OBJECTIVE: To observe the effect of electroacupuncture (EA) on behavior and hippocampal protein phosphorylation in rats with chronic fatigue syndrome (CFS), so as to explore its mechanisms underlying improvement of CFS.
METHODS: Male SD rats were randomly divided into control, model and EA groups (n=12 rats in each group). The CFS model was established by chronic multifactor combined with stress stimulation (treadmill training + restraint stress + sleep disturbance + crowded environment). For rats of the EA group, EA (1 mA, frequency of 10 Hz) was applied to \"Shenting\" (GV24) (with an acupuncture needle penetrated from GV24 to \"Baihui\" ［GV20］) and \"Dazhui\" (GV14) for 15 min, once daily for 28 days. After treatment, the body weight, food intake and water intake of rats in each group were observed. The fatigue degree of rats was evaluated by Semi-quantitative score observation table of the general condition of experimental rats.The open field test (OFT) was used to assess the rats\'anxiety severity by detecting the total number of grid-crossing and the times of the central area entered in 5 min, and Morris water maze test was employed to assess the rats\' learning-memory ability by detecting the escape latency in 1 min, and the times of the original platform quadrant crossing in 1 min. The hippocampaus was taken for phosphorylated Label-free quantitative proteomics analysis by using Maxquant technology based on full scan mode to calculate the integral of each peptide signal of liquid chromatography-mass spectrometry(LC-MS). The differentially-expressed proteins (>1.5 folds for up-regulation or <0.67 folds for down-regulation) were evaluated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.
RESULTS: Compared with the control group, the body weight, food intake, and the times of original-platform quadrant crossing of spatial exploring of Morris water maze test were significantly decreased (P<0.01, P<0.05) , and the score of general conditions, times of grid-crossing and center area-entering of OFT, and the escape latency of navigation task were apparently increased (P<0.01) in rats of the model group. After EA intervention, the decreased original-platform quadrant crossing, and the increased score of general conditions, times of grid-crossing and the escape latency of navigation task were all reversed (P<0.01, P<0.05). Outcomes of proteomics analysis indicated that compared with the model group, there were 297 differentially expressed peptide (48 up-regulated and 249 down-regulated) segments in the control group, and there were 245 differentially expressed peptide (185 up-regulated and 60 down-regulated) segments in the EA group, in which, 25 overlapping peptide segments were reversed after EA treatment, corresponding to 24 proteins, mainly involving cytoskeletal structure. GO function annotation analysis showed that the top three differentially expressed phosphorylated proteins involved in the effect of EA intervention were the actin filament polymerization, protein depolymerization and cytoskeletal tissue in the biological process, the actin binding, structural molecular activity and cytoskeletal protein binding in the molecular function, and the cytoskeleton, dendrites and dendritic trees in the cellular component, respectively. The KEGG pathway annotation analysis for differentially expressed phosphorylated proteins showed that theinsulin secretion, axon guidance, phosphatidylinositol signaling system and lysine biosynthesis, etc. were involved in the effect of EA intervention.
CONCLUSIONS: EA of GV24-GV20 and GV14 can improve the general state, anxiety and learning-memory ability of CFS model rats, which may be related to its functions in regulating the hippocampal protein phosphorylation level, and repairing the structure and function of synapses in hippocampus.
目的: 观察电针对慢性疲劳综合征（CFS）大鼠行为学和海马组织蛋白磷酸化的影响，探讨电针治疗CFS的作用机制。方法: 将雄性SD大鼠随机分为空白组、模型组和电针组，每组12只。采用多因素慢性复合应激法制备CFS模型。电针组大鼠给予电针“神庭”（透刺“百会”）和“大椎”治疗，每日1次，每次15 min，连续28 d。治疗结束后观察各组大鼠体质量、摄食量和饮水量，采用实验大鼠一般情况半定量评分观察表评价大鼠的疲劳程度，采用旷场实验及Morris水迷宫实验评价大鼠焦虑程度和学习记忆能力。取各组大鼠海马组织进行磷酸化Label-free定量蛋白质组学检测。结果: 治疗结束后，与空白组比较，模型组大鼠体质量降低（P<0.01），摄食量减少（P<0.05），一般情况半定量评分升高（P<0.01），旷场实验总穿格次数和进入中央区次数均增多（P<0.01），Morris水迷宫实验逃避潜伏期延长（P<0.01）、穿越原平台次数减少（P<0.01）。与模型组比较，电针组大鼠一般情况半定量评分降低（P<0.01），旷场实验总穿格次数减少（P<0.05），Morris水迷宫实验逃避潜伏期缩短（P<0.01）、穿越原平台次数增加（P<0.01）。与空白组比较，模型组有297个差异表达肽段，对应255个蛋白，与模型组比较，电针组有245个差异表达肽段，对应198个蛋白，其中共有24个重合蛋白在电针治疗后表达回调。GO分析表明，电针干预的作用在生物学过程方面主要为对蛋白质聚合和细胞骨架组织的调节，在分子功能聚类上表现为对蛋白质聚合的调节，在细胞组分聚类方面表现为对突触功能的影响。KEGG分析结果显示，电针干预对胰岛素分泌、轴突导引、磷脂酰肌醇信号系统及赖氨酸生物合成等对中枢神经系统组织功能有重要作用的信号通路产生了影响。结论: 电针可以改善CFS模型大鼠的疲劳状态，缓解焦虑情绪，提高学习记忆能力，其机制可能与调节海马组织蛋白磷酸化水平有关。.

BACKGROUND: Chronic fatigue syndrome (CFS) is a long-term and complex chronic disease that seriously affects the physical and mental health and quality of life of patients. Massage, as one of the methods in traditional Chinese medicine, can treat both symptoms and root causes and is widely used to treat CFS. The main purpose is to systematically evaluate the impact of massage therapy on the efficacy and safety of CFS patients, providing a reference for clinical practice.
METHODS: By searching for literature published in PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, VIP Database, and China National Knowledge Infrastructure Database until November 2023, randomized controlled trial studies were selected according to the established inclusion and exclusion criteria. The Cochrane system evaluation manual was used to evaluate the quality of the included studies, and RevMan5.4 software was used for meta-analysis.
RESULTS: 32 randomized controlled trials were included, with a total of 2594 CFS patients. Meta-analysis showed that the total score of the fatigue scale (FS-14) in the treatment group, MD = -1.59, 95% CI (-1.84, -1.34), P < .00001; Physical fatigue score, MD = -1.30, 95% CI (-1.60, -1.00), P < .00001; Mental fatigue score, MD = -0.84, 95% CI (-0.99, -0.72), P < .0001]; Effective rate [RR = 1.23, 95% CI (1.19,1.28), P < .00001]; all indicators were superior to the control group, Only one study reported adverse reactions, including local swelling, skin bruising, and nausea.
CONCLUSIONS: Our research findings suggest that massage therapy has a significant therapeutic effect on CFS, avoiding adverse reactions and improving fatigue symptoms. Therefore, massage therapy for chronic fatigue syndrome should be further promoted and applied.

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Central fatigue is a common pathological state characterized by psychological loss of drive, lack of appetite, drowsiness, and decreased psychic alertness. The mechanism underlying central fatigue is still unclear, and there is no widely accepted successful animal model that fully represents human characteristics. We aimed to construct a more clinically relevant and comprehensive animal model of central fatigue. In this study, we utilized the Modified Multiple Platform Method (MMPM) combined with alternate-day fasting (ADF) to create the animal model. The model group rats are placed on a stationary water environment platform for sleep deprivation at a fixed time each day, and they were subjected to ADF treatment. On non-fasting days, the rats were allowed unrestricted access to food. This process was sustained over a period of 21 days. We evaluated the model using behavioral assessments such as open field test, elevated plus maze test, tail suspension test, Morris water maze test, grip strength test, and forced swimming test, as well as serum biochemical laboratory indices. Additionally, we conducted pathological observations of the hippocampus and quadriceps muscle tissues, transmission electron microscope observation of mitochondrial ultrastructure, and assessment of mitochondrial energy metabolism and oxidative stress-related markers. The results revealed that the model rats displayed emotional anomalies resembling symptoms of depression and anxiety, decreased exploratory behavior, decline in learning and memory function, and signs of skeletal muscle fatigue, successfully replicating human features of negative emotions, cognitive decline, and physical fatigue. Pathological damage and mitochondrial ultrastructural alterations were observed in the hippocampus and quadriceps muscle tissues, accompanied by abnormal mitochondrial energy metabolism and oxidative stress in the form of decreased ATP and increased ROS levels. In conclusion, our ADF+MMPM model comprehensively replicated the features of human central fatigue and is a promising platform for preclinical research. Furthermore, the pivotal role of mitochondrial energy metabolism and oxidative stress damage in the occurrence of central fatigue in the hippocampus and skeletal muscle tissues was corroborated.

BACKGROUND: Chronic fatigue syndrome (CFS) severely impact patients\' quality of life and lacks well-acknowledged drug therapy. Sijunzi decoction (SJZD), a classical Chinese herbal formula, has been widely used for spleen deficiency syndrome like fatigue in China. However, there is a lack of evidence on the efficacy of SJZD in treating CFS.
OBJECTIVE: To evaluate the efficacy and safety of SJZD for CFS.
METHODS: A multi-center, double-blinded, randomized controlled trial.
METHODS: Participants with definite diagnoses of CFS and spleen deficiency syndrome were randomly assigned in 1:1 ratio to receive SJZD or placebo granules for 2 months. The primary outcome was the change of Chalder fatigue questionnaire (CFQ) scoring after treatment. Other outcomes included changes in short form-36 physical function (SF36-PF) score, spleen deficiency scale score, Euroqol Questionnaire-Visual Analogue Scale (ED-VAS) score, and clinical global impression (CGI) evaluating by corresponding questionnaires. Fecal metagenome sequencing was conducted to explore the potential mechanism of SJZD effect.
RESULTS: From June 2020 to July 2021, 105 of 127 participants completed the study at four hospitals in China. After a 2-month treatment, intention-to-treat (ITT) analysis found participants who received SJZD had larger reduction than placebo control (mean change 6.65 [standard deviation (SD) 6.11] points vs. 5.31 [SD 5.19] points; difference 1.34, 95 % confidence interval [CI] -0.65 to 3.33). Per-protocol (PP) analysis reported confirmative results with a significant difference between SJZD and placebo groups (2.24, 95 % CI 0.10 to 4.39). SJZD also significantly improved overall health status compared with placebo in per-protocol population (p = 0.009). No significant difference was found between groups in changes of SF36-PF, spleen deficiency scale scoring, and CGI. Fecal metagenome sequencing and correlation analyses indicated that the beneficial effect of SJZD may be related to the abundance change of Pediococcus acidilactici. No serious adverse event or abnormal laboratory test was found during the whole study.
CONCLUSIONS: Our results indicated that SJZD can improve fatigue symptom and overall health status in patients with CFS under good medication adherence. Potential therapeutic effects may be related to the regulation of gut microbiota. Large-scale trials with longer intervention period are encouraged to further support SJZD\'s application.
BACKGROUND: (ID, ISRCTN23930966, URL = https://www.isrctn.com/ISRCTN23930966).

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID.
OBJECTIVE: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers.
METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5′-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR).
RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709).
CONCLUSIONS: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors. To delineate the impact of ACE + NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles. ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls. Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated). Partial least squares analysis shows that ACE + NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor. The physiosomatic and FF symptoms of FE-MDMD are partly caused by immune-associated neurotoxicity due to T helper (Th)-1 polarization and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

BACKGROUND: Fatigue is a common symptom after viral infection. Chinese herbal medicine (CHM) is thought to be a potential effective intervention in relieving fatigue.
OBJECTIVE: To assess the effectiveness and safety of CHM for the treatment of post-viral fatigue.
METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs).
METHODS: The protocol of this systematic review was registered on PROSPERO (CRD42022380356). Trials reported changes of fatigue symptom, which compared CHM to no treatment, placebo or drugs, were included. Six electronic databases and three clinical trial registration platforms were searched from inception to November 2023. Literature screening, data extraction, and risk bias assessment were independently carried out by two reviewers. Quality of the included trials was evaluated using Cochrane risk of bias tool, and the certainty of the evidence was evaluated using GRADE. The meta-analysis was performed using Review Manager 5.4, mean difference (MD) and its 95% confidence interval (CI) was used for estimate effect of continuous data. Heterogeneity among trials was assessed through I2 value.
RESULTS: Overall, nineteen studies with 1921 patients were included. Results of individual trial or meta-analysis showed that CHM was better than no treatment (MD = -0.80 scores, 95%CI -1.43 to -0.17 scores, P = 0.01, 60 participants, 1 trial), placebo (MD = -1.90 scores, 95%CI -2.38 to -1.42 scores, P<0.00001, 184 participants, 1 trial), placebo on basis of rehabilitation therapy (MD = -14.90 scores, 95%CI -24.53 to -5.27 scores, P = 0.02, 118 participants, 1 trial) or drugs (MD = -0.38 scores, 95%CI -0.48 to -0.27 scores, I2 = 0%, P<0.00001, 498 participants, 4 trials) on relieving fatigue symptoms assessing by Traditional Chinese Medicine fatigue scores. Trials compared CHM plus drugs to drugs alone also showed better effect of combination therapy (average MD = -0.56 scores). In addition, CHM may improve the percentage of CD4 T lymphocytes and reduce the level of serum IL-6 (MD = -14.64 scores, 95%CI 18.36 to -10.91 scores, I2 = 0%, P<0.00001, 146 participants, 2 trials).
CONCLUSIONS: Current systematic review found that the participation of CHM can improve the symptoms of post-viral fatigue and some immune indicators. However, the safety of CHM remains unknown and large sample, high quality multicenter RCTs are still needed in the future.

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS.
METHODS: Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at \"Shenting\" (GV24) penetrating \"Baihui\" (GV20), \"Dazhui\" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats\' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) β1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-β1 in hippocampal CA1 region were detected by immunofluorescence staining.
RESULTS: Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-β1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-β1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-β1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-β1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group.
CONCLUSIONS: EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.
目的: 观察电针对慢性疲劳综合征（CFS）大鼠行为学及海马炎性因子变化的影响，探讨电针治疗CFS的作用机制。方法: SD大鼠随机分为对照组、模型组和电针组，每组9只。采用改良慢性多因素复合应激刺激法复制CFS模型。电针组大鼠电针“神庭”透刺“百会”和“大椎”，15 min/次，每日2次，治疗14 d。用实验大鼠一般情况半定量评分评估大鼠一般状态，Morris水迷宫实验评价大鼠学习记忆能力，旷场实验评价大鼠焦虑抑郁状态，力竭跑台时间评估大鼠疲劳情况，HE染色法观察大鼠海马CA1区神经元形态结构，ELISA法检测大鼠海马和血清中白细胞介素（IL）-10、IL-17、转化生长因子（TGF）-β1含量，免疫荧光染色法检测海马CA1区IL-10、IL-17、TGF-β1表达。结果: 与对照组比较，模型组大鼠一般情况半定量评分升高（P<0.05），逃避潜伏期延长（P<0.05），穿越原平台次数减少（P<0.05），穿格次数及进入中央区次数增加（P<0.05），力竭跑台时间缩短（P<0.05）；模型组海马区神经元数量减少，排列紊乱，结构疏松，少量神经元细胞核缺失；模型组海马和血清中的IL-10含量降低（P<0.05），IL-17、TGF-β1含量升高（P<0.05）；模型组海马中的IL-10免疫荧光强度降低（P<0.05），IL-17、TGF-β1免疫荧光强度升高（P<0.05）。与模型组比较，电针组大鼠一般情况半定量评分降低（P<0.05），逃避潜伏期缩短（P<0.05），穿越原平台次数增多（P<0.05），穿格次数及进入中央区次数减少（P<0.05），力竭跑台时间延长（P<0.05）；电针组海马神经元数量增加，排列整齐，结构较紧密，坏死神经元减少；电针组海马和血清中的IL-10含量升高（P<0.05），IL-17、TGF-β1含量降低（P<0.05）；电针组海马IL-10免疫荧光强度升高（P<0.05），IL-17、TGF-β1免疫荧光强度降低（P<0.05）。结论: 电针可缓解CFS大鼠疲劳程度，提高空间学习、记忆能力，可能与调节外周及中枢炎性因子有关。.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.