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Archive > Volume 16 Issue 1 > 2024,16(1):132-142. DOI:https://doi.org/10.1016/j.chmed.2023.09.004 Prev Next

逍遙散對抑郁癥大鼠運動能力和肝臟線粒體代謝組學的影響

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Effects of Xiaoyao San on exercise capacity and liver mitochondrial metabolomics in rat depression model

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    摘要:
    目的：基于代謝組學和網(wǎng)絡(luò)藥理學闡明逍遙散改善慢性不可預測輕度應(yīng)激(CUMS)抑郁癥大鼠運動能力的作用機制。方法：將大鼠隨機分為空白組（C組）、CUMS模型組（M組）、文拉法辛組（V組）和逍遙散組（X組），邊造模邊給藥，持續(xù)28天。通過大鼠體重、曠場實驗和糖水偏愛實驗評價大鼠抑郁行為，爬桿實驗和轉(zhuǎn)棒實驗評價大鼠運動能力，基于LC-MS代謝組學方法對大鼠肝臟線粒體進行代謝組學分析。利用TCMSP數(shù)據(jù)庫和GeneCards數(shù)據(jù)庫篩選獲得逍遙散治療抑郁癥的潛在靶點，并通過蛋白質(zhì)互作網(wǎng)絡(luò)分析，篩選逍遙散治療抑郁癥的關(guān)鍵網(wǎng)絡(luò)靶標，進行生物功能富集及通路分析。結(jié)果：（1）與C組相比，M組大鼠體重、糖水偏愛率、曠場穿越格數(shù)、直立次數(shù)、爬桿得分和轉(zhuǎn)棒在棒時間均顯著降低（P<0.01）。與M組相比，V組和X組大鼠上述行為學和運動能力指標顯著回調(diào)（P<0.01，P<0.05）。（2）線粒體代謝組學結(jié)果顯示，與C組相比，M組大鼠肝臟線粒體中蘋果酸、?；撬岷凸劝彼岬?8種差異代謝物發(fā)生變化；X組大鼠肝臟線粒體中天冬氨酸、乳酸和亮氨酸等9種差異代謝物回調(diào)，并調(diào)節(jié)6條代謝通路，包括苯丙氨酸代謝，谷胱甘肽代謝及丙氨酸、天冬氨酸和谷氨酸代謝等。（3）網(wǎng)絡(luò)藥理學結(jié)果顯示，篩選了差異化合物的223個相關(guān)靶點，與抑郁癥的相關(guān)靶點進行映射，得到交集靶點88個，其中IL-1β、IL-6、TNF等15個關(guān)鍵靶點被預測為治療抑郁癥的主要差異靶點；獲得1553條GO信號通路和181條KEGG信號通路，主要的生物學通路為AGE-RAGE信號通路、HIF-1信號通路和鈣信號通路。結(jié)論：逍遙散能夠正向調(diào)節(jié)抑郁大鼠肝臟線粒體代謝物變化，改善能量代謝，提高其運動能力；并通過AGE-RAGE信號通路、癌癥通路、HIF-1信號通路等多條途徑發(fā)揮抗抑郁作用，具有多靶點、多途徑特點。

    Abstract:
    Objective: This study aimed to investigate the therapeutic effects of Xiaoyao San (XYS), a herbal medicine formula, on exercise capacity and liver mitochondrial metabolomics in a rat model of depression induced by chronic unpredictable mild stress (CUMS). Methods: A total of 24 male SD rats were randomly divided into four groups: control group (C), CUMS control group (M), Venlafaxine positive treatment group (V), and XYS treatment group (X). Depressive behaviour and exercise capacity of rats were assessed by body weight, sugar-water preference test, open field test, pole test, and rotarod test. The liver mitochondria metabolomics were analyzed by using liquid chromatography-mass spectrometry (LC-MS) method. TCMSP database and GeneCards database were used to screen XYS for potential targets for depression, and GO and KEGG enrichment analyses were performed. Results: Compared with C group, rats in M group showed significantly lower body weight, sugar water preference rate, number of crossing and rearing in the open field test, climbing down time in the pole test, and retention time on the rotarod test (P < 0.01). The above behaviors and exercise capacity indices were significantly modulated in rats in V and X groups compared with M group (P < 0.05, 0.01). Compared with C group, a total of 18 different metabolites were changed in the liver mitochondria of rats in M group. Nine different metabolites and six metabolic pathways were regulated in the liver mitochondria of rats in X group compared with M group. The results of network pharmacology showed that 88 intersecting targets for depression and XYS were obtained, among which 15 key targets such as IL-1b, IL-6, and TNF were predicted to be the main differential targets for the treatment of depression. Additionally, a total of 1 553 GO signaling pathways and 181 KEGG signaling pathways were identified, and the main biological pathways were AGE-RAGE signaling pathway, HIF-1 signaling pathway, and calcium signaling pathway. Conclusion: XYS treatment could improve depressive symptoms, enhance exercise capacity, positively regulate the changes of mitochondrial metabolites and improve energy metabolism in the liver of depressed rats. These findings suggest that XYS exerts antidepressant effects through multi-target and multi-pathway.

    關(guān)鍵詞:
    抑郁癥、運動能力、肝臟、線粒體代謝組學、逍遙散

    Keywords:


    Project Supported:
    The experiments were carried out at Shanxi University. The authors thank the institution’s technological infrastructure and funding support. This work was supported by the National Natural Science Foundation of China, China (No. 82074147) and the Project of Natural Science Research of the Shanxi Province, China (No. 202103021224027).

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