食品工业科技

Mol ID	分子名称	分子量	口服生物利用度（%）	成分转运速率	血脑屏障	药物依赖性
MOL007348	维生素K1	450.77	47.60	1.53	0.81	0.66
MOL002773	β-胡罗卜素	536.96	37.18	2.25	1.52	0.58
MOL000493	菜油甾醇	400.76	37.58	1.31	0.93	0.71
MOL000449	豆固醇	412.77	43.83	1.44	1.00	0.76
MOL000359	β-谷甾醇	414.79	36.91	1.32	0.99	0.75

Mol ID	分子名称	分子量	口服生物利用度（%）	成分转运速率	血脑屏障	药物依赖性
MOL007348	维生素K1	450.77	47.60	1.53	0.81	0.66
MOL002773	β-胡罗卜素	536.96	37.18	2.25	1.52	0.58
MOL000493	菜油甾醇	400.76	37.58	1.31	0.93	0.71
MOL000449	豆固醇	412.77	43.83	1.44	1.00	0.76
MOL000359	β-谷甾醇	414.79	36.91	1.32	0.99	0.75

信号通路	Pvalue
IL-17 signaling pathway	1.0254×10⁻¹⁰
AGE-RAGE signaling pathway	1.32025×10⁻⁹
NOD-like receptor signaling pathway	7.85608×10⁻⁵
NF-kappa B signaling pathway	9.26072×10⁻⁵
TNF signaling pathway	1.11146×10⁻⁴
Lipid and atherosclerosis	2.42619×10⁻⁴
Human cytomegalovirus infection	5.88903×10⁻⁴
Salmonella infection	7.36521×10⁻⁴
Amoebiasis	8.79045×10⁻⁴
Alzheimer disease	9.38366×10⁻⁴
PI3K-Akt signaling pathway	1.028559×10⁻³
MAPK signaling pathway	1.208223×10⁻³
VEGF signaling pathway	1.420703×10⁻³
Inflammatory bowel disease	1.524149×10⁻³
Cellular senescence	1.541343×10⁻³
JAK-STAT signaling pathway	1.821069×10⁻³
AMPK signaling pathway	2.027217×10⁻³
Estrogen signaling pathway	2.130708×10⁻³
EGFR tyrosine kinase inhibitor resistance	2.219202×10⁻³
Th17 cell differentiation	2.918831×10⁻³
HIF-1 signaling pathway	0.024261899
Cytokine-cytokine receptor interaction	0.025261899
Pathways of neurodegeneration-multiple diseases	0.030889031
Colorectal cancer	0.032251914
Bladder cancer	0.032714909
Graft-versus-host disease	0.033360456
FoxO signaling pathway	0.037561737
Endocrine resistance	0.039544123
Thyroid hormone synthesis	0.040043078
C-type lectin receptor signaling pathway	0.040043078
Parathyroid hormone synthesis, secretion and action	0.046272634
Toll-like receptor signaling pathway	0.048634643

信号通路	Pvalue
IL-17 signaling pathway	1.0254×10⁻¹⁰
AGE-RAGE signaling pathway	1.32025×10⁻⁹
NOD-like receptor signaling pathway	7.85608×10⁻⁵
NF-kappa B signaling pathway	9.26072×10⁻⁵
TNF signaling pathway	1.11146×10⁻⁴
Lipid and atherosclerosis	2.42619×10⁻⁴
Human cytomegalovirus infection	5.88903×10⁻⁴
Salmonella infection	7.36521×10⁻⁴
Amoebiasis	8.79045×10⁻⁴
Alzheimer disease	9.38366×10⁻⁴
PI3K-Akt signaling pathway	1.028559×10⁻³
MAPK signaling pathway	1.208223×10⁻³
VEGF signaling pathway	1.420703×10⁻³
Inflammatory bowel disease	1.524149×10⁻³
Cellular senescence	1.541343×10⁻³
JAK-STAT signaling pathway	1.821069×10⁻³
AMPK signaling pathway	2.027217×10⁻³
Estrogen signaling pathway	2.130708×10⁻³
EGFR tyrosine kinase inhibitor resistance	2.219202×10⁻³
Th17 cell differentiation	2.918831×10⁻³
HIF-1 signaling pathway	0.024261899
Cytokine-cytokine receptor interaction	0.025261899
Pathways of neurodegeneration-multiple diseases	0.030889031
Colorectal cancer	0.032251914
Bladder cancer	0.032714909
Graft-versus-host disease	0.033360456
FoxO signaling pathway	0.037561737
Endocrine resistance	0.039544123
Thyroid hormone synthesis	0.040043078
C-type lectin receptor signaling pathway	0.040043078
Parathyroid hormone synthesis, secretion and action	0.046272634
Toll-like receptor signaling pathway	0.048634643

通路蛋白	菜油甾醇（kJ/mol）	17-β-雌二醇（kJ/mol）	孕酮（kJ/mol）
IL 17A	−12.67	−10.27	−11.07
C/EBPβ	−11.77	−4.27	−3.89
TAK1	−11.32	−4.12	−3.12
ACT1	−10.34	−1.24	−2.23
NF-κB	−9.65	−3.15	−4.05
IKKβ	−8.37	−1.07	−1.27
IKBα	−7.09	−2.05	−3.19
TARF6	−8.03	−3.23	−4.51

通路蛋白	菜油甾醇（kJ/mol）	17-β-雌二醇（kJ/mol）	孕酮（kJ/mol）
IL 17A	−12.67	−10.27	−11.07
C/EBPβ	−11.77	−4.27	−3.89
TAK1	−11.32	−4.12	−3.12
ACT1	−10.34	−1.24	−2.23
NF-κB	−9.65	−3.15	−4.05
IKKβ	−8.37	−1.07	−1.27
IKBα	−7.09	−2.05	−3.19
TARF6	−8.03	−3.23	−4.51

组别	n	潜伏期（s）	滞留时间（s）	运动距离（cm）
空白	10	16.21±1.26	89.31±9.26	2578.45±72.43
模型	10	98.24±8.19^##	22.03±4.17^##	1012.39±65.29
高剂量	10	47.27±6.29^**	69.72±7.28^**	2025.88±59.27^**
中剂量	10	66.36±8.06^*	52.24±5.17^*	1671.49±83.13^*
低剂量	10	75.57±7.39^*	42.32±6.39^*	1352.67±60.41^*

组别	n	潜伏期（s）	滞留时间（s）	运动距离（cm）
空白	10	16.21±1.26	89.31±9.26	2578.45±72.43
模型	10	98.24±8.19^##	22.03±4.17^##	1012.39±65.29
高剂量	10	47.27±6.29^**	69.72±7.28^**	2025.88±59.27^**
中剂量	10	66.36±8.06^*	52.24±5.17^*	1671.49±83.13^*
低剂量	10	75.57±7.39^*	42.32±6.39^*	1352.67±60.41^*

基于网络药理学探讨哈蟆油改善慢性疲劳综合征的作用机制

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裴科 , 林喆 , 刘萌萌 , 苗钰康 , 郭文韬 , 王雨辰 , 林贺 , 律广富 ^*

食品工业科技 | 营养与保健 2026,47(6): 346-358

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食品工业科技 |营养与保健 2026 , 47 (6) : 346 -358

基于网络药理学探讨哈蟆油改善慢性疲劳综合征的作用机制

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裴科, 林喆, 刘萌萌, 苗钰康, 郭文韬, 王雨辰, 林贺, 律广富^*

作者信息

长春中医药大学，吉林长春 130117

通讯作者:

律广富（1984−），男，博士，副教授，研究方向：中药学，E-mail：lvgf@ccucm.edu.cn。

作者简介:

裴科（1996−），男，博士研究生，研究方向：中药药理学，E-mail：1306713701@qq.com

Mechanism of Action of Oviductus ranae in Alleviating Chronic Fatigue Syndrome Based on Network Pharmacology

Ke PEI, Zhe LIN, Mengmeng LIU, Yukang MIAO, Wentao GUO, Yuchen WANG, He LIN, Guangfu LÜ^*

Affiliations

Changchun University of Chinese Medicine, Changchun 130117, China

出版时间: 2026-03-15 doi: 10.13386/j.issn1002-0306.2025020168

文章导航

摘要

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目的：研究哈蟆油改善慢性疲劳综合征（chronic fatigue syndrome，CFS）的作用机制。方法：本研究采用TCMSP、BATMAN、GeneCards等数据库以“哈蟆油”和“CFS”为关键词筛选相关活性成分及作用靶点，利用分子对接评估其活性成分与靶点的结合能力。同时，采用力竭游泳和慢性束缚交替应激实验制备CFS小鼠模型，给予不同剂量哈蟆油混悬液（800、400、200 mg/kg）灌胃两周后，检测小鼠血清、肌肉、肝脏和脑组织中的生化指标及炎症因子表达，考察哈蟆油对CFS的改善作用。结果：实验共筛选出5个符合条件的活性成分和8个改善CFS的核心靶点，其中，哈蟆油改善CFS的作用与IL-17/TRAF-6信号通路相关。进一步分子对接结果表明，哈蟆油中的菜油甾醇（Campesterol）可能是发挥抗疲劳作用的主要成分。体内动物实验结果表明，哈蟆油对CFS模型小鼠具有显著的治疗效果，能够有效改善其行为学指标和生理生化异常。在行为学方面，与模型组相比，给药组小鼠的体重和饮食量显著增加，糖水偏好率明显提高（P<0.01或P<0.05）。通过多项行为学测试发现：在强迫游泳实验（FST）和悬尾实验（TST）中，给药组小鼠的不动时间显著缩短（P<0.01）；在旷场实验（OFT）中，运动速度、运动总距离和站立次数均显著增加（P<0.01或P<0.05）；在水迷宫实验（MWM）中，逃避潜伏期明显缩短，同时运动距离和目标象限停留时间显著延长（P<0.01或P<0.05）。生化指标检测结果显示，给药组小鼠的尿素氮（BUN）、IL-6、TNF-α、COX-2和MDA水平显著降低，而SOD和GSH-Px活性明显升高（P<0.01或P<0.05）。此外，肌肉组织中乳酸含量也显著降低（P<0.01或P<0.05）。Western blot结果显示，给药组小鼠体内IL-17A、TRAF-6、ACT-1、TAK-1、IKKβ、IκBα、NF-κB、C/EBPβ关键信号蛋白的表达水平均显著下调（P<0.01或P<0.05），同时下游炎症因子IL-6、TNF-α和COX-2的表达也明显降低（P<0.01或P<0.05）。这些结果表明，哈蟆油可能通过抑制IL-17/TRAF-6/NF-κB信号通路的活化，减轻氧化应激和炎症反应，从而改善CFS症状。结论：哈蟆油通过调控IL-17/TRAF-6信号通路改善CFS，为CFS的临床治疗提供了新的思路。

关键词

哈蟆油 / 慢性疲劳综合征 / 网络药理学 / IL17/TRAF6信号通路 / 体内实验

Abstract

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Objective: This study aimed to investigate the therapeutic mechanism of Oviductus ranae (OR) in chronic fatigue syndrome (CFS). Methods: Active ingredients and potential targets of OR were screened using TCMSP, BATMAN, and GeneCards databases with the keywords "OR" and "CFS". Molecular docking was performed to assess binding affinities between bioactive compounds and their targets. A mouse model of CFS was constructed using an exhausting swim and chronic restraint stress. Mice were treated with OR suspension (800, 400, or 200 mg/kg) via oral gavage for 14 days. Biochemical parameters and inflammatory markers were analyzed in serum, muscle, liver and brain tissue. Results: Five bioactive compounds and eight core targets associated with CFS improvement were identified. OR exerts its therapeutic effect primarily through modulation of the IL-17/TRAF6 signaling pathway. Molecular docking results indicated that campesterol, a component of OR, exhibits the strongest binding affinity, suggesting its role as a key active ingredient. Results from in vivo animal experiments demonstrated that OR had a significant therapeutic effect on CFS model mice, effectively improving their behavioural indicators and resolving their physiological and biochemical abnormalities. In terms of behavioural aspects, the mice in the administered group showed significant increases in body weight and diet, as well as a significant increase in sugar-water preference (P<0.01 or P<0.05), compared with the model group. Several behavioural tests revealed that, in the forced swimming test (FST) and the tail suspension test (TST), the administered group's immobility time was significantly shorter (P<0.01). In the open-field test (OFT), locomotion speed, total locomotion distance and the number of times standing up were all significantly increased (P<0.01 or P<0.05). In the Morris Water Maze (MWM), avoidance latency was significantly shorter. Concurrently, the movement distance and residence time in the target quadrant were significantly prolonged (P<0.01 or P<0.05). The assay results of the biochemical indicator showed that BUN levels, IL-6 levels, TNF-α levels, COX-2 levels and MDA levels were significantly reduced, while SOD activity and GSH-Px activity were significantly increased in the administered group of mice (P<0.01 or P<0.05). Additionally, lactic acid content in muscle tissue decreased significantly (P<0.01 or P<0.05). Studies of the molecular mechanism suggested that OR may exert therapeutic effects by modulating the IL-17/TRAF6 signalling pathway. Conclusion: OR ameliorates CFS by modulating the IL-17/TRAF6 signaling pathway, thereby providing a novel perspective for the clinical management of CFS.

Key words

oviductus ranae / chronic fatigue syndrome / network pharmacology / IL17/TRAF6 signaling pathway / in vivo experiments

引用本文

裴科, 林喆, 刘萌萌, 苗钰康, 郭文韬, 王雨辰, 林贺, 律广富. 基于网络药理学探讨哈蟆油改善慢性疲劳综合征的作用机制. 食品工业科技, 2026 , 47 (6) : 346 -358 . DOI: 10.13386/j.issn1002-0306.2025020168

Ke PEI, Zhe LIN, Mengmeng LIU, Yukang MIAO, Wentao GUO, Yuchen WANG, He LIN, Guangfu LÜ. Mechanism of Action of Oviductus ranae in Alleviating Chronic Fatigue Syndrome Based on Network Pharmacology[J]. Science and Technology of Food Industry, 2026 , 47 (6) : 346 -358 . DOI: 10.13386/j.issn1002-0306.2025020168

正文

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慢性疲劳综合征（chronic fatigue syndrome，CFS）是一种以持续或反复发作的严重疲劳为主要特征的疾病，病程通常超过半年。其典型症状包括失眠、全身性疼痛、记忆力减退、协调能力下降、行动迟缓及反应迟钝等多系统功能异常^[1−2]，并且流行病学调查表明，日本和英国的CFS患病率超过2%，CFS不仅导致机体功能障碍，还可能引起免疫系统和神经内分泌系统紊乱^[3−4]。随着现代生活节奏的加快，CFS的发病率逐年上升，对患者的身心健康造成显著损害，严重降低其生活质量。世界卫生组织已将疲劳列为21世纪危害人类健康的主要因素之一^[5]，因此，CFS的机制研究及干预策略已成为医学界关注的重点，改善疲劳症状是当前亟待解决的重要问题。

目前医学上对CFS的解释还不完全清楚^[6]。CFS会导致代谢紊乱、肠道菌群失调及营养失衡等营养学相关机制，随着现代生活方式改变，饮食结构不合理、精神压力增加等因素加剧了CFS的流行，营养干预作为非药物手段的重要性日益凸显，代谢紊乱与营养干预相关，能量代谢异常会导致细胞线粒体功能受损、三羧酸循环效率降低及糖脂代谢失衡，使细胞能量供应不足；CFS会导致关键营养素缺乏，例如ω-3多不饱和脂肪酸，而维生素及多酚类物质可中和自由基，减轻氧化应激损伤，含有维生素、镁等成分的食品，通过协同作用提升代谢效率，缓解疲劳^[7−8]；西医对CFS的治疗手段主要包括药物治疗等，临床常用药物大多都与神经系统相关，多具有药物依赖性和毒副作用，治疗效果不佳，所以大家渐渐把目光放到了中医药治疗CFS上，这为临床治疗本病提供了新思路^[9]。

CFS目前的治疗主要以缓解症状为主，缺乏特效药物。西医常用抗抑郁药、免疫调节剂等，但疗效有限且伴随较多副作用。相比之下，中医药在改善疲劳方面具有独特优势。研究表明，人参、黄芪等补益类中药可通过调节免疫、抗氧化等途径改善CFS症状。补益类中药在缓解疲劳方面具有显著优势，常见的补益类药物具有抗氧化应激、抗炎和免疫调节等功效^[10−11]。哈蟆油是中国林蛙（Rana temporaria chensinensis David）雌蛙干燥的输卵管，未被列入药食同源目录，但一直食用至今，现代研究证实，哈蟆油的营养成分与生物活性物质符合保健食品功能需求，它含48%以上蛋白质、18种氨基酸（含8种必需氨基酸）、多不饱和脂肪酸、维生素（A、D、E等）及微量元素（锌、硒、镁等），兼具营养强化与代谢调节作用，在现代营养学与保健食品领域展现出独特价值^[12−14]。综上所述，因其历史积淀与现代营养学验证，成为CFS干预的理想选择，传统上用于缓解精神疲乏等症状，这些特性与CFS的病理机制高度相关，提示哈蟆油在改善CFS方面具有潜在的应用价值。已有研究表明，哈蟆油匀浆水溶液和蛋白酶解物具有显著的抗疲劳作用^[15−17]，然而，针对哈蟆油改善CFS的研究较为有限，其活性成分、作用靶点及分子机制尚未系统阐明。尽管CFS的发病机制涉及免疫系统、HPA轴、单胺神经内分泌系统、线粒体功能以及能量代谢等多个方面，但具体机制尚不明确，这极大地限制了其在临床中的进一步应用，仍需进一步研究。本研究旨在通过网络药理学和分子对接技术筛选哈蟆油改善CFS的活性成分及其作用靶点，并通过动物实验验证其药效及作用机制。研究结果将为哈蟆油改善CFS提供科学依据，为其在临床中的应用奠定理论基础，同时也为CFS的治疗提供新的思路和方法。

1　材料与方法

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1.1　材料与仪器

哈蟆油　通化鼎参药业提供，长春中医药大学药学院中药鉴定教研室鉴定为中国林蛙雌蛙干燥的输卵管；甲醇　北京化工厂提供；全蛋白提取试剂盒、BCA试剂盒　索莱宝生物科技有限公司；制胶试剂盒　雅酶生物科技有限公司提供；蛋白质常规分子量标记、β-actin、白介素-17A（IL-17A）、泛素连接酶（TRAF-6）、核因子κB激活剂（ACT-1）、转化生长因子激酶1（TAK-1）、核因子κB抑制物激酶β（IKKβ）、核因子κB抑制蛋白α（IKBα）、核因子κB（NF-κB）、增强子结合蛋白β（C/EBPβ）、白介素6（IL-6）、肿瘤坏死因子α（TNF-α）、环氧合酶-2（COX-2）抗体　武汉三鹰生物有限公司；超敏ECL化学发光试剂盒　碧云天生物；PVDF膜　美国伯乐公司；尿素氮（BUN）、IL-6、TNF-α、环氧合酶-2（COX-2）、丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）　江苏酶联免疫生物试剂有限公司；肝糖原、肌糖原试剂盒　南京建成生物有限公司；雄性ICR小鼠60只（体重18~22 g），由长春市亿斯实验动物技术有限责任公司提供，生产许可证号：SCXK-（吉）2011-0004；基础饲料也由该公司提供，生产许可证号：SCXK-（吉）2010-0001；饲养在实验动物部，使用许可证号：SYXK（吉）2010-0011。

TMV-100S行为试验系统　成都泰盟仪器公司；Epoch-2酶标仪　美国伯腾公司；041BR103094电泳仪　美国伯乐公司；Q9-Aliance凝胶成像系统英国UVItec公司。

1.2　实验方法

1.2.1　哈蟆油有效成分及靶点筛选和疾病相关靶点的获取

通过查阅大量文献和书籍，归类总结出哈蟆油化学成分，之后再借助BATMAN数据库和TCMSP搜索哈蟆油的全部靶点，按所需条件筛选哈蟆油活性成分（口服生物利用度≥30%、药物依赖性≥0.18）^[18−19]，同时通过TCMSP获取活性成分对应的靶点蛋白；利用UniProt平台将靶点蛋白全称转变成相对应的基因名，搜索时以“人类”（Homo sapiens）为物种来源。以“CFS”为检索词，通过GeneCard、CTD、DisGeNET数据库获取疾病靶点。找到3个疾病数据库中共有疾病靶点与哈蟆油作用靶点之间的交集，即哈蟆油改善疲劳的潜在靶点，通过R语言软件绘制韦恩图^[20−22]。

1.2.2　哈蟆油-疲劳-成分-靶点网络的构建和网络拓扑学分析

将哈蟆油活性成分、治疗疲劳的潜在靶点导入Cytoscape制作“哈蟆油-疲劳-成分-靶点”网络，然后再利用Cytoscape中的插件进行成分靶点网络拓扑学分析，以degree值大于中位数为条件筛选的2个有效成分，6个靶点，为下一步分析做准备^[23]。

1.2.3　蛋白互作网络（PPI）构建、GO功能富集和KEGG通路分析

药物-疾病共有靶点被导入 String数据库^[24−25]，以“medium confidence>0.4”为相互作用阈值，默认其余设置构建PPI网络。使用DAVID和Metascape数据库联合进行GO富集分析，再利用KEGG网站进行通路分析，并都以P值为筛选条件，选择排名前五的通路与关键靶点做分析，获得与之最相关的通路和物质基础^[26−27]。

1.2.4　成分结构绘制和分子对接

将化学成分绘制并按照degree值选取排在前三位的哈蟆油化学成分与核心靶点进行分子对接，利用pubchem导出保存文件至.sdf格式，转到.mol2格式，然后导入PyMOL，进行加氢，去水等一系列修饰，导出保存文件至.pdb格式；运用PDB平台（https://www.rcsb.org/）获取靶点的3D结构，并保存文件至.pdb格式，将小分子化合物和关键靶点导入Autodock软件进行分子对接，最后用PyMOL等软件分析对接强度^[28−30]。

1.2.5　动物实验分组、造模和给药

将60只小鼠平均分成空白组，模型组，哈蟆油高、中、低剂量三组^[25,28,31]，每组12只（避免造模过程中死亡，至少保证每组十只），除了空白组外，其余小鼠进行应激造模，利用力竭游泳和慢性束缚交替应激对雄性小鼠进行造模，使小鼠在水温22±3 ℃的光滑内壁玻璃桶中每天游泳10 min，连续28 d通过行为学实验评价模型，发现模型组小鼠静止不动时间增加、活动减少以及出现绝望焦虑样状态，说明模型成功，然后以小鼠与人体表面积折算小鼠的等效给药量，用药比设置为1:2:4的低、中、高剂量组，按照浓度将哈蟆油粉末分别用水稀释，然后进行灌胃给药；空白组给予等体积生理盐水；哈蟆油高、中、低组每日给予浓度为800、400、200 mg/kg的哈蟆油混悬液灌胃，连续灌胃14 d，所有动物实验操作都经过长春中医药大学实验动物伦理委员会批准（2024742）。

1.2.6　观察指标

1.2.6.1　一般状态观察和行为学检测

实验整个过程中，每日观察小鼠的体重、饮食量、糖水偏好、精神状态以及行为情况等一般状态。每日进行体重测定，每周进行饮食量测定，记录并进行比较。

参考文献^[32−35]描述的方法，有所改动，最后一次给药之后30 min，进行相关行为学检测，将小鼠放入黑色无盖的旷场箱中，记录小鼠5 min内移动总路程、运动平均速度、站立次数（两只前腿全脱离箱底）；第2 d进行小鼠悬尾实验，该实验主要用于评价模型成功与否，以及受试药干预是否有效，将小鼠固定在试验箱上，使其呈倒挂状态，通过软件记录5 min内不动时间；第3 d进行强迫游泳实验，记录5 min内漂浮不动时间；随后一周进行水迷宫训练和正式实验，记录小鼠从入水到爬上平台所需时间（超过120 s，按120 s算）以及有效区域滞留时间。

1.2.6.2　生化指标检测

禁食不禁水12 h后，先用异弗烷将小鼠麻醉，再进行眼球取血，于4 ℃下3000 r/min离心15 min获得血清，−80 ℃保存备用，用试剂盒检测血清中BUN、MDA、SOD、GSH-Px、IL-6、TNFα、COX-2浓度，肌肉中乳酸的浓度，肝脏中肝糖原和肌糖原的含量。

1.2.6.3　蛋白免疫印迹检测相关蛋白指标

通过网络药理学预测，得到相关通路和靶点，利用蛋白免疫印迹检测相关蛋白表达，取小鼠脑组织，加入裂解液，在冰水中研磨、裂解，12000 r/min离心15 min，取上清液，采用BCA的方法定量蛋白质，然后制成相应浓度样品，先制备分离胶和浓缩胶，再加20 µL对应样品，然后在100 V下电泳90 min，在400 mA下转膜40 min，脱脂奶粉封闭2 h，用TBST洗膜三次，按蛋白分子量剪膜，按照抗体稀释比例加入一抗稀释液，加入制备完的一抗IL-17A、ACT-1、IKKβ、IKBα、TRAF6、TAK-1、NF-κB、C/EBPβ、IL-6、TNF-α、COX-2、β-actin，冰箱4 ℃孵育过夜，第二天先用TBST洗涤3次每次5 min，再加入二抗室温孵育2 h，孵育结束后再用TBST洗涤3次，在避光条件下加入ECL试剂，最后使用凝胶成像系统成像。

1.3　数据处理

采用SPSS对数据进行统计分析，数据以平均数±标准差（x±s）的形式表示，单因素方差分析用于多组间比较，t检验用于两两比较，用Image J软件分析蛋白免疫印迹条带灰度值，P<0.05为差异有统计学意义，P<0.01有显著差异性。

2　结果与分析

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2.1　网络药理学和分子对接结果

2.1.1　哈蟆油的活性成分及相关靶点和CFS相关靶点

本研究通过筛选共获得哈蟆油32个活性成分，其中符合口服生物利用度和药物依赖性条件的有5个（表1）。这些活性成分对应的潜在靶点共218个。通过GeneCards数据库检索获得7558个与CFS相关的靶点，DisGeNET数据库检索获得118个CFS相关靶点，CTD数据库检索获得536个CFS相关靶点。将各数据库检索结果进行整合并与哈蟆油的靶点取交集，最终筛选出8个哈蟆油干预CFS的潜在关键靶点（IL-18、COMT、NR3C1、IL-1B、IL-6、IL-10、PTGS-2、TH）。这一结果为后续研究哈蟆油改善CFS的作用机制提供了重要线索。

2.1.2　药物-疾病-成分-靶点构建和PPI网络以及网络拓朴学分析

通过Cytoscape软件构建哈蟆油-CFS-成分-靶点网络和成分拓扑学分析见图1（按degree值排序取前18个），其中度值排在前三位的是菜油甾醇、17-β-雌二醇、孕酮；将8个交集核心靶点导入至STRING数据库，构建出PPI网络，通过PPI网络图显示，共有8个节点，781条边，平均节点度为4.51，将这8个靶点进行网络拓扑学分析；度值由大到小的靶点是IL-1B、IL-6、NR3C1、PTGS-2、IL-10、TH、IL-18、COMT，推测这些靶点可能是治疗CFS的关键靶点。

2.1.3　哈蟆油治疗CFS的GO富集和KEGG通路分析

GO富集分析得到58个生物学进程（按P<0.01取前4个）、4个细胞学组分、4个分子功能，KEGG通路分析得到32个通路（表2），结果如图2A所示，哈蟆油治疗CFS的生物学进程主要包括炎症反应、生长因子活力、蛋白结合、活性反应、细胞因子活性、氧化应激等；如图2B所示，信号通路主要为IL-17信号通路、NF-κB通路、阿尔兹海默症、TNF信号通路等；通路与关键靶点的分析如图2C热图所示，IL-17信号通路与IL-18，IL-10蛋白关系密切，TNF信号通路和NOD样受体信号通路与关键蛋白相关性较大，NF-κB通路与IL-1B，PTGS-2蛋白相关性较大，ACE-RAGE信号通路与IL-1B，IL-6蛋白相关性较大，从以上所有数据提示，哈蟆油的有效成分可能通过IL-17信号通路、氧化应激等而发挥相互联合治疗的潜在作用机制（图3）。

2.1.4　分子对接结果

哈蟆油中degree值排前三的活性成分与通路相关靶点进行对接，由表3可见，分子对接结合能均<−5 kJ/mol，对接结果具有较好的可靠性，将结合构象的相互作用进行可视化展示，见图4。

2.2　哈蟆油对CFS小鼠的基本状况和行为学的影响

如图5所示，造模前各组小鼠的体重、饮食量及糖水偏好均无显著差异。造模4周后，模型组小鼠体重增长明显减缓，饮食量显著下降，糖水偏好程度减弱，此外，如表4和图6所示，造模后模型组小鼠在旷场试验中的运动速度、运动距离及站立次数均显著减少，水迷宫实验中，模型组小鼠的逃避潜伏期显著延长，有效区停留时间显著缩短（P<0.01），在强迫游泳实验和悬尾实验中的不动时间显著延长。给予哈蟆油后，上述指标均得到显著改善，表明哈蟆油能够显著改善CFS模型小鼠的体重、饮食量、糖水偏好、运动能力及行为学表现，可以缓解疲劳状态。其作用机制可能与调节能量代谢、改善肌肉功能及中枢神经系统功能有关。

2.3　生化分析结果和蛋白免疫印记结果

2.3.1　哈蟆油对CFS小鼠血清中MDA、SOD和GSH-Px的影响

如图7所示，与空白组相比，CFS模型组小鼠血清中MDA含量显著升高，SOD和GSH-Px的含量显著降低（P<0.01），给予哈蟆油干预后，上述指标均得到不同程度的改善，与模型组相比，实验组小鼠血清中MDA含量显著降低，SOD和GSH-Px的含量显著升高（P<0.05或P<0.01），体内氧化应激降低，导致自由基（例如活性氧ROS）的生成大量减少，脂质过氧化反应消除，减少MDA等代谢产物的生成，所以MDA含量的减少也反映了CFS小鼠体内脂质过氧化程度的降低，SOD和GSH-Px是机体内具有清除自由基作用的抗氧化酶，给药后CFS状态下的自由基的生成会减少，进而抗氧化酶消耗也减少，同时可以缓解过度的氧化应激，激活抗氧化酶的活性，恢复SOD和GSH-Px含量，一系列结果表明哈蟆油可能通过清除自由基、增强抗氧化酶活性来缓解氧化应激，进而缓解CFS。

2.3.2　哈蟆油对CFS小鼠血清中IL6、TNF-α和COX-2的影响

如图8所示，与空白组相比，CFS模型组小鼠血清中IL-6、TNF-α和COX-2的含量显著升高（P<0.01）；与模型组相比，实验组小鼠血清中IL-6、TNF-α和COX-2含量显著降低（P<0.05或P<0.01），因为CFS模型小鼠体内促炎性细胞因子IL-6和TNF-α被哈蟆油抑制，COX-2含量降低，进一步抑制前列腺素的合成，减轻了炎症反应，恢复CFS小鼠的免疫系统失调以及神经内分泌紊乱，说明其可以减轻炎症反应造成的CFS。

2.3.3　哈蟆油对CFS小鼠血清中BUN和肌肉中乳酸浓度、肝糖原和肌糖原的影响

如图9所示，与模型组相比，给药组小鼠血清中BUN含量和肌肉中乳酸含量显著降低，肝脏和肌肉中的糖原储备显著增加（P<0.05或P<0.01），并改善了CFS模型小鼠的能量代谢紊乱，减少了肌肉蛋白分解以及肾脏排泄功能下降会产生过量的BUN，恢复能量代谢途径损伤，糖酵解活性上升，进而降低乳酸生成，增加糖原合成，缓解机体出现疲劳症状，哈蟆油可能通过改善肾功能和能量代谢恢复。

2.3.4　哈蟆油对CFS 小鼠脑内IL17/TRAF6通路蛋白表达的影响

如图10所示，与模型组相比，给药组小鼠脑组织中，通路相关蛋白IL-17A、TRAF6、ACT-1、TAK-1、IKKβ、IKBα、NF-κB、C/EBPβ、IL-6、TNF-α及COX-2的表达水平显著降低（P<0.05或P<0.01），提示IL-17/TRAF-6信号通路的激活会引发神经炎症反应，哈蟆油阻断上游信号传导抑制这条通路，进而抑制炎症因子的表达，表明哈蟆油可以减轻小鼠脑内存在显著的炎症反应，从而改善CFS相关的疲劳、认知功能障碍及行为异常，为其改善CFS症状提供了分子机制依据。这一发现为哈蟆油在CFS治疗中的应用提供了重要的理论支持。

3　讨论与结论

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在网络药理学结果分析中，发现 IL-1B、IL-6、NR3C1、PTGS2、IL-10等靶点被识别为哈蟆油干预CFS的核心基因，GO和KEGG分析表明哈蟆油可能通过IL-17信号通路、NF-κB通路、AGE-RAGE信号通路、TNF信号通路等发挥抗疲劳作用，并且核心基因与通路之间有联系；GO富集分析表明哈蟆油干预疲劳与炎症，氧化应激，免疫等相关，分子对接结果表明，哈蟆油可能通过IL-17A/TRAF-6通路改善CFS。

根据CFS临床上的心理（抑郁，失望心态等）和生理（体力或智力上的疲劳，难以集中注意力，记忆力下降等）症状，与模型小鼠的行为学结果做对比，行为学研究结果显示，在小鼠经历疲劳模型制备后，由于过度劳累，小鼠的饮食量明显降低，对糖水的偏好程度下降，出现快感缺失，在水中漂浮时间明显增加，运动速度明显减慢，空间探索能力下降，经过哈蟆油的干预，这种情况有所改善，CFS小鼠的糖水偏好率，运动速度和活跃程度，逃避潜伏期，以及学习记忆能力都有了明显改善。综上所述，通过以上结果可以进一步证明，哈蟆油具有缓解CFS的作用，并对小鼠的空间探索能力、学习记忆能力、身心疲劳程度和情绪产生积极的影响。

当机体处于疲劳状态时，糖酵解过程会被加速，导致乳酸产生增加，此时，果糖磷酸激酶的活性会受到抑制，进而导致糖酵解速度的变慢，影响肌力的产生^[36]。另外，蛋白质经过有氧代谢后会产生BUN，当机体中糖酵解反应不够时，蛋白质或氨基酸经过尿素循环代谢产生BUN，因此，乳酸和BUN被认为是疲劳时重要的生化指标，乳酸的堆积和糖酵解的加速会消耗机体的糖原来维持体内的血糖水平和能量供应，从而缓解疲劳^[37]。本研究发现，哈蟆油能降低乳酸和BUN的含量，同时提高肝糖原和肌糖原的含量，这使得机体能够维持动态平衡的血糖水平，并通过糖酵解和无氧酵解来提供能量，从而减轻疲劳。另外，哈蟆油还能提高抗氧化酶（如SOD和GSH-Px）的活性，这两种酶能够清除和修复氧化自由基，从而增强细胞的抗氧化能力^[38]。此外，哈蟆油还能减少肌细胞中的MDA和乳酸的生成，进一步提高抗氧化活性，减少疲劳对细胞的损害。研究还发现，机体抗氧化系统被损伤后，线粒体DNA的氧化损伤可能导致线粒体功能紊乱，降低ATP的合成能力，进而形成疲劳状态^[39]。一些研究通过建立小鼠CFS模型，发现该模型中小鼠的外周血中促炎因子（如IL-1B、IL-6和TNF-α）的水平升高，而低氧浓度暴露有助于恢复这些炎症因子的水平^[40]。另外，一些研究表明，可以通过降低炎症因子的含量来抑制炎症反应和改善疲劳症状，而具体机制涉及减少代谢产物的积累以及改善细胞炎症等因素^[36]。实验结果表明哈蟆油可以降低CFS小鼠血清中IL6、TNF-α、COX-2、MDA的含量和肌肉中的乳酸含量，升高血清中SOD、GSH-Px的含量，证明哈蟆油还可以改善CFS相关生化指标。

IL-17A是IL-17家族中首个被发现且研究最广泛的成员，它与多种自身免疫和炎症疾病相关，如疲劳性骨折、急性肝损伤和牙周炎^[41−42]。研究表明IL-17A通过与细胞表面受体 IL-17RA 结合，激活ACT-1蛋白，进而ACT-1可以结合泛素化TRAF-6从而激活NF-κB转录因子，促进炎症基因的表达。TRAF-6在NF-κB信号转导中起着重要的调节作用，并在炎症产生后发生聚集，激活NF-κB信号通路。研究表明，通过抑制TRAF-6可以调节NF-κB信号通路^[43−46]。IL-17A/TRAF-6信号通路是一种重要的细胞信号传导路径，它参与调节免疫系统的炎症反应和免疫应答^[47−49]，这些促炎因子在CFS的发生和发展中起重要作用。IL-6属于急性反应因子，在炎症和伤害等病理情况下会增加^[50]。TNF-α可以刺激IL-6的产生，二者通常协同刺激急性反应，血清TNF-α和IL-6水平可作为反映CFS严重程度的指标，并与BUN水平呈正相关^[51]。研究已证实，促炎因子TNF-α和IL-6参与慢性炎症的形成，可能引发类似疲劳和抑郁的症状，成功建立的CFS模型表明，其特征为促炎因子TNF-α和IL-6水平升高和免疫功能下降^[52]。在生理条件下，PTGS-2在肾脏和大脑组织中表达下调，然而，在病理条件下，例如癌症组织中，PTGS-2的表达也会上调，PTGS-2的主要功能是负责炎症前列腺素的产生，炎症条件下，PTGS-2的上调与细胞黏附增加、细胞表型改变、细胞凋亡抵抗以及肿瘤血管生成等过程相关^[53−54]。本研究结果表明，哈蟆油可以通过抑制IL-17A/TRAF-6信号通路，下调ACT-1、TAK-1、NF-κB、C/EBPβ的表达，降低炎症因子表达水平和氧化应激，缓解疲劳。

本研究综合运用网络药理学、分子对接技术及小鼠CFS模型，对哈蟆油的活性成分及其作用机制进行了系统性探究。通过网络药理学分析，筛选出哈蟆油潜在活性成分5个，并预测其可能通过IL-1B、IL-6、NR3C1、PTGS-2、IL-10等多个核心靶点，以及抗氧化、免疫调节等多环节发挥防治CFS的作用。分子对接结果显示，哈蟆油活性成分与上述靶点具有较高的结合能，进一步支持了网络药理学的预测结果。体内实验验证表明，哈蟆油能够显著改善CFS模型小鼠的行为学表现及生理指标。这些结果表明，哈蟆油通过调控IL-17/TRAF-6信号通路抑制神经炎症反应，从而缓解CFS症状，为哈蟆油在CFS治疗中的应用提供了科学依据，同时也为CFS的中医治疗策略提供了新的理论支持。

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2026年第47卷第6期

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doi: 10.13386/j.issn1002-0306.2025020168

接收时间：2025-02-24
首发时间：2026-10-24
出版时间：2026-03-15

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收稿日期：2025-02-24

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长春中医药大学，吉林长春 130117

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律广富（1984−），男，博士，副教授，研究方向：中药学，E-mail：lvgf@ccucm.edu.cn。

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Mol ID	分子名称	分子量	口服生物利用度（%）	成分转运速率	血脑屏障	药物依赖性
MOL007348	维生素K1	450.77	47.60	1.53	0.81	0.66
MOL002773	β-胡罗卜素	536.96	37.18	2.25	1.52	0.58
MOL000493	菜油甾醇	400.76	37.58	1.31	0.93	0.71
MOL000449	豆固醇	412.77	43.83	1.44	1.00	0.76
MOL000359	β-谷甾醇	414.79	36.91	1.32	0.99	0.75

Mol ID

分子
名称

分子量

口服生物
利用度（%）

成分转运
速率

血脑
屏障

药物
依赖性

MOL007348

维生素K1

450.77

47.60

1.53

0.81

0.66

MOL002773

β-胡罗卜素

536.96

37.18

2.25

1.52

0.58

MOL000493

菜油甾醇

400.76

37.58

1.31

0.93

0.71

MOL000449

豆固醇

412.77

43.83

1.44

1.00

0.76

MOL000359

β-谷甾醇

414.79

36.91

1.32

0.99

0.75

信号通路	Pvalue
IL-17 signaling pathway	1.0254×10⁻¹⁰
AGE-RAGE signaling pathway	1.32025×10⁻⁹
NOD-like receptor signaling pathway	7.85608×10⁻⁵
NF-kappa B signaling pathway	9.26072×10⁻⁵
TNF signaling pathway	1.11146×10⁻⁴
Lipid and atherosclerosis	2.42619×10⁻⁴
Human cytomegalovirus infection	5.88903×10⁻⁴
Salmonella infection	7.36521×10⁻⁴
Amoebiasis	8.79045×10⁻⁴
Alzheimer disease	9.38366×10⁻⁴
PI3K-Akt signaling pathway	1.028559×10⁻³
MAPK signaling pathway	1.208223×10⁻³
VEGF signaling pathway	1.420703×10⁻³
Inflammatory bowel disease	1.524149×10⁻³
Cellular senescence	1.541343×10⁻³
JAK-STAT signaling pathway	1.821069×10⁻³
AMPK signaling pathway	2.027217×10⁻³
Estrogen signaling pathway	2.130708×10⁻³
EGFR tyrosine kinase inhibitor resistance	2.219202×10⁻³
Th17 cell differentiation	2.918831×10⁻³
HIF-1 signaling pathway	0.024261899
Cytokine-cytokine receptor interaction	0.025261899
Pathways of neurodegeneration-multiple diseases	0.030889031
Colorectal cancer	0.032251914
Bladder cancer	0.032714909
Graft-versus-host disease	0.033360456
FoxO signaling pathway	0.037561737
Endocrine resistance	0.039544123
Thyroid hormone synthesis	0.040043078
C-type lectin receptor signaling pathway	0.040043078
Parathyroid hormone synthesis, secretion and action	0.046272634
Toll-like receptor signaling pathway	0.048634643

信号通路

Pvalue

IL-17 signaling pathway

1.0254×10⁻¹⁰

AGE-RAGE signaling pathway

1.32025×10⁻⁹

NOD-like receptor signaling pathway

7.85608×10⁻⁵

NF-kappa B signaling pathway

9.26072×10⁻⁵

TNF signaling pathway

1.11146×10⁻⁴

Lipid and atherosclerosis

2.42619×10⁻⁴

Human cytomegalovirus infection

5.88903×10⁻⁴

Salmonella infection

7.36521×10⁻⁴

Amoebiasis

8.79045×10⁻⁴

Alzheimer disease

9.38366×10⁻⁴

PI3K-Akt signaling pathway

1.028559×10⁻³

MAPK signaling pathway

1.208223×10⁻³

VEGF signaling pathway

1.420703×10⁻³

Inflammatory bowel disease

1.524149×10⁻³

Cellular senescence

1.541343×10⁻³

JAK-STAT signaling pathway

1.821069×10⁻³

AMPK signaling pathway

2.027217×10⁻³

Estrogen signaling pathway

2.130708×10⁻³

EGFR tyrosine kinase inhibitor resistance

2.219202×10⁻³

Th17 cell differentiation

2.918831×10⁻³

HIF-1 signaling pathway

0.024261899

Cytokine-cytokine receptor interaction

0.025261899

Pathways of neurodegeneration-multiple diseases

0.030889031

Colorectal cancer

0.032251914

Bladder cancer

0.032714909

Graft-versus-host disease

0.033360456

FoxO signaling pathway

0.037561737

Endocrine resistance

0.039544123

Thyroid hormone synthesis

0.040043078

C-type lectin receptor signaling pathway

0.040043078

Parathyroid hormone synthesis, secretion and action

0.046272634

Toll-like receptor signaling pathway

0.048634643

通路蛋白	菜油甾醇（kJ/mol）	17-β-雌二醇（kJ/mol）	孕酮（kJ/mol）
IL 17A	−12.67	−10.27	−11.07
C/EBPβ	−11.77	−4.27	−3.89
TAK1	−11.32	−4.12	−3.12
ACT1	−10.34	−1.24	−2.23
NF-κB	−9.65	−3.15	−4.05
IKKβ	−8.37	−1.07	−1.27
IKBα	−7.09	−2.05	−3.19
TARF6	−8.03	−3.23	−4.51

通路蛋白

菜油甾醇（kJ/mol）

17-β-雌二醇（kJ/mol）

孕酮（kJ/mol）

IL 17A

−12.67

−10.27

−11.07

C/EBPβ

−11.77

−4.27

−3.89

TAK1

−11.32

−4.12

−3.12

ACT1

−10.34

−1.24

−2.23

NF-κB

−9.65

−3.15

−4.05

IKKβ

−8.37

−1.07

−1.27

IKBα

−7.09

−2.05

−3.19

TARF6

−8.03

−3.23

−4.51

组别	n	潜伏期（s）	滞留时间（s）	运动距离（cm）
空白	10	16.21±1.26	89.31±9.26	2578.45±72.43
模型	10	98.24±8.19^##	22.03±4.17^##	1012.39±65.29
高剂量	10	47.27±6.29^**	69.72±7.28^**	2025.88±59.27^**
中剂量	10	66.36±8.06^*	52.24±5.17^*	1671.49±83.13^*
低剂量	10	75.57±7.39^*	42.32±6.39^*	1352.67±60.41^*

组别

潜伏期（s）

滞留时间（s）

运动距离（cm）

空白

16.21±1.26

89.31±9.26

2578.45±72.43

模型

98.24±8.19^##

22.03±4.17^##

1012.39±65.29

高剂量

47.27±6.29^**

69.72±7.28^**

2025.88±59.27^**

中剂量

66.36±8.06^*

52.24±5.17^*

1671.49±83.13^*

低剂量

75.57±7.39^*

42.32±6.39^*

1352.67±60.41^*