Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study

doi:10.19852/j.cnki.jtcm.2025.03.012

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (3): 571-585.DOI: 10.19852/j.cnki.jtcm.2025.03.012

Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study

FENG Chuwen¹^,², LI Chaoran³, Yang Yan⁴, QU Yuanyuan¹^,², SUN Zhongren⁴, SUN Weibo⁶, LIU Tingting⁵, LI Shulin¹^,²(), Yang Tiansong¹^,²()

1 Rehabilitation Department Ⅱ, the First Affiliated Hospital of Heilongjiang University of Chinese Medicine; Harbin 150040, China
2 Heilongjiang Province Key Laboratory of Traditional Chinese Medicine Information, Harbin 150040, China
3 Department of Acupuncture, Zhejiang Chinese Medical University, Hangzhou 310000, China
4 College of Basic Medicine of Heilongjiang University of Chinese Medicine, Harbin 150040, China
5 Graduate School of Heilongjiang University of Chinese Medicine, Harbin 150040, China
6 Graduate School of Harbin Medical University, Harbin 150040, China

Received:2024-11-22 Accepted:2025-02-25 Online:2025-06-15 Published:2025-05-21
Contact: Prof. LI Shulin, Rehabilitation Department Ⅱ, the First Affiliated Hospital of Heilongjiang University of Chinese Medicine; Harbin 150040, China; Heilongjiang Province Key Laboratory of Traditional Chinese Medicine Information, Harbin 150040, China. lisl0022@163.com;Prof. YANG Tiansong, Rehabilitation Department II, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine; Harbin 150040, China; Heilongjiang Province Key Laboratory of Traditional Chinese Medicine Information, Harbin 150040, China. yangtiansong2006@163.com,Telephone: +86-18846178111
Supported by:
National Natural Science Foundation of China projects: Research on the Mechanism of Moxibustion Activating Calcium/ Calmodulin-dependent Protein Kinase ⅡPhosphorylation Mediating Long-term Potentiation to Regulate Synaptic Plasticity in the Treatment of Chronic Fatigue Syndrome Cognitive Impairment(82305394);Research on the Mechanism of Electroacupuncture Regulating Murine Double Minute 2 Ubiquitination Postsynaptic Density Protein 95 Levels to Reshape the Synaptic Structure of Hippocampal Neurons and Improve Chronic Fatigue Syndrome Cognitive Impairment(82074539);Outstanding Youth Project of Heilongjiang Provincial Natural Science Foundation: the Mechanism of Moxibustion in Improving Chronic Fatigue Syndrome Cognitive Impairment by Regulating Calcium/Calmodulin-dependent Protein Kinase II-mediated Long-Term Potentiation(YQ2023H019);Youth Talent Support Project of the Chinese Association of Traditional Chinese Medicine: Research on the Molecular Pathways of Moxibustion at the Zusanli (ST36) Point in Regulating Synaptic Plasticity to Improve Chronic Fatigue Syndrome Cognitive Impairment(2023-QNRC2-A04);China Postdoctoral Science Foundation: Research on the Mechanism of Moxibustion in Regulating Mitochondrial Autophagy Mediating Microglial Polarization to Promote Synaptic Remodeling in Chronic Fatigue Syndrome Cognitive Impairment(2024MD763980);Post-doctoral Program of Heilongjiang Province: based on the Calcium/Calmodulin-dependent Protein Kinase II/Parkin/NLR Family Pyrin Domain Containing 3 Signaling Axis to Explore the Mechanism of Moxibustion in Mitochondrial Autophagy Mediating Microglial Polarization to Promote Synaptic Remodeling in Chronic Fatigue Syndrome Cognitive Impairment(LBH-TZ2420);Study on the Mechanism of Moxibustion at the Zusanli (ST36) Regulating Long-Term Potentiation to Promote Synaptic Remodeling and Improve Cognitive Impairment in Chronic Fatigue Syndrome(LBH-Z23281);Chunhui Plan of the Ministry of Education: Study on the Mechanism of the Tongdu YuPi Tiaoshen Acupuncture in Improving Hippocampal Synaptic Plasticity of Chronic Fatigue Syndrome Cognitive Impairment(HZKY20220308-202201357);Youth Talent Support Project of the Heilongjiang Provincial Association of Traditional Chinese Medicine: Study on the Effect and Mechanism of Tongdu Yupi Tiaoshen Acupuncture on Improving Hippocampal Synaptic Plasticity in Chronic Fatigue Syndrome Cognitive Impairment(2022-QNRC1-05);Research Project of Traditional Chinese Medicine in Heilongjiang Province: Study on the Mechanism of Acupuncture in Improving Hippocampal Synaptic Plasticity of Chronic Fatigue Syndrome Cognitive Impairment(ZHY2022-136)

1. .pdf(6376KB)

Abstract

Abstract:

OBJECTIVE: To observe the effects of moxibustion at Zusanli (ST36) on rats with chronic fatigue syndrome (CFS) and to analyze the mechanisms of moxibustion through hippocampal Proteomics.
METHODS: Male Sprague-Dawley (SD) rats were randomly divided into three groups: control group (CON), model group (MOD), and moxibustion group (MOX), with 12 rats in each group. The MOD and MOX groups underwent chronic multi-factor stress stimulation for 35 d to establish the CFS model. After modeling, the rats in the MOX group received mild moxibustion at Zusanli (ST36) (bilateral) for 10 minutes daily for 28 d. During the treatment period, rats in both the MOD and MOX groups continued modeling, while the CON group was kept under normal breeding conditions. The general condition of the rats was monitored, and behaviors were assessed using the Open Field Test (OFT), Exhaustion Treadmill Test, and Morris Water Maze (MWM). Hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM) were employed to observe morphological changes in the hippocampus. Label-free Proteomics were utilized to identify differentially expressed proteins (DEPs) in the hippocampus, followed by bioinformatics analysis. The reliability of the Proteomics results was verified using Parallel Reaction Monitoring.
RESULTS: A: Moxibustion at Zusanli (ST36) significantly reduced the general condition score of CFS rats, improved their behavioral performance in OFT, treadmill and MWM, and repaired the pathological and synaptic structural damage in the hippocampus.B: We identified DEPs by applying a fold change threshold of 1.2 and a significance level of P < 0.05. In the comparison between the CON and the MOD, we identified a total of 72 DEPs (31 up-regulated and 41 down-regulated) associated with the development of CFS. In the comparison between the MOX and the MOD group, we identified a total of 103 DEPs (40 up-regulated and 63 down-regulated) related to the therapeutic effects of moxibustion. Gene Ontology (GO) enrichment analysis showed that CFS and moxibustion treatment were related to multiple biological processes, molecular functions, and cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that CFS pathogenesis was linked to base excision repair, steroid biosynthesis, and systemic lupus erythematosus, Furthermore, the treatment of CFS with moxibustion was relevant to terpenoid skeleton biosynthesis.C: Compared with the two comparison groups, we identified 16 potential biomarkers, noting that moxibustion reversed the up-regulation of 14 DEPs and the down-regulation of 2 DEPs in CFS. These proteins are mainly associated with synaptic plasticity, ribosomal function, neurotransmitter secretion, glycine metabolism, and mitochondrial function.
CONCLUSION: Moxibustion at Zusanli (ST36) is effective in treating CFS, the potential biomarkers identified by Proteomics confirm that the mechanisms of moxibustion involve multiple targets and pathways, which may be key to regulating the structural and functional damage in the hippocampus associated with CFS, highlighting their significant value for future research.

Key words: moxibustion, point ST36 (Zusanli), fatigue syndrome, chronic, proteomics, computational biology

FENG Chuwen, LI Chaoran, Yang Yan, QU Yuanyuan, SUN Zhongren, SUN Weibo, LIU Tingting, LI Shulin, Yang Tiansong. Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study[J]. Journal of Traditional Chinese Medicine, 2025, 45(3): 571-585.

Figures/Tables 3

Figure 1 Effects of Moxibustion Zusanli (ST36) on general condition score and behavioristics of rats A: result of general condition score variation among the three groups; B: result of exhaustive treadmill time variation among the three groups; C: result of OFT; C1: crossing score among the three groups; C2: numbers of crossing the central regionin among the three groups; D: result of MWW test; D1: crossing score among the three groups; D2: Numbers of crossing the central regionin among the three groups. CON group: Normal breeding; MOD group: Modeling + Binding during treatment; MOX group: Modeling + Moxibustion at bilateral Zusanli (ST36) 10 min/d for 4 weeks. M represents the molding stage and A represents the moxibustion treatment stage. OFT: Open Field Test; MWW: Morris Water Maze. Statistical analyses were measured using one-way analysis of variance followed by post hoc Bonferroni correction for multiple comparisons. Data were presented as mean ± standard deviation (n = 12), aP < 0.05, compared with the CON group; bP < 0.05, compared with the MOD group.

Figure 2 Effects of Moxibustion Zusanli (ST36) on the morphological structure of CA1 region in hippocampus of rats A: results of HE staining (× 200，X = 50 μm, the arrows represent the phenomenon of nerve fibers being twisted into knots); B: results of TEM (×20050, X = 500 nm, the red box represents typical synaptic structural damage); A1, B1: CON group; A2, B2: MOD group; A3, B3: MOX group. CON group: Normal breeding; MOD group: Modeling + Binding during treatment; MOX group: Modeling + Moxibustion at bilateral Zusanli (ST36) 10 min/d for 4 weeks. HE: hematoxylin and eosin; TEM: transmission electron microscopy.

Table 1 Potential Biomarkers for Moxibustion Treatment of CFS Rats

Accession	Protein name	Gene symbol	CON vs MOD		MOX vs MOD
Accession	Protein name	Gene symbol	Fold change	P value	Fold change	P value
Q157S1	CREB-regulated transcription coactivator 1	Crtc1	1.528	0.029	1.427	0.022
B0K008	Eukaryotic Translation Initiation Factor 1	Eif1	1.498	0.014	1.741	0.031
Q6AYS2	Sideroflexin	Sfxn1	0.822	0.044	0.778	0.020
Q642B0	Glypican 4	Gpc4	0.802	0.045	0.784	0.040
D4A3M8	Non-Catalytic Region Of Tyrosine Kinase Adaptor Protein 2 (Predicted)	Nck2	0.751	0.037	0.743	0.049
P61354	60s Ribosomal Protein L27	Rpl27	0.738	0.035	0.739	0.030
A0A0G2K7F7	Tropomyosin Alpha-1 Chain	Tpm1	0.738	0.028	0.712	<0.00001
B5DF51	Membrane Magnesium Transporter 1	Mmgt1	0.723	0.022	0.729	0.036
Q6AY71	Protein C8orf37 Homolog	N/A	0.719	0.034	0.627	0.005
Q4V7F2	Cysteine-Rich With EGF-Like Domain Protein 1	Creld1	0.706	0.030	0.731	0.030
Q76IJ9	Elav-Like Protein	Elavl3	0.706	0.030	0.744	0.034
A0A0G2JY31	Alpha-1-Antiproteinase	Serpina1	0.680	0.014	0.764	0.020
Q5RK10	60s Ribosomal Protein L13a	Rpl13a	0.657	0.021	0.732	0.045
G3V6M3	Synaptotagmin Ⅱ	Syt2	0.619	0.006	0.607	0.005
Q5I0P2	Glycine Cleavage System H Protein, Mitochondrial	Gcsh	0.605	0.012	0.66	0.049
D3Z9Z0	Ankyrin 1, Erythroid	Ank1	0.587	0.039	0.668	0.014

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Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study

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