加味柴胡桂枝汤通过抑制JAK2/STAT3信号通路改善慢性不可预见性温和应激模型小鼠的焦虑和抑郁状态

doi:10.12122/j.issn.1673-4254.2025.10.11

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (10): 2146-2159.doi: 10.12122/j.issn.1673-4254.2025.10.11

• • 上一篇

加味柴胡桂枝汤通过抑制JAK2/STAT3信号通路改善慢性不可预见性温和应激模型小鼠的焦虑和抑郁状态

梁晓涛¹(), 梁小珊², 熊一凡¹, 谢诗如¹, 朱晓煜¹, 谢炜¹^,²()

^1.南方医科大学中医药学院，广东广州 510515
^2.南方医科大学南方医院中医科，广东广州 510515

收稿日期:2025-07-25 出版日期:2025-10-20 发布日期:2025-10-24
通讯作者: 谢炜 E-mail:1092296938@qq.com;xieweizn@126.com
作者简介:梁晓涛，医师，博士，E-mail: 1092296938@qq.com
基金资助:
国家自然科学基金(82405378);第二届全国名中医工作室(G724290126);中国博士后科学基金(2024M761351);中国博士后科学基金(2025T181075);重大疑难疾病中西医临床协作项目

Modified Chaihu Guizhi Decoction alleviates anxiety- and depression-like behaviors in mice with chronic unpredictable mild stress by inhibiting the JAK2/STAT3 signaling pathway

Xiaotao LIANG¹(), Xiaoshan LIANG², Yifan XIONG¹, Shiru XIE¹, Xiaoyu ZHU¹, Wei XIE¹^,²()

^1.School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
^2.Department of Traditional Chinese Medicine, Nanfang Hospital of Southern Medical University, Guangzhou 510515, China

Received:2025-07-25 Online:2025-10-20 Published:2025-10-24
Contact: Wei XIE E-mail:1092296938@qq.com;xieweizn@126.com
Supported by:
National Natural Science Foundation of China(82405378)

摘要/Abstract

摘要：

目的探讨加味柴胡桂枝汤（MCGD）对慢性不可预见性温和应激模型（CUMS）小鼠焦虑抑郁的干预作用及机制。方法通过文献检索获取加味柴胡桂枝汤的主要化学成分，使用多重数据库分析预测药理机制。动物实验验证：选用雄性SPF C57BL/6J小鼠，每日给予小鼠2次随机应激刺激，共持续28 d，制备CUMS模型。以加味柴胡桂枝汤灌胃或氟西汀腹腔注射进行干预，根据干预方式的不同将小鼠分为对照组（Control）、慢性不可预见性温和应激模型组（CUMS）、氟西汀阳性对照组（FLX）、加味柴胡桂枝汤低剂量组（MCGD-L）、加味柴胡桂枝汤高剂量组（MCGD-H），15只/组。利用蔗糖偏好、强迫游泳实验评估小鼠抑郁状态，利用旷场、高架十字实验评估小鼠焦虑状态，RT-qPCR检测时钟基因、炎症因子，Western blotting检测JAK2/STAT3通路表达水平，免疫荧光检测小胶质细胞的活化水平。结果网络药理学结果显示，加味柴胡桂枝汤改善焦虑抑郁的主要活性成分为槲皮素、金合欢素、芒柄花素、川陈皮素、黄芩素等；GO功能富集分析共得到607条信号通路，其中生物过程447条，细胞组分61条，分子功能99条；KEGG富集分析显示，加味柴胡桂枝汤改善焦虑抑郁的通路主要涉及JAK2/STAT3和NF-κB信号通路。动物实验成功构建CUMS模型，氟西汀阳性对照组和加味柴胡桂枝汤治疗组小鼠焦虑、抑郁状态减轻。加味柴胡桂枝汤可降低Iba1的表达（P<0.01），改善炎症相关指标（P<0.01），逆转时钟基因昼夜节律紊乱（P<0.01）；下调JAK2、p-STAT3、p-NF-κB、IL-1β、IL-6蛋白表达水平（P<0.01）。结论加味柴胡桂枝汤能有效调节炎症通路，抑制JAK2/STAT3信号转导和小胶质细胞过度活化，改善焦虑抑郁状态。

关键词: 加味柴胡桂枝汤, 慢性不可预见性温和应激模型, JAK2/STAT3, 网络药理学, 焦虑, 抑郁

Abstract:

Objective To investigate the mechanisms of Modified Chaihu Guizhi Decoction (MCGD) for ameliorating anxiety- and depression-like behaviors in a mouse model of chronic unpredictable mild stress (CUMS). Methods The main chemical constituents of MCGD were identified through literature review, and network pharmacology analysis was performed to predict the potential pharmacological mechanisms of MCGD. For in vivo validation, male C57BL/6J mice were randomized into control group, CUMS model group, fluoxetine (FLX) treatment group, and low- and high-dose MCGD treatment groups (n=15), and in all but the control group, CUMS models were established by daily exposure to two randomized stressors for 28 consecutive days. Starting from 3 days prior to modeling, MCGD and fluoxetine treatments were administered daily via gavage and intraperitoneal injection, respectively. Depression- and anxiety-like behaviors of the mice were assessed using sucrose preference test, forced swim test, open field test and elevated plus maze test. The changes in mRNA expressions of the clock genes and inflammatory markers and expressions of the JAK2/STAT3 signaling proteins were detected using RT-qPCR and Western blotting, and immunofluorescence staining was used to detect microglia activation in the mice. Results The key active compounds in MCGD identified by network pharmacology analysis included quercetin, acacetin, formononetin, nobiletin, and baicalein. GO analysis identified 607 enriched pathways, and KEGG pathway enrichment revealed significant involvement of the JAK2/STAT3 and NF-κB signaling pathways. In the mouse models of CUMS, treatment with both fluoxetine and MCGD significantly alleviated anxiety- and depression-like behaviors. MCGD treatment significantly reduced Iba1 expression, improved the inflammatory markers, reversed the decrease in clock gene circadian rhythm amplitude, and obviously downregulated the expressions of JAK2, p-STAT3, p-NF-κB, IL-1β, and IL-6 proteins. Conclusion MCGD effectively alleviates anxiety- and depression-like behaviors in CUMS mice by modulating the inflammatory pathways and inhibiting the JAK2/STAT3 signaling pathway.

Key words: Modified Chaihu Guizhi Decoction, chronic unpredictable mild stress model, JAK2/STAT3, network pharmacology, anxiety, depression

梁晓涛, 梁小珊, 熊一凡, 谢诗如, 朱晓煜, 谢炜. 加味柴胡桂枝汤通过抑制JAK2/STAT3信号通路改善慢性不可预见性温和应激模型小鼠的焦虑和抑郁状态[J]. 南方医科大学学报, 2025, 45(10): 2146-2159.

Xiaotao LIANG, Xiaoshan LIANG, Yifan XIONG, Shiru XIE, Xiaoyu ZHU, Wei XIE. Modified Chaihu Guizhi Decoction alleviates anxiety- and depression-like behaviors in mice with chronic unpredictable mild stress by inhibiting the JAK2/STAT3 signaling pathway[J]. Journal of Southern Medical University, 2025, 45(10): 2146-2159.

图/表 12

表1 本研究涉及引物序列

Tab.1 Primer sequences used for RT-qPCR in this study

Primer name	Sequence
IFN-γ Forward	AGCAACAACATAAGCGTCATTGA
IFN-γ Reverse	TGACCTCAAACTTGGCAATACTC
TNF-α Forward	GCCTCCCTCTCATCAGTTCTATG
TNF-α Reverse	ACCTGGGAGTAGACAAGGTACAA
IL-1β Forward	GCAACTGTTCCTGAACTCAACT
IL-1β Reverse	ATCTTTTGGGGTCCGTCAACT
IL-4 Forward	TCCTCACAGCAACGAAGAACA
IL-4 Reverse	AGGCATCGAAAAGCCCGAAA
IL-6 Forward	ACAACCACGGCCTTCCCTACTT
IL-6 Reverse	CACGATTTCCCAGAGAACATGTG
IL-10 Forward	GGTTGCCAAGCCTTATCGGA
IL-10 Reverse	AGACACCTTGGTCTTGGAGCTTA
Bmal1 Forward	CTCCAGGAGGCAAGAAGATTC
Bmal1 Reverse	ATAGTCCAGTGGAAGGAATG
Clock Forward	TTCCTTCCTTAGAGACGAGACT
Clock Reverse	CTAAATGCTACCCTGAGGATAGAG
Cry1 Forward	GATCCACCATTTAGCCAGACAC
Cry1 Reverse	ACAGCCACATCCAACTTCCA
Cry2 Forward	CAAGCACTTGGAACGGAAGG
Cry2 Reverse	GAAGAGGCGGCAGGAGAG
Per1 Forward	CAGGCTAACCAGGAATATTACCAGC
Per1 Reverse	CACAGCCACAGAGAAGGTGTCCTGG
Per2 Forward	CCACACTTGCCTCCGAAATA
Per2 Reverse	ACTGCCTCTGGACTGGAAGA
GAPDH Forward	CAACTACATGGTCTACATGTTC
GAPDH Reverse	CTCGCTCCTGGAAGATG

图1 网络药理学探讨加味柴胡桂枝汤(MCGD)减轻慢性不可预测性温和应激模型(CUMS)焦虑抑郁状态的作用机制

Fig.1 Network pharmacology analysis of the mechanisms by which Modified Chaihu Guizhi Decoction (MCGD) alleviates anxiety- and depression-like behavior in CUMS. A: Venn diagram of shared targets between MCGD and depression. B: Component-target-disease map. C: Core intersection targets. D: Gene Ontology (GO) analysis of the shared targets, categorized into Biological Processes (BP), Molecular Functions (MF), and Cellular Components (CC). E: Bubble chart of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the shared targets.

表2 加味柴胡桂枝汤治疗抑郁症的关键活性成分

Tab.2 Key active components in Modified Chaihu Guizhi Decoction (MCGD) for treatment of depression

Code	ID	Name	Relevance	Soucre
CH9	MOL000098	Quercetin	128	Chinese thorawax root
HQ1	MOL001689	Acacetin	62	Baikal skullcap root
BS4	MOL000422	Kaempferol	55	White peony root
GC9	MOL003896	7-Methoxy-2-methyl Isoflavone	40	Liquorice root
GC10	MOL000392	Formononetin	36	Liquorice root
ZK4	MOL005828	Nobiletin	33	Submature bitter orange
CH10	MOL000354	Isorhamnetin	32	Chinese thorawax root
GC6	MOL002565	Medicarpin	32	Liquorice root
BX3	MOL002714	Baicalein	31	Ternate pinellia
GC63	MOL000497	Licochalcone a	30	Liquorice root

表3 加味柴胡桂枝汤治疗抑郁症核心活性成分与核心靶分子JAK2、STAT3对接结合能

Tab.3 Binding energies of the core active components of MCGD for depression treatment for docking with the core target molecules JAK2 and STAT3

Target	Sample	Estimated ΔG (kcal/mol)
JAK2	CH9	-6.45
JAK2	HQ1	-6.48
JAK2	BS4	-6.40
JAK2	GC9	-5.53
JAK2	GC10	-6.27
JAK2	ZK4	-6.27
JAK2	CH10	-6.7
JAK2	GC6	-5.73
JAK2	BX3	-5.43
JAK2	GC63	-6.13
STAT3	CH9	-5.48
STAT3	HQ1	-5.16
STAT3	BS4	-5.08
STAT3	GC9	-5.9
STAT3	GC10	-5.09
STAT3	ZK4	-7.44
STAT3	CH10	-5.64
STAT3	GC6	-5.02
STAT3	BX3	-4.78
STAT3	GC63	-5.8

图2 分子对接结果可视化

Fig.2 Visualization of the results of molecular docking analysis. A: Docked molecular conformation of JAK2 with CH9. B: Molecular conformation of JAK2 docked with CH10. C: Molecular conformation of JAK2 docked with BS4. D: Molecular conformation of JAK2 docked with ZK4. E: Molecular conformation of JAK2 docked with HQ1.

图3 分子对接结果可视化

Fig.3 Visualization of the results of molecular docking analysis. A: Docked molecular conformation of STAT3 with CH9. B: Molecular conformation of STAT3 docked with CH10. C: Molecular conformation of STAT3 docked with ZK4. D: Molecular conformation of STAT3 docked with GC9. E: Molecular conformation of STAT3 docked with GC63.

图4 加味柴胡桂枝汤显著改善CUMS小鼠的抑郁样行为

Fig.4 MCGD significantly improves depression-like behavior in CUMS mice. A: Experimental design. B: Sucrose preference percentage in the sucrose preference test (SPT). C: Immobility time in the forced swim test (FST). D: Swimming times in the FST. Data are presented as Mean±SD (n=15). Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. ##P<0.01 vs Control group; *P<0.05, **P<0.01 vs CUMS group.

图5 加味柴胡桂枝汤显著改善CUMS小鼠的焦虑样行为

Fig.5 MCGD significantly improves anxiety-like behavior in CUMS mice. A: Trajectory map in the open field test (OFT). B: Total distance in OFT. C: Time percentage spent in center of OFT. D: Trajectory map in the elevated plus maze test (EPM). E: Time percentage spent in open arms of EPM. F: Number of entries spent into open arms of EPM. Data are presented as Mean±SD (n=15). Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. ##P<0.01 vs Control group; **P<0.01 vs CUMS group.

图6 加味柴胡桂枝汤对CUMS小鼠海马组织炎症因子表达水平的影响

Fig.6 Effects of MCGD on mRNA expression of inflammatory factors in the hippocampus of CUMS mice. A: Relative mRNA level of IL-1β. B: Relative mRNA level of IL-6. C: Relative mRNA level of TNF-α. D: Relative mRNA level of IFN-γ. E: Relative mRNA level of IL-4. F: Relative mRNA level of IL-10. Data are presented as Mean±SD (n=6). Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. #P<0.05, ##P<0.01 vs Control group; *P<0.05, **P<0.01 vs CUMS group.

图7 加味柴胡桂枝汤对CUMS小鼠海马组织JAK2/STAT3信号通路的调控作用

Fig.7 Effects of MCGD on the JAK2/STAT3 signaling pathway in the hippocampus of CUMS mice. A: Protein bands of JAK2, p-STAT3, STAT3, p-NF-κB, NF-κB, IL-1β, and IL-6 detected by Western blotting. B-F: Quantitative analysis of JAK2, p-STAT3, STAT3, p-NF-κB, NF-κB, IL-6, and IL-1β protein expression levels. Data are presented as Mean±SD (n=3). Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. ##P<0.01 vs Control group; *P<0.05, **P<0.01 vs CUMS group.

图8 加味柴胡桂枝汤对CUMS小鼠海马组织时钟蛋白基因表达水平的调控作用

Fig.8 Regulatory effect of MCGD on expression levels of clock protein genes in the hippocampus of CUMS mice. A: Normalized circadian rhythm amplitude of Bmal1. B: Normalized circadian rhythm amplitude of Clock1. C: Normalized circadian rhythm amplitude of Cry1. D: Normalized circadian rhythm amplitude of Cry2. E: Normalized circadian rhythm amplitude of Per1. F: Normalized circadian rhythm amplitude of Per2. Data are presented as Mean±SD (n=3). Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. #P<0.05, ##P<0.01 vs Control group; *P<0.05, **P<0.01 vs CUMS group.

图9 加味柴胡桂枝汤对CUMS小鼠海马CA1区小胶质细胞活化水平的影响

Fig.9 Effects of MCGD on microglia activation level in the hippocampal CA1 region of CUMS mice. A: Immunofluorescence images of Iba1 expression (Original magnification: ×200). B: Statistics of Iba1+ cells in the hippocampal CA1 region. C: Statistics of microglia total length of process in the hippocampal CA1 region. Each group included 3 mice, and 4 slices were analyzed per mouse. Data are presented as Mean±SD. Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. ##P<0.01 vs Control group; **P<0.01 vs CUMS group.

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加味柴胡桂枝汤通过抑制JAK2/STAT3信号通路改善慢性不可预见性温和应激模型小鼠的焦虑和抑郁状态

Modified Chaihu Guizhi Decoction alleviates anxiety- and depression-like behaviors in mice with chronic unpredictable mild stress by inhibiting the JAK2/STAT3 signaling pathway

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