Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San (加味丹栀逍遥散) in a chronic unpredictable mild stress mouse model of depression

doi:10.19852/j.cnki.jtcm.2025.01.003

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (1): 22-31.DOI: 10.19852/j.cnki.jtcm.2025.01.003

Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San (加味丹栀逍遥散) in a chronic unpredictable mild stress mouse model of depression

LI Yajing¹^,², WANG Baoying¹^,², SHAO Wenxue³^,⁴, LU Shuaifei³^,⁵, SU Pan¹^,², BAI Ming¹^,², XU Erping³^,⁴(), LI Yucheng¹^,²()

1 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Zhengzhou 450046, China
2 Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China
3 Henan Collaborative Innovation Center for Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China
4 School of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
5 School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China

Received:2023-12-22 Accepted:2024-04-15 Online:2025-02-15 Published:2025-01-10
Contact: XU Erping, Henan Collaborative Innovation Center for Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China; School of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China. xuerping0371@163.com; LI Yucheng, Henan Collaborative Innovation Center for Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China; Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China. liyucheng@hactcm. edu.cn, Telephone: +86-13633836165; +86-13938231459
Supported by:
the National Natural Science Foundation of China: Study on the Biological Basis of Jiawei Danzhi Xiaoyaosan in Treatment of Depression based on Network Pharmacology and Proteomics(81973739);Natural Science Excellent Youth Fund of Henan Province: the Mechanism of Baicalin Regulates the GSK3B-Mediated Axoplasmic Transport in the Treatment of Depression(202300410249);Science and Technology Research Project of Henan Province: Study on the Antidepressant Mechanism of Jiawei Danzhi Xiaoyaosan based on the NOD-like Receptor Thermal Protein Domain-associated Protein and Tripartite Motif-containing Protein 31 Ubiquitination Pathway(222102310233);Study on the Mechanism of Jiawei Danzhi Xiaoyaosan in the Treatment of Depression by Regulating M1/M2 Polarization and Microglia Autophagy(232102310419)

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Abstract

Abstract:

OBJECTIVE: To reveal the antidepressant mechanisms of Jiawei DanZhiXiaoYaoSan (加味丹栀逍遥散,JD) in chronic unpredictable mild stress (CUMS)-induced depression in mice.

METHODS: Using the CUMS mouse model of depression, the antidepressant effects of JD were assessed using the sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Tandem mass tag (TMT)-based quantitative proteomic analysis of the brain was performed following JD treatment. Hierarchical clustering, Gene Ontology function annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interactions (PPIs) were used to analyze differentially expressed proteins (DEPs), which were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.

RESULTS: Behavioral tests confirmed the anti-depressant effects of JD, and bioinformatics analysis revealed 59 DEPs, including 33 up-regulated and 26 down-regulated proteins, between the CUMS and JD-M groups. KEGG and PPI analyses revealed that neuro-filament proteins and the Ras signaling pathway may be key targets of JD in the treatment of depression. qRT-PCR and Western blotting results demonstrated that CUMS reduced the protein expression of neurofilament light (NEFL) and medium (NEFM) and inhibited the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2), whereas JD promoted the phosphorylation of ERK1/2 and up-regulated the protein expression of NEFL and NEFM.

CONCLUSIONS: The antidepressant mechanism of JD may be related to the up-regulation of p-ERK1/2 and neurofilament proteins.

Key words: depression, proteomics, intermediate filaments, mitogen-activated protein kinases, Jiawei Danzhi Xiaoyaosan

LI Yajing, WANG Baoying, SHAO Wenxue, LU Shuaifei, SU Pan, BAI Ming, XU Erping, LI Yucheng. Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San (加味丹栀逍遥散) in a chronic unpredictable mild stress mouse model of depression[J]. Journal of Traditional Chinese Medicine, 2025, 45(1): 22-31.

Figures/Tables 6

Figure 1 The quality control of aqueous decoction of JD A: BPC diagram of mixed standards (positive ions); B: BPC diagram of mixed standards (negative ions); C: BPC diagram of Chinese medicine decoction about JD (positive ions); D: BPC diagram of Chinese medicine decoction about JD (negative ions).1: N-acetylglucosamine; 2: paeoniflorin; 3: quercetin; 4: naringin; 5: kaempferol; 6: formononetin; 7: licoricchalcone-A. The black numbers in the figure correspond to the substances detected in the mixed standards, while the red numbers represent the substances detected in the JD decoction. JD: Jiawei Danzhi Xiaoyaosan; BPC: business process chart.

Figure 2 Effects of JD on the depression-like behaviors in CUMS mice A: sucrose preference test; B: forced swimming test; C: tail suspension test. Control: normal healthy mice were given an equal volume of normal saline by gavage once daily from weeks 9 to 12; CUMS: mice subjected to chronic unpredictable mild stress for 12 weeks to induce a depression model were administered an equal volume of normal saline once daily from weeks 9 to 12; FLX: depression model mice treated with fluoxetine at dose of 20 mg/kg once daily from weeks 9 to 12; JD-L: depression model mice treated with Jiawei Danzhi Xiaoyaosan at dose of 17.6 mg/kg once daily from weeks 9 to 12; JD-M: depression model mice treated with Jiawei Danzhi Xiaoyaosan at dose of 35.2 mg/kg once daily from weeks 9 to 12; JD-H: depression model mice treated with Jiawei Danzhi Xiaoyaosan at dose of 52.8 mg/kg once daily from weeks 9 to 12. CUMS: chronic unpredictable mild stress; FLX: fluoxetine; JD-L: Jiawei Danzhi Xiaoyaosan low dose; JD-M: Jiawei Danzhi Xiaoyaosan medium dose; JD-H: Jiawei Danzhi Xiaoyaosan high dose; LSD: least significant difference. The data were expressed as the mean ± standard error of the mean (n = 8 for each group) and analyzed by one-way analysis of variance followed by Fisher’s LSD post hoc test. Compared to the CUMS group, aP < 0.01, bP < 0.001, and cP < 0.05.

Table 1 The detailed information of 59 differentially expressed proteins

No.	ID	Protein name	FC	P value
1	P19246	Neurofilament heavy polypeptide	1.6	0.010
2	P60202	Myelin proteolipid protein	1.5	0.032
3	Q9WVT6	Carbonic anhydrase 14	1.5	0.033
4	P04370	Myelin basic protein	1.5	0.029
5	Q921C1	Gap junction gamma-3 protein	1.4	0.004
6	Q6PHZ8	Kv channel-interacting protein 4	1.4	0.021
7	P08553	Neurofilament medium polypeptide	1.4	0.040
8	P20917	Myelin-associated glycoprotein	1.4	0.044
9	Q8BGN3	Glycerophosphocholine cholinephosphodiesterase ENPP6	1.4	0.030
10	P08551	Neurofilament light polypeptide	1.4	0.020
11	Q9JL62	Glycolipid transfer protein	1.4	0.039
12	Q8K298	Anillin	1.4	0.027
13	P61953	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11	1.3	0.031
14	P28661	Septin-4	1.3	0.020
15	Q8K406	Leucine-rich repeat LGI family member 3	1.3	0.014
16	P46660	Alpha-internexin	1.3	0.023
17	P51910	Apolipoprotein D	1.3	0.035
18	Q3UH99	Protein shisa-6	1.3	0.036
19	Q0VGY8	Protein TANC1	1.3	0.003
20	Q5NCI0	Up-regulator of cell proliferation	1.3	0.034
21	P55012	Solute carrier family 12 member 2	1.3	0.008
22	Q9QYB1	Chloride intracellular channel protein 4	1.3	0.047
23	Q8BM92	Cadherin-7	1.3	0.040
24	P26350	Prothymosin alpha	1.2	0.033
25	Q9ESM3	Hyaluronan and proteoglycan link protein 2	1.2	0.005
26	Q6P8J2	Diamine acetyltransferase 2	1.2	0.022
27	Q9D154	Leukocyte elastase inhibitor A	1.2	0.029
28	Q62442	Vesicle-associated membrane protein 1	1.2	0.013
29	Q8BWC0	Two pore calcium channel protein 2	1.2	0.038
30	Q91YE5	Bromodomain adjacent to zinc finger domain protein 2A	1.2	0.022
31	O54991	Contactin-associated protein 1	1.2	0.019
32	P00920	Carbonic anhydrase 2	1.2	0.050
33	Q3V0K9	Plastin-1	1.2	0.035
34	P20357	Microtubule-associated protein 2	0.8	0.014
35	Q8CG79	Apoptosis-stimulating of p53 protein	0.8	0.020
36	P70392	Ras-specific guanine nucleotide-releasing factor 2	0.8	0.032
37	Q6PGF2	MORN repeat-containing protein 4	0.8	0.040
38	Q61810	Latent-transforming growth factor beta-binding protein 3	0.8	0.008
39	Q5ND34	WD repeat-containing protein 81	0.8	0.047
40	O35710	Nocturnin	0.8	0.032
41	Q80Z24	Neuronal growth regulator 1	0.8	0.006
42	P16390	Potassium voltage-gated channel subfamily A member 3	0.8	0.036
43	Q922S4	cGMP-dependent 3',5'-cyclic phosphodiesterase	0.8	0.042
44	P49813	Tropomodulin-1	0.8	0.020
45	Q3UH93	Plexin-D1	0.8	0.024
46	Q8CHT1	Ephexin-1	0.8	0.036
47	Q99J85	Neuronal pentraxin receptor	0.8	0.017
48	Q8K3Z0	Nucleotide-binding oligomerization domain-containing protein 2	0.8	0.008
49	Q6NS52	Diacylglycerol kinase beta	0.8	0.028
50	Q9JJ69	Kv channel-interacting protein 2	0.8	0.043
51	Q9R111	Guanine deaminase	0.8	0.031
52	Q9QZB1	Regulator of G-protein signaling 20	0.8	0.009
53	Q7TPR4	Alpha-actinin-1	0.8	0.029
54	P60764	Ras-related C3 botulinum toxin substrate 3	0.8	0.044
55	P97441	Zinc transporter 3	0.7	0.027
56	Q8BGZ1	Hippocalcin-like protein 4	0.7	0.025
57	Q8K012	Formin-binding protein 1-like	0.7	0.026
58	Q8JZW4	Copine-5	0.7	0.022
59	D3YVF0	A-kinase anchor protein 5	0.7	0.040

Table 1 The detailed information of 59 differentially expressed proteins

No.	ID	Protein name	FC	P value
1	P19246	Neurofilament heavy polypeptide	1.6	0.010
2	P60202	Myelin proteolipid protein	1.5	0.032
3	Q9WVT6	Carbonic anhydrase 14	1.5	0.033
4	P04370	Myelin basic protein	1.5	0.029
5	Q921C1	Gap junction gamma-3 protein	1.4	0.004
6	Q6PHZ8	Kv channel-interacting protein 4	1.4	0.021
7	P08553	Neurofilament medium polypeptide	1.4	0.040
8	P20917	Myelin-associated glycoprotein	1.4	0.044
9	Q8BGN3	Glycerophosphocholine cholinephosphodiesterase ENPP6	1.4	0.030
10	P08551	Neurofilament light polypeptide	1.4	0.020
11	Q9JL62	Glycolipid transfer protein	1.4	0.039
12	Q8K298	Anillin	1.4	0.027
13	P61953	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11	1.3	0.031
14	P28661	Septin-4	1.3	0.020
15	Q8K406	Leucine-rich repeat LGI family member 3	1.3	0.014
16	P46660	Alpha-internexin	1.3	0.023
17	P51910	Apolipoprotein D	1.3	0.035
18	Q3UH99	Protein shisa-6	1.3	0.036
19	Q0VGY8	Protein TANC1	1.3	0.003
20	Q5NCI0	Up-regulator of cell proliferation	1.3	0.034
21	P55012	Solute carrier family 12 member 2	1.3	0.008
22	Q9QYB1	Chloride intracellular channel protein 4	1.3	0.047
23	Q8BM92	Cadherin-7	1.3	0.040
24	P26350	Prothymosin alpha	1.2	0.033
25	Q9ESM3	Hyaluronan and proteoglycan link protein 2	1.2	0.005
26	Q6P8J2	Diamine acetyltransferase 2	1.2	0.022
27	Q9D154	Leukocyte elastase inhibitor A	1.2	0.029
28	Q62442	Vesicle-associated membrane protein 1	1.2	0.013
29	Q8BWC0	Two pore calcium channel protein 2	1.2	0.038
30	Q91YE5	Bromodomain adjacent to zinc finger domain protein 2A	1.2	0.022
31	O54991	Contactin-associated protein 1	1.2	0.019
32	P00920	Carbonic anhydrase 2	1.2	0.050
33	Q3V0K9	Plastin-1	1.2	0.035
34	P20357	Microtubule-associated protein 2	0.8	0.014
35	Q8CG79	Apoptosis-stimulating of p53 protein	0.8	0.020
36	P70392	Ras-specific guanine nucleotide-releasing factor 2	0.8	0.032
37	Q6PGF2	MORN repeat-containing protein 4	0.8	0.040
38	Q61810	Latent-transforming growth factor beta-binding protein 3	0.8	0.008
39	Q5ND34	WD repeat-containing protein 81	0.8	0.047
40	O35710	Nocturnin	0.8	0.032
41	Q80Z24	Neuronal growth regulator 1	0.8	0.006
42	P16390	Potassium voltage-gated channel subfamily A member 3	0.8	0.036
43	Q922S4	cGMP-dependent 3',5'-cyclic phosphodiesterase	0.8	0.042
44	P49813	Tropomodulin-1	0.8	0.020
45	Q3UH93	Plexin-D1	0.8	0.024
46	Q8CHT1	Ephexin-1	0.8	0.036
47	Q99J85	Neuronal pentraxin receptor	0.8	0.017
48	Q8K3Z0	Nucleotide-binding oligomerization domain-containing protein 2	0.8	0.008
49	Q6NS52	Diacylglycerol kinase beta	0.8	0.028
50	Q9JJ69	Kv channel-interacting protein 2	0.8	0.043
51	Q9R111	Guanine deaminase	0.8	0.031
52	Q9QZB1	Regulator of G-protein signaling 20	0.8	0.009
53	Q7TPR4	Alpha-actinin-1	0.8	0.029
54	P60764	Ras-related C3 botulinum toxin substrate 3	0.8	0.044
55	P97441	Zinc transporter 3	0.7	0.027
56	Q8BGZ1	Hippocalcin-like protein 4	0.7	0.025
57	Q8K012	Formin-binding protein 1-like	0.7	0.026
58	Q8JZW4	Copine-5	0.7	0.022
59	D3YVF0	A-kinase anchor protein 5	0.7	0.040

Figure 3 Proteomic analysis of mouse brains from the CUMS and JD groups A: volcano plots for the distribution of DEPs; B: heatmap of 59 DEPs between the CUMS and JD groups. M: model group, mice subjected to CUMS for 12 weeks to induce a depression model were administered an equal volume of saline once daily from weeks 9 to 12; JD: JD group, depression model mice treated with Jiawei Danzhi Xiaoyaosan at dose of 35.2 mg/kg once daily from weeks 9 to 12. Blue dots represent down-regulation of expression, red dots represent up-regulation and gray dots represent no significant change compared to the model group. P19246, P08553, and P08551 represented NEFH, NEFM, and NEFL, respectively. Blue squares represent down-regulation of expression and red squares represent up-regulation when compared to the model group. CUMS: chronic unpredictable mild stress; JD: Jiawei Danzhi Xiaoyaosan; DEPs: differentially expressed proteins; NEFH: neurofilament heavy polypeptide; NEFM: neurofilament medium polypeptide; NEFL: neurofilament light polypeptide. P-values were calculated between the JD and M groups followed by independent samples t-test. Changes ratios > 1.2 or < 0.83 and P-values < 0.05 were considered to be DEPs. n = 3 for each group.

Table 2 The score of protein-protein interaction

Protein1	Protein2	Protein-Protein interaction score
Nefm	Nefl	0.989
Plp1	Mbp	0.952
Plp1	Mag	0.934
Mbp	Mag	0.914
Rac3	Ngef	0.889
Nefl	Nefh	0.821
Nefm	Nefh	0.819
Mbp	Cntnap1	0.812
Nefl	Map2	0.786
Rac3	Gng11	0.774

Figure 4 Effects of JD on the mRNA and protein expression of NEFH, NEFM and NEFL, and the protein expression of ERK1/2 and p38 MAPK in CUMS mice A: mRNA levels of NEFH; B: mRNA levels of NEFM; C: mRNA levels of NEFL; D: immunoblot bands for NEFH, NEFM, and NEFL; E: relative protein levels of NEFH; F: relative protein levels of NEFM; G: relative protein levels of NEFL; H: immunoblot bands for ERK1/2 and p-ERK1/2; I: rate of p-ERK1/2/ ERK1/2; J: immunoblot bands for p-p38 and p38; K: rate of p-p38/p38. Control: normal healthy mice; CUMS: mice subjected to chronic unpredictable mild stress for 12 weeks to induce depression model; JD-M: depression model mice treated with Jiawei Danzhi Xiaoyaosan at dose of 35.2 mg/kg from weeks 9-12, once daily. CUMS: chronic unpredictable mild stress; FLX: fluoxetine; JD-L: Jiawei Danzhi Xiaoyaosan low dose; JD-M: Jiawei Danzhi Xiaoyaosan medium dose; JD-H: Jiawei Danzhi Xiaoyaosan high dose; NEFH: neurofilament heavy polypeptide; NEFM: neurofilament medium polypeptide; NEFL: neurofilament light polypeptide; ERK1/2: extracellular signal-regulated kinase 1/2; p-ERK1/2: phospho-ERK1/2; p38 MAPK: p38 mitogen-activated protein kinase; p-p38: phospho-p38; qPCR: real-time quantitative polymerase chain reaction; WB: Western blot. The data were expressed as the mean ± standard error of the mean (n = 5 in qPCR; n = 3 in WB). Compared to the CUMS group, aP < 0.001, bP < 0.01, and cP < 0.05.

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Quantitative proteomic analysis of the brain reveals the potential antidepressant mechanism of Jiawei Danzhi Xiaoyao San (加味丹栀逍遥散) in a chronic unpredictable mild stress mouse model of depression

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