Mechanism of Xiaochaihutang in treating gastroesophageal reflux disease with insomnia based on network pharmacology
-
摘要:目的
基于网络药理学探讨小柴胡汤治疗胃食管反流病(GERD)合并失眠的潜在作用机制。
方法通过在线数据库筛选小柴胡汤的活性成分、药物靶点以及GERD和失眠的疾病靶点; 取药物靶点和疾病靶点的交集，利用STRING数据库分析交集靶点的相互作用; 通过Cytoscape软件构建和分析“活性成分-靶点”“药物-活性成分-共同靶点-疾病”、蛋白质相互作用(PPI)网络; 通过DAVID数据库对交集靶点进行基因本体(GO)功能富集和京都基因与基因组百科全书(KEGG)通路富集分析; 通过BioGPS对核心靶点进行基因定位，结合Cytoscape构建“成分-靶点-通路-器官/组织”网络; 使用AutoDockVina进行主要活性成分与核心靶点的分子对接。
结果小柴胡汤治疗GERD合并失眠的主要活性成分包括槲皮素、山奈酚、黄芩素等多种化合物，关键靶点包括丝氨酸/苏氨酸激酶1(AKT1)、白细胞介素-1B(IL-1B)、白细胞介素-6(IL-6)、肿瘤坏死因子(TNF)、肿瘤蛋白53(TP53)等，与RNA聚合酶Ⅱ启动子转录的正调控、炎症应答、信号转导等生物过程相关，涉及的通路包括癌症途径、AGE-RAGE信号通路、TNF信号通路、MAPK信号通路等，关键基因定位于胰岛、胰腺、松果体、胸腺以及相关免疫细胞。分子对接结果表明，槲皮素能够与核心靶点结合并展现出较稳定的构象。
结论小柴胡汤可能通过调控炎症免疫、糖脂代谢、昼夜节律而发挥治疗GERD合并失眠的作用。
Abstract:ObjectiveTo elucidate the potential mechanism of Xiaochaihutang (XCHT) in treating gastroesophageal reflux disease (GERD) with insomnia by using network pharmacology.
MethodsThe active ingredients and drug targets of Xiaochaihutang, diseases targets of GERD and insomnia were screened through online databases. The intersection of drug targets and disease targets was taken, and the interaction of the intersection targets was analyzed using STRING database. The "active ingredient-target" "drug-active ingredient-common target-disease" and protein-protein interaction (PPI) networks were constructed and analyzed by Cytoscape software. Gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the intersection targets by the DAVID database. Gene localization of core targets was performed by BioGPS, and the "ingredient-target-pathway-organ/tissue" network was constructed by Cytoscape. AutoDock Vina was used for the molecular docking of main active components with core targets.
ResultsThe main active ingredients of Xiaochaihutang in the treatment of GERD complicated with insomnia included Quercetin, Kaempferol, Baicalein and other ingredients. The key targets included serine/threonine kinase 1(AKT1), interleukin-1B(IL-1B), interleukin-6(IL-6), tumor necrosis factor (TNF), tumor protein 53 (TP53) and so on, which were related to the positive regulation of RNA polymerase Ⅱ promoter transcription, inflammatory response, signal transduction, and other biological processes. The involved pathways included cancer pathway, AGE-RAGE signaling pathway, TNF signaling pathway and MAPK signaling pathway and so on. Key genes were located in the islet, pancreas, pineal gland, thymus and related immune cells. Molecular docking results showed that Quercetin could bind to the core target and exhibit stable conformation.
ConclusionXiaochaihutang may play a role in the treatment of GERD complicated with insomnia by regulating inflammatory immunity, glucose and lipid metabolism and circadian rhythm.
-
-
表 1 共同活性成分
共同活性成分 Mol ID 来源 OB/% DL 黄芩甘 MOL002776 柴胡、半夏 40.12 0.75 山奈酚 MOL000422 柴胡、人参、甘草 41.88 0.24 豆甾醇 MOL000449 柴胡、黄芩、半夏、人参、生姜、大枣 43.83 0.76 槲皮 MOL000098 素柴胡、甘草、大枣 46.43 0.28 异鼠李素 MOL000354 柴胡、甘草 49.6 0.31 黄芩素 MOL002714 黄芩、半夏 33.52 0.21 β-谷甾醇 MOL000358 黄芩、半夏、人参、生姜、大枣 36.91 0.75 谷甾醇 MOL000359 黄芩、甘草 36.91 0.75 邻苯二甲酸二异辛酯 MOL002879 黄芩、人参 43.59 0.39 蓝堇碱 MOL000787 人参、大枣 59.26 0.83 丁子香萜 MOL000211 甘草、大枣 55.38 0.78 
下载: 导出CSV
表 2 前10活性成分的拓扑属性
活性成分 MOI ID 中介中心性 接近中心性 度 槲皮素 MOL000098 0.095 0.517 189 山奈酚 MOL000422 0.029 0.449 81 β-谷甾醇 MOL000358 0.020 0.440 76 豆甾醇 MOL000449 0.020 0.440 61 黄芩素 MOL002714 0.006 0.368 26 异鼠李素 MOL000354 0.006 0.418 22 柚皮苷 MOL004328 0.015 0.423 18 蓝堇碱 MOL000787 0.003 0.362 18 7-甲氧基-2-甲基异黄酮 MOL003896 0.007 0.422 16 汉黄芩素 MOL000173 0.009 0.420 15
下载: 导出CSV
表 3 排名前5位基因及其对应成分
基因 基因度值 MOI ID 活性成分 活性成分度值 AKT1 36 MOL000098 槲皮素 189 MOL000422 山柰酚 81 MOL002714 黄芩素 26 MOL004328 柚皮素 18 MOL000173 汉黄芩素 15 MOL002773 β-胡萝卜素 11 IL-6 35 MOL000098 槲皮素 189 MOL000173 汉黄芩素 15 MOL002928 千层纸素A 8 TNF 33 MOL000098 槲皮素 189 MOL000422 山柰酚 81 MOL000173 汉黄芩素 15 MOL005344 人参皂苷rh2 5 STAT3 32 MOL000497 甘草查尔酮A 12 IL-1B 30 MOL000098 槲皮素 189 MOL005344 人参皂苷rh2 5 TP53 30 MOL000098 槲皮素 189 MOL002714 黄芩素 26 MOL000173 汉黄芩素 15 MOL001689 刺槐素 9 AKT1 : 丝氨酸/苏氨酸激酶1; IL-6 : 白细胞介素-6; TNF: 肿瘤坏死因子; STAT3 : 信号转导及转录激活因子3;
IL-1B : 白细胞介素-1B; TP53 : 肿瘤蛋白53。
下载: 导出CSV
表 4 分子对接结果
基因 活性成分 结合能/(kcal/mol) 结合类型 AKT1 -8.0 IL-1B -6.9 IL-6 槲皮素 -6.7 氢键、疏水、范德华力 TNF -10.0 TP53 -6.8 AKT1 : 丝氨酸/苏氨酸激酶1; IL-1B : 白细胞介素-1B;
IL-6 : 白细胞介素-6; TNF: 肿瘤坏死因子; TP53 : 肿瘤蛋白53。
下载: 导出CSV
-
[1] 李欣瑜, 刘俊宏, 王淼蕾, 等. 胃食管反流病的中西医诊疗进展[J]. 实用中医内科杂志, 2023, 37(2): 5-8. https://www.cnki.com.cn/Article/CJFDTOTAL-SYZY202302002.htm [2] 李军祥, 谢胜, 唐旭东, 等. 消化系统常见病胃食管反流病中医诊疗指南(基层医生版)[J]. 中华中医药杂志, 2020, 35(6): 2995-2998. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY202006082.htm [3] 窦维佳, 王新, 胡博, 等. 胃食管反流病与睡眠障碍相关性的临床研究[J]. 医学研究杂志, 2020, 49(8): 154-157. https://www.cnki.com.cn/Article/CJFDTOTAL-YXYZ202008037.htm [4] 任小华. 不同亚型胃食管反流病患者的精神心理异常状况及其对患者自然病史的影响[J]. 实用临床医药杂志, 2018, 22(13): 77-79. doi: 10.7619/jcmp.201813022 [5] ABE Y, KOIKE T, SAITO M, et al. The ameliorating effect of switching to vonoprazan: a novel potassium-competitive acid blocker in patients with proton pump inhibitor refractory non-erosive reflux disease[J]. Digestion, 2021, 102(3): 480-488. doi: 10.1159/000506152
[6] 郑林洁, 谢菊, 钟红卫. 小柴胡汤加减治疗肝郁化火型失眠症的临床疗效观察[J]. 基层医学论坛, 2019, 23(4): 548-549. https://www.cnki.com.cn/Article/CJFDTOTAL-YXLT201904067.htm [7] 李赛美, 李宇航. 伤寒论讲义[M]. 3版. 北京: 人民卫生出版社, 2016: 1-15. [8] 殷江龙, 彭卓嵛, 石林韬, 等. 基于Citespace中医药治疗胃食管反流病相关研究的可视化分析[J]. 实用临床医药杂志, 2022, 26(22): 65-71. doi: 10.7619/jcmp.20221681 [9] RAO C V, VIJAYAKUMAR M. Effect of quercetin, flavonoids and alpha-tocopherol, an antioxidant vitamin, on experimental reflux oesophagitis in rats[J]. Eur J Pharmacol, 2008, 589(1/2/3): 233-238.
[10] LIU G, JIANG C S, LI D Z, et al. Isorhamnetin alleviates esophageal mucosal injury in a chronic model of reflux esophagitis[J]. Eur J Pharmacol, 2019, 864: 172720. doi: 10.1016/j.ejphar.2019.172720
[11] KAMBE D, KOTANI M, YOSHIMOTO M, et al. Effects of quercetin on the sleep-wake cycle in rats: involvement of gamma-aminobutyric acid receptor type A in regulation of rapid eye movement sleep[J]. Brain Res, 2010, 1330: 83-88.
[12] LIU W L, WU B F, SHANG J H, et al. Moringa oleifera seed ethanol extract and its active component kaempferol potentiate pentobarbital-induced sleeping behaviours in mice via a GABAergic mechanism[J]. Pharm Biol, 2022, 60(1): 810-824.
[13] ZHENG X Z, SEHGAL A. AKT and TOR signaling set the pace of the circadian pacemaker[J]. Curr Biol, 2010, 20(13): 1203-1208.
[14] TIAN B Q, LIU J D, ZHANG N S, et al. Oncogenic SNORD12B activates the AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma via nucleus partitioning of PP-1α[J]. Oncogene, 2021, 40(21): 3734-3747.
[15] 翟玉萱, 赵怡, 项荣武, 等. 基于加权网络药理学的小柴胡汤抗肝癌作用机制研究[J]. 中国药物化学杂志, 2020, 30(11): 658-668. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGYH202011004.htm [16] AGHELAN Z, KARIMA S, KHAZAIE H, et al. Interleukin-1α and tumor necrosis factor α as an inducer for reactive-oxygen-species-mediated NOD-like receptor protein 1/NOD-like receptor protein 3 inflammasome activation in mononuclear blood cells from individuals with chronic insomnia disorder[J]. Eur J Neurol, 2022, 29(12): 3647-3657.
[17] CARROLL J E, CARRILLO C, OLMSTEAD R, et al. Sleep deprivation and divergent toll-like receptor-4 activation of cellular inflammation in aging[J]. Sleep, 2015, 38(2): 205-211.
[18] ZAVALA-SOLARES M R, FONSECA-CAMARILLO G, VALDOVINOS M, et al. Gene expression profiling of inflammatory cytokines in esophageal biopsies of different phenotypes of gastroesophageal reflux disease: a cross-sectional study[J]. BMC Gastroenterol, 2021, 21(1): 201.
[19] ALI T, CHOE J, AWAB A, et al. Sleep, immunity and inflammation in gastrointestinal disorders[J]. World J Gastroenterol, 2013, 19(48): 9231-9239.
[20] KAVANAGH M E, O'SULLIVAN K E, O'HANLON C, et al. The esophagitis to adenocarcinoma sequence; the role of inflammation[J]. Cancer Lett, 2014, 345(2): 182-189.
[21] 兰斌, 张钰, 龙睿, 等. 小柴胡汤"去滓重煎"对LPS诱导发热白兔模型体温及血清IL-1β、IL-6和TNF-α水平的影响[J]. 湖南中医药大学学报, 2020, 40(12): 1468-1472. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZX202012006.htm [22] FUKUCHI T, HIRASAWA K, SATO C, et al. Potential roles of gastroesophageal reflux in patients with superficial esophageal squamous cell carcinoma without major causative risk factors[J]. J Gastroenterol, 2021, 56(10): 891-902.
[23] AHMAD S, AKHTER F, SHAHAB U, et al. Do all roads lead to the Rome?The glycation perspective![J]. Semin Cancer Biol, 2018, 49: 9-19.
[24] 邓雅凤, 王洋洋, 鱼涛. 基于网络药理学与分子对接的化肝煎对失眠、慢性萎缩性胃炎和胃食管反流病"异病同治"作用机制探讨[J]. 药物评价研究, 2022, 45(11): 2176-2187. https://www.cnki.com.cn/Article/CJFDTOTAL-YWPJ202211003.htm [25] 郑雪娜, 吴雪芬, 郭鑫, 等. 不同经穴组合针刺对失眠大鼠松果体褪黑素含量的影响[J]. 针刺研究, 2018, 43(6): 360-364. https://www.cnki.com.cn/Article/CJFDTOTAL-XCYJ201806006.htm [26] CLAUSTRAT B, BRUN J, CHAZOT G. The basic physiology and pathophysiology of melatonin[J]. Sleep Med Rev, 2005, 9(1): 11-24.
[27] BAN H J, KIM S C, SEO J, et al. Genetic and metabolic characterization of insomnia[J]. PLoS One, 2011, 6(4): e18455.
[28] 刘凯利, 阮君, 尚浩南, 等. 小柴胡汤和解少阳枢机不利防治代谢综合征组分疾病[J]. 现代中西医结合杂志, 2021, 30(22): 2496-2500. https://www.cnki.com.cn/Article/CJFDTOTAL-XDJH202122026.htm [29] KANDULSKI A, MALFERTHEINER P. Gastroesophageal reflux disease: from reflux episodes to mucosal inflammation[J]. Nat Rev Gastroenterol Hepatol, 2011, 9(1): 15-22.
[30] 王丽敏, 于静, 张林, 等. 小柴胡汤对CFA大鼠血清细胞因子TNF-α、IL-1β、IL-6、M-CSF作用的实验研究[J]. 中华中医药学刊, 2020, 38(1): 15-19. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYHS202001005.htm -
期刊类型引用(8)
1. 鲁志兵，李瑞娟，吴志清，肖永娟. 微小核糖核酸-451a在人参养荣汤治疗鼻咽癌放射性黏膜损伤中的机制研究. 临床医药实践. 2024(04): 243-247 . 
百度学术
2. 罗红梅，王颖杰，李京辰，海丽娜. 复方苦参注射液治疗放射性肺损伤有效性的meta分析. 北京医学. 2024(05): 415-420 . 百度学术
3. 孙丕云，石彧，郭会，于鹏，梁艳艳，吴腾. 益气解毒利咽方灌胃对放射性唾液腺损伤小鼠的治疗作用及机制. 山东医药. 2024(22): 42-46 . 百度学术
4. 付小燕，王洪. 穴位揿针疗法对鼻咽癌患者化疗后恶心呕吐及生活质量的影响. 山西医药杂志. 2024(10): 775-778 . 百度学术
5. 杨玲. 复方苦参注射液治疗放疗所致口腔黏膜炎的有效性的Meta分析. 中国医院用药评价与分析. 2024(08): 995-998 . 百度学术
6. 孙蕊，李东芳. 黎月恒论治鼻咽癌临证经验. 中医药导报. 2023(02): 203-206+224 . 百度学术
7. 周义浪，田杰，朱国庆，吴晓勇，孙丽娥，徐静. 中医药在恶性肿瘤“全人群、全周期、全方位”管理中的应用与思考. 基层中医药. 2023(06): 19-24 . 百度学术
8. 张小云，山惠萍，奚兰花，冀胜军. 咀嚼运动联合穴位按摩在鼻咽癌放疗患者放射性口干症中的应用. 护理实践与研究. 2023(22): 3394-3399 . 百度学术
其他类型引用(0)
计量
- 文章访问数: 226
- HTML全文浏览量: 58
- PDF下载量: 32
- 被引次数: 8
苏公网安备 32100302010246号
