中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (32): 6927-6938.doi: 10.12307/2025.936

• 组织构建细胞学实验 cytology experiments in tissue construction • 上一篇    下一篇

烟雾病生物标志物及中药靶点分析

周汝霖1，胡远征2，王宗清2，周国平3，张保朝4，徐  茜2，白方会5   

  1. 1新乡医学院研究生院，河南省新乡市  453000；2南阳师范学院生命科学院，河南省南阳市  473000；南阳市中心医院，3神经外科，4神经内科，5医务科，河南省南阳市  473000


  • 收稿日期:2024-09-27 接受日期:2024-12-06 出版日期:2025-11-18 发布日期:2025-04-27
  • 通讯作者: 张保朝，教授，硕士生导师，南阳市中心医院神经内科，河南省南阳市 473000 通讯作者：徐茜，副教授,硕士生导师,南阳师范学院生命科学院，河南省南阳市 473000 通讯作者：白方会，副教授,硕士生导师,南阳市中心医院医务科，河南省南阳市 473000
  • 作者简介:周汝霖，男，1996年生，河南省信阳市人，汉族，硕士，医师，主要从事脑血管病方面的研究。
  • 基金资助:
    河南省重点研发专项项目(231111310900)，项目负责人：白方会；河南省科技攻关项目(232102310198)，项目负责人：白方会；南阳市基础与前言技术研究专项项目(23JCQY1007)，项目负责人：白方会

Exploration of biomarkers for moyamoya disease and analysis of traditional Chinese medicine targets#br#
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Zhou Rulin1, Hu Yuanzheng2, Wang Zongqing2, Zhou Guoping3, Zhang Baochao4, Xu Qian2, Bai Fanghui5   

  1. 1Graduate School of Xinxiang Medical University, Xinxiang 453000, Henan Province, China; 2School of Life Science, Nanyang Normal University, Nanyang 473000, Henan Province, China; 3Department of Neurosurgery, 4Department of Neurology, 5Department of Medical Service, Nanyang Central Hospital, Nanyang 473000, Henan Province, China
  • Received:2024-09-27 Accepted:2024-12-06 Online:2025-11-18 Published:2025-04-27
  • Contact: Zhang Baochao, Professor, Master’s supervisor, Department of Neurology, Nanyang Central Hospital, Nanyang 473000, Henan Province, China Co-corresponding author: Xu Qian, Associate professor, Master’s supervisor, School of Life Science, Nanyang Normal University, Nanyang 473000, Henan Province, China Co-corresponding author: Bai Fanghui, Associate professor, Master’s supervisor, Department of Medical Service, Nanyang Central Hospital, Nanyang 473000, Henan Province, China
  • About author:Zhou Rulin, Master, Physician, Nanyang Central Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
  • Supported by:
    Henan Provincial Key Research and Development Special Project, No. 231111310900 (to BFH); Henan Provincial Science and Technology Tackling Project, No. 232102310198 (to BFH); Nanyang Basic and Foreword Technology Research Special Project, No. 23JCQY1007 (to BFH)

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摘要：


文题释义：
GEO数据库：是美国国家生物技术信息中心建立的包含高通量微阵列、二代测序、质谱等多种技术平台数据的数据库。
烟雾病：是一种不明原因的慢性进展性颅内血管狭窄或闭塞性疾病，临床表现多样，以反复发生的出血性和缺血性脑卒中为主，对患者健康造成巨大危害。烟雾病的特征是双侧颅内远端颈内动脉狭窄，并伴有烟雾状侧支血管的形成。

背景：目前烟雾病的发病机制尚不清楚，缺乏早期诊断方法及有效的内科治疗手段。
目的：通过机器学习识别烟雾病的生物标志物，分析补黄四五汤治疗烟雾病的作用机制。
方法：从GEO数据库获取烟雾病基因数据集，使用R语言进行差异基因筛选，对差异基因进行富集分析；通过LASSO和支持向量机递归特征消除机器学习算法筛选烟雾病的生物标志物。通过建立列线图构建诊断模型，评估其临床效用及诊断价值，并通过临床烟雾病患者血清标志物检测进行进一步验证。利用体外实验观察补黄四五汤含药血清对氧糖剥夺下脐静脉内皮细胞的影响，选取补黄四五汤的主要成分与筛选出的靶点进行分子对接、分子动力学模拟，以探索其潜在的作用机制。
结果与结论：此次研究共筛选出76个差异基因，这些差异基因主要富集于免疫和代谢相关通路。通过机器学习得到CFD和DKFZp434L192两个潜在烟雾病生物标志物；校准曲线、决策曲线分析、临床影响曲线显示列线图具有很好的预测能力，qRT-PCR分析表明烟雾病患者血清中CFD和DKFZp434L192表达显著上调(P < 0.001)。体外实验结果显示，补黄四五汤可显著提升氧糖剥夺下脐静脉内皮细胞的活性和迁移能力(P < 0.01)，分子对接显示补黄四五汤的4种有效成分均可与目标靶点结合，动力学模拟结果进一步验证了其结合的稳定性。结果表明CFD和DKFZp434L192对烟雾病表现出较好的诊断效能，可作为烟雾病潜在的诊断生物标志物及治疗靶点；补黄四五汤对缺血状态下的血管内皮细胞存在一定保护作用，该方可能与CFD存在作用关系。
https://orcid.org/0009-0004-9476-1843(周汝霖)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 烟雾病, 数据挖掘, 生物标志物, 补黄四五汤, 人脐静脉内皮细胞, 工程化组织构建

Abstract: BACKGROUND: The pathogenesis of moyamoya disease is unclear, and there is a lack of early diagnostic methods and effective medical treatments.
OBJECTIVE: To identify biomarkers of moyamoya disease through machine learning, and analyze the therapeutic mechanism of Bu Huang Si Wu Tang in moyamoya disease.
METHODS: Moyamoya disease gene dataset from gene expression omnibus database was retrieved. R language was used to screen differentially expressed genes and perform enrichment analysis on differentially expressed genes. Moyamoya disease biomarkers were screened using least absolute shrinkage and selection operator and support vector machine-recursive feature elimination machine learning algorithms. A diagnostic model was constructed by establishing a column chart, and its clinical utility and diagnostic value were evaluated and further validated through detecting clinical serum markers of patients with moyamoya disease. In vitro experiments were performed to observe the effect of Bu Huang Si Wu Tang on umbilical vein endothelial cells under oxygen glucose deprivation, and the main components of Bu Huang Si Wu Tang were selected for molecular docking and molecular dynamics simulation with the screened targets to explore its potential mechanism.
RESULTS AND CONCLUSION: This study identified 76 differentially expressed genes, mainly enriched in immune and metabolic related pathways. Two potential biomarkers, complement factor D (CFD) and DKFZp434L192, were obtained through machine learning. The calibration curve, decision curve analysis, and clinical impact curve showed that the column chart had good predictive ability. qRT-PCR analysis showed that CFD and DKFZp434L192 expression levels were significantly upregulated in patients with moyamoya disease (P < 0.001). In vitro experiments showed that Bu Huang Si Wu Tang significantly enhanced the activity and migration ability (P < 0.01) of umbilical vein endothelial cells under oxygen glucose deprivation. Molecular docking results showed that all four active ingredients of Bu Huang Si Wu Tang could bind to the target site, and the dynamic simulation results further verified its binding stability. To conclude, CFD and DKFZp434L192 exhibit good diagnostic efficacy for moyamoya disease and can serve as potential diagnostic biomarkers and therapeutic targets for moyamoya disease. Bu Huang Si Wu Tang has a certain protective effect on vascular endothelial cells under ischemic conditions, which may be related to CFD.

Key words: moyamoya disease, data mining, biomarkers, Bu Huang Si Wu Tang, human umbilical vein endothelial cells, engineered tissue construction

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