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"

ZHANG Suya; MA Zhaochen; GAO Shuangrong; CHEN Weiheng; ZHANG Yanqiong; LIN Na

doi:10.13422/j.cnki.syfjx.20231037

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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"

更新时间：2023-11-20

- 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"
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 29, Issue 24, Pages: 42-53(2023)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20231037
  CLC： R2-0;R33;R274;R289
- Published：20 December 2023，
  
  Published Online：04 August 2023，
  
  Received：02 May 2023，
- 稿件说明：
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张苏雅,马兆臣,高双荣等.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[J].中国实验方剂学杂志,2023,29(24):42-53.

ZHANG Suya,MA Zhaochen,GAO Shuangrong,et al.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"[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(24):42-53.
张苏雅,马兆臣,高双荣等.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[J].中国实验方剂学杂志,2023,29(24):42-53. DOI： 10.13422/j.cnki.syfjx.20231037.

ZHANG Suya,MA Zhaochen,GAO Shuangrong,et al.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"[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(24):42-53. DOI： 10.13422/j.cnki.syfjx.20231037.

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

1（CTNNB1）、表皮生长因子受体（EGFR）、热休克蛋白90-

（HSP90AA1）、磷脂酰肌醇3-激酶催化亚基

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-

B（NF-

B）、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验证，结果表明该方可通过抑制PI3K/Akt信号轴的活化而发挥其加速骨形成、促进骨折愈合的作用。

结论

恒古骨伤愈合剂“异病同治”4种骨伤疾病的主要机制涉及细胞功能调节和免疫炎症相关信号通路，其中，PI3K/Akt信号轴可能是该方促进骨再生、骨重建，维持骨代谢平衡的关键作用通路之一。

Abstract

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-

B）， 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， Osteoking may relieve lipid metabolism disorders by targeting and regulating lipid-related pathways， accelerate bone formation and bone repair， and delay the progression of femoral head necrosis. Osteoking may relieve the symptoms of pain by acting on neurological pathways to reduce local nociceptive stimulation in patients with osteoarthritis and lumbar disc herniation. Further experimental validation demonstrates that the PI3K/Akt signaling pathway is the most significantly enriched pathway for the key network targets of Osteoking for the four diseases. The candidate target of Osteoking may have the strongest association with the network of fracture-related genes. Therefore， this study chooses fracture as the target disease to verify the efficacy of Osteoking. The results show that Osteoking can accelerate bone formation and promote fracture healing by inhibiting the activation of the PI3K/Akt signaling axis.

Conclusion

The study shows that the main mechanism of "treating different diseases with an identical treatment" of four bone injury diseases with Osteoking involves cell function regulation and immune inflammation-related signaling pathways. Further experimental validation identifies that the PI3K/Akt signaling axis may be one of the key pathways of Osteoking to promote bone regeneration， bone reconstruction， and bone metabolism homeostasis.

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

Keywords

Osteokingheterogeneous information networktreating different diseases with an identical treatmentfracturefemoral head necrosisosteoarthritislumbar disc herniation

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