摘要
目的利用孟德尔随机化(Mendelian randomization,MR)探究帕金森病(Parkinson′s disease,PD)与肠道微生物(intestinal flora,IF)的因果关联,预测调控IF干预PD的潜在中药及成分,从铁死亡视角解析其作用机制。方法基于Mibiogen和IEU数据库的全基因组关联研究数据开展两样本MR分析。利用g:SNPense和Coremine数据库定位单核苷酸多态性(single nucleotide polymorphism,SNP)邻近基因并预测中药,结合药典与教材规范中药分类。对预测靶标进行单细胞亚群表达分析。基于GEO数据集比较PD与铁死亡基因表达差异,加权基因共表达网络分析(WGCNA)筛选枢纽基因。从TCMSP和Herb数据库收集中药活性成分靶标,使用DrugnomeAI预测可药用性,对网药结果进行分子对接验证。结果Candidatus Soleaferrea(OR,1.192;95%CI:1.041~1.366,P=0.011)、Clostridium sensu strictol(OR,1.356;95%CI:1.089~1.690,P=0.007)为PD风险菌群。潜在中药以寒、平性,甘、苦、辛味为主,多归心、肝、脾经,清热解毒类占比突出,其中合欢花、连翘、菝葜关联度较高。单细胞分析表明药靶在细胞亚群中表达存在差异。铁死亡相关基因FDFT1在PD中显著表达,WGCNA筛选出223个枢纽基因,与药物靶标交集18个,其中CYP2A6、MAP2K2等11个靶标可药用性良好,分子对接显示bicuculline-TOP1结合最优。结论IF与铁死亡相关基因表达的关联提供了探索PD治疗新策略的双重视角,为PD治疗策略的创新提供了新的思路。
Objective To explore the causal association between Parkinson′s disease(PD)and intestinal microbiota(IF)through Mendelian randomization(MR),predict potential Chinese herbal medicines and components that treat PD by regulating IF,and analyzing its mechanism of action from the perspective of ferroptosis.Methods Two sample MR analysis was carried out based on genome-wide association study data from Mibiogen and IEU databases.g:Snpense and Coremine databases were used to locate single nucleotide polymorphism(SNP)neighboring genes and predict Chinese herbal medicine,and the classification of Chinese herbal medicine was standardized in combination with pharmacopoeia and textbooks.Single cell subpopulation expression analysis was performed on the predicted targets.Based on the GEO dataset,the expression differences of PD and ferroptosis genes were compared,and the hub genes were screened by weighted gene coexpression network analysis(WGCNA).The active ingredient targets of Chinese herbal medicine were collected from TCMSP and Herb databases,and DrugnomeAI was used to predict the druggability and perform molecular docking validation.Results MR analysis found that Candidatus Soleaferrea(OR,1.192;95%CI:1.041~1.366,P=0.011),Clostridium sensu strictol(OR,1.356;95%CI:1.089~1.690,P=0.007)are risk factors of PD.The primary therapeutic Chinese herbal medicines involved cooling and neutral properties,Sweet,bitter and pungent flavours,primarily targeting the heart,liver,and spleen meridians,and were mostly categorized as heat-clearing and detoxifying,Albizzia julibrissin,Forsythia suspensa and Smilax are highly correlated.Single cell analysis showed that there were differences in the expression of drug targets in cell subsets.Ferroptosis related gene FDFT1 is significantly expressed in PD.223 hub genes were screened by WGCNA,and 18 of them intersected with drug targets.11 targets such as CYP2A6 and MAP2K2 have good druggability.Molecular docking showed that bicuculline-TOP1 binds best.Conclusion The association between IF and ferroptosis related gene expression provides a dual perspective for exploring new strategies for PD treatment,and provides a new idea for the innovation of PD treatment strategies.
作者
陈军磊
丁图南
孔维泰
王维浩
张振国
李嘉怡
赵钰沅
李张恺
郑洪博
郭媛媛
付强
付殷
CHEN Junlei;DING Tunan;KONG Weitai;WANG Weihao;ZHANG Zhenguo;LI Jiayi;ZHAO Yuyuan;LI Zhangkai;ZHENG Hongbo;GUO Yuanyuan;FU Qiang;FU Yin(The First Clinical College of Heilongjiang University of Chinese Medicine,Harbin 150006,China;School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102401,China;School of Basic Medicine,Heilongjiang University of Chinese Medicine,Harbin 150040,China)
出处
《药学研究》
2025年第9期833-843,858,共12页
Journal of Pharmaceutical Research
基金
国家自然科学基金项目(No.81874426)
中国博士后科学基金第15批特别资助项目(站中)(No.2022T150069)
大学生创新创业训练计划项目(国家重点支持领域项目)(No.202310228063)
大学生创新创业训练计划项目(国家级一般项目)(No.202310228031)
北京中医药大学大学生创新创业训练计划项目(市级)(No.S202410026025)
大学生创新创业训练计划项目(省级指导)(No.S202310228002)
黑龙江中医药大学科技创新项目(No.KY2022-04)。
关键词
帕金森
肠道微生物
孟德尔随机化
合欢花
菝葜
连翘
网络药理学
Parkinson′s disease
Intestinal flora
Mendelian randomization
Albizia Flower
Smilax
Forsythia
Network Pharmacology
