异构信息网络驱动的恒古骨伤愈合剂“异病同治”4种骨伤疾病的作用机制  

Investigation on Mechanisms of Osteoking Against Four Types of Bone Injury Diseases Based on Heterogeneous Information Network with Concept of"Treating Different Diseases with an Identical Treatment"

作　　者：张苏雅 马兆臣 高双荣[1] 陈卫衡 张彦琼 林娜[1] ZHANG Suya;MA Zhaochen;GAO Shuangrong;CHEN Weiheng;ZHANG Yanqiong;LIN Na(Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China;The Third Affiliated Hospital of Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]中国中医科学院中药研究所,北京100700 [2]北京中医药大学第三附属医院,北京100029

出　　处：《中国实验方剂学杂志》2023年第24期42-53,共12页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：中国中医科学院科技创新工程项目(C12021A03808);中国中医科学院中药研究所技术研发项目(20211024)。

摘　　要：目的:通过整合异构信息网络挖掘与实验验证,阐释恒古骨伤愈合剂“异病同治”骨折、股骨头坏死、骨性关节炎和腰椎间盘突出症的作用机制。方法:依托疾病相关数据库和转录组表达谱数据集,以及中医药百科全书数据库,通过生物信息学数据整合与分析,获得4种目标疾病相关基因集和恒古骨伤愈合剂候选靶标谱,进而构建“疾病-证候-方药-靶点-通路-效应”异构信息网络,整合功能富集分析,筛选恒古骨伤愈合剂干预4种骨伤疾病失衡网络的核心靶标,及其参与的生物学通路和对应的临床症状,并加以动物实验验证。结果:异构信息网络挖掘表明,恒古骨伤愈合剂矫正骨折、股骨头坏死、骨性关节炎、腰椎间盘突出症失衡网络的共性机制是,通过调控相关核心候选靶标如蛋白激酶B(Akt1)、连环蛋白β1(CTNNB1)、表皮生长因子受体(EGFR)、热休克蛋白90-α(HSP90AA1)、磷脂酰肌醇3-激酶催化亚基α亚型(PI3KCA)等,及相关生物学通路如磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)、Janus激酶/信号换能器和转录激活剂(JAK/STAT)、肿瘤坏死因子(TNF)、核转录因子-κB(NF-κB)、Toll样受体等,发挥其调节细胞功能与活性、抑制炎症反应、减少骨质破坏、提高机体免疫功能的药理作用;在个性机制方面,恒古骨伤愈合剂可通过调节疾病靶位的血液循环而改善骨折断端血供;通过调控激素相关通路而维持骨代谢平衡,促进骨折愈合;通过靶向调控脂质相关通路纠正脂代谢紊乱,加速骨形成和骨修复,延缓股骨头坏死的病情进展;通过作用于神经功能调节通路减轻骨性关节炎与腰椎间盘突出症患者病变局部的痛觉刺激,缓解患者疼痛的症状。进一步发现,PI3K/Akt信号通路是该方干预4种疾病关键网络靶标最显著富集的通路,且该方候选靶标与骨折相关基因的网络关联性最强,故选择骨折作为目标疾病进行实验Objective:To elucidate the mechanism of Osteoking against fracture,femoral head necrosis,osteoarthritis,and lumbar disc herniation by integrating heterogeneous information network mining and experimental validation.Method:On the basis of the disease-related database and transcriptome expression profiling dataset,as well as the ETCM database,the gene sets related to four target diseases and the candidate target spectrum of Osteoking were obtained through the integration and analysis of bioinformatics data,and a"disease-syndrome-formula-target-pathway-effect"heterogeneous information network was constructed.In addition,by functional enrichment analysis,the core targets of Osteoking in interfering with the imbalance network of four kinds of bone injury diseases,the biological pathways involved,and the corresponding clinical symptoms were screened,and they were verified in animal experiments.Result:Heterogeneous information network mining indicates that Osteoking may commonly reverse the imbalance networks of fracture,femoral head necrosis,osteoarthritis,and lumbar disc herniation via regulating cell function and activity,inhibiting inflammatory response,reducing bone destruction,and improving the immune function of the body by modulating relevant core candidate targets such as RAC-alpha serine/threonine-protein kinase(Akt1),catenin beta-1(CTNNB1),epidermal growth factor receptor(EGFR),heat shock protein 90-alpha(HSP90AA1),and phosphatidylinositol 3-kinase catalytic subunit alpha isoform(PI3KCA),as well as related biological pathways such as phosphatidylinositide 3-kinases/protein kinase B(PI3K/Akt),janus kinase/signal transducer and activator of transcription(JAK/STAT),tumor necrosis factor(TNF),nuclear factor kappa-B(NF-κB),and Toll-like receptors.In particular,Osteoking may improve the blood supply of the fracture end by regulating blood circulation at the target site of the disease,and it may maintain the balance of bone metabolism by regulating hormone-related pathways to promote fracture healing.In addition,Os

关 键 词：恒古骨伤愈合剂 异构信息网络 异病同治 骨折 股骨头坏死 骨性关节炎 腰椎间盘突出症 

分 类 号：R2-0[医药卫生—中医学] R33R274R289