vs H, and 6 enriched pathways containing purine metabolism, glycine/serine/threonine metabolism, phenylalanine metabolism, carbon fixation in photosynthetic organisms, thiamine metabolism, and ABC transporters were overlapped.
CONCLUSIONS
Though the underlying pharmacological mechanism of BHD is still lacking, we provided evidence that BHD could improve dopaminergic neurons in MPTP-induced PD mice by regulating liver metabolism and brain transcriptome. The correlation between the liver and the brain was preliminarily revealed in this study.
背景
帕金森病（PD）是一种常见的、复杂的、慢性的神经退行性疾病，涉及多系统。目前，PD 的治疗药物有很多局限性。补阳还五汤（BHD）是一种著名的中药方剂，在中国临床上用于治疗 PD。然而，其治疗机制尚不清楚。
目的
我们旨在通过整合肝代谢组学和脑转录组学分析，探讨 BHD 缓解 PD 的药理机制。
方法
采用 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导 PD 小鼠。采用行为学测试和免疫组织化学方法评价 BHD 的神经保护作用。采用 UHPLC-Q-Exactive MS/MS 方法对肝内差异积累代谢物（DAMs）进行非靶向代谢组学分析。采用 Illumina 测序平台进行脑转录组分析，研究脑内差异表达基因（DEGs）。采用整合代谢组学和转录组学方法研究 DAMs 和 DEGs 的相关性。
结果
行为学测试和免疫组织化学结果证实 BHD 对 PD 症状有缓解作用。在正离子模式下，分别用低剂量（L 组）和高剂量（H 组）BHD 处理的小鼠中，共检测到 14 种和 36 种 DAMs。与 PD 模型组（M 组）相比，L 组和 H 组均有 3 个富集通路，包括代谢通路、ABC 转运体和氨基酸生物合成。转录组分析表明，BHD 可调节大量基因的表达，其中一些基因是 Ben-Ldopa 的靶点，如 Creb5、Gm45623、Ccer2、Cd180、Fosl2、Crip3 和 Noxred1。基于整合代谢组学和转录组学分析，在 4 个比较中发现了 7 个代谢物-基因对，包括 C 与 M、M 与 P、M 与 L 和 M 与 H，并且重叠了包含嘌呤代谢、甘氨酸/丝氨酸/苏氨酸代谢、苯丙氨酸代谢、光合生物固碳、硫胺素代谢和 ABC 转运体的 6 个富集通路。
结论
虽然 BHD 的潜在药理机制仍有待阐明，但我们提供的证据表明，BHD 可以通过调节肝代谢和脑转录组来改善 MPTP 诱导的 PD 小鼠中的多巴胺能神经元。本研究初步揭示了肝与脑之间的相关性。
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