Mechanism of Action of Chinese Medicinal Herbs in the Treatment of Primary Myelofibrosis based on Bioinformatics and Molecular Dynamics

GUO Jiayuan; XIN Jile; ZHANG Man; LIU Mingxin; LIU Jingwen; SU Yajing; SHI Huihui; GUO Jue; LIU Wenqing; WEI Kailu; SONG Yalin; MA Qiuling

doi:10.13288/j.11-2166/r.2024.21.013

您当前的位置：

首页 >

文章列表页 >

Mechanism of Action of Chinese Medicinal Herbs in the Treatment of Primary Myelofibrosis based on Bioinformatics and Molecular Dynamics

更新时间：2024-10-30

- Mechanism of Action of Chinese Medicinal Herbs in the Treatment of Primary Myelofibrosis based on Bioinformatics and Molecular Dynamics
- Journal of Traditional Chinese Medicine Vol. 65, Issue 21, Pages: 2250-2258(2024)
- 作者机构：
  
  1.河南中医药大学第二临床医学院，河南省郑州市金水区东风路六号，450002
  2.河南中医药大学药学院
  3.河南省中医院/河南中医药大学第二附属医院
  4.河南省中西医结合防治血液病工程研究中心
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2024.21.013
  CLC：
- Received：25 June 2024，
  
  Revised：2024-08-27，
  
  Published：02 November 2024
- 稿件说明：
移动端阅览
郭家缘,新吉乐,张曼等.基于生物信息学和分子动力学的中药治疗原发性骨髓纤维化作用机制研究[J].中医杂志,2024,65(21):2250-2258.

GUO Jiayuan,XIN Jile,ZHANG Man,et al.Mechanism of Action of Chinese Medicinal Herbs in the Treatment of Primary Myelofibrosis based on Bioinformatics and Molecular Dynamics[J].Journal of Traditional Chinese Medicine,2024,65(21):2250-2258.
郭家缘,新吉乐,张曼等.基于生物信息学和分子动力学的中药治疗原发性骨髓纤维化作用机制研究[J].中医杂志,2024,65(21):2250-2258. DOI： 10.13288/j.11-2166/r.2024.21.013.

GUO Jiayuan,XIN Jile,ZHANG Man,et al.Mechanism of Action of Chinese Medicinal Herbs in the Treatment of Primary Myelofibrosis based on Bioinformatics and Molecular Dynamics[J].Journal of Traditional Chinese Medicine,2024,65(21):2250-2258. DOI： 10.13288/j.11-2166/r.2024.21.013.

摘要

目的

利用生物信息学和分子动力学方法探讨中药治疗原发性骨髓纤维化（PMF）的分子机制。

方法

通过检索中国知网数据库（CNKI）、中文科技期刊数据库（CCD）和中国学术期刊数据库（CSPD）相关文献，发掘整理1985—2024年间用于PMF治疗的高频中药，利用TCMSP、SwissTargetPrediction数据库及相关文献检索高频中药的主要活性成分及其相关靶点；GEO数据库下载PMF的基因表达谱数据集GSE44426和GSE124281，并运用R软件进行数据归一化处理和差异表达基因筛选；运用加权基因共表达网络分析（WGCNA）获取关键模块枢纽基因。取中药活性成分靶点、差异表达基因和关键模块枢纽基因的共同交集基因，运用Cytoscape3.9.2软件生成目标网络，通过拓扑分析生成核心靶点网络，通过GO和KEGG通路富集分析选取关键通路，并从String数据库获得蛋白相互作用关系，构建药物-成分-靶点网络和蛋白质互作网络（PPI）关系图。利用Discovery Studio 2020软件进行分子对接，GROMACS程序进行分子动力学模拟。

结果

共搜集21首处方，涉及121种中药，用药频次≥10次的中药有9种，由高到低排序依次为丹参、黄芪、白术、当归、党参、甘草、白芍、茯苓、熟地黄。9种高频中药共获得98种活性成分和1125个潜在靶点。GSE44426和GSE124281数据集共筛选24个基因样本，其中健康对照组（14例）和PMF组（10例），共鉴定出319个PMF组与健康对照组之间的差异表达基因，包含122个上调基因，197个下调基因。WGCNA共筛选24个共表达模块基因，发现与PMF发病密切相关的5个模块分别为MEpink、MEdarkred、MEblack、MEgrey、MEturquoise，包含7112个关键模块枢纽基因。GO和KEGG通路富集分析显示，上述高频中药治疗PMF主要涉及脂质和动脉粥样硬化通路，包含热休克蛋白90家族（HSP90AA1、HSP90AB1）、酪氨酸激酶（SRC）、丝裂原活化蛋白激酶（MAPK1）、白细胞介素10（IL-10）和白细胞介素1β（IL-1β）6个核心靶点。从药物-成分-靶点网络找到靶向于这6个核心靶点的中药成分共7种活性成分，包括毛蕊花糖苷、毛蕊异黄酮、山柰酚、木犀草素、柚皮素、槲皮素和茯苓酸。分子对接和分子动力学分析显示，关键中药为熟地黄、黄芪、白芍、丹参、甘草和茯苓，7个活性成分中毛蕊异黄酮与HSP90AB1结合最稳定。

结论

治疗PMF的主要中药可能为熟地黄、黄芪、白芍、丹参、甘草和茯苓，有效成分包括毛蕊花糖苷、毛蕊异黄酮、山柰酚、木犀草素、柚皮素、槲皮素、茯苓酸，相关靶点为HSP90AA1、HSP90AB1、SRC、MAPK1、IL-10、IL-1β，最关键通路为脂质和动脉粥样硬化通路。

Abstract

Objective

To explore the molecular mechanism implicated in the treatment of primary myelofibrosis （PMF） using Chinese medicinal herbs （CMH） by bioinformatics and molecular dynamics.

Methods

Data mining was performed to find the high-frequency CMH in treating PMF between the year of 1985 and 2024 by searching CNKI， Chinese Science and Technology Journal Database （CCD）， and China Academic Journal Database （CSPD）. TCMSP， SwissTargetPrediction and related reports were used to collect the main active ingredients of high-frequency CMH and their targets. The PMF datasets GSE44426 and GSE124281 were downloaded from GEO database， and R software was used for data normalization and differentially expressed genes （DEGs） screening. Key module hub genes were obtained by weighted gene co-expression network analysis （WGCNA） analysis. The common intersection genes of active ingredient targets， DEGs and key module hub genes of CMH were selected， and the target network was generated using Cytoscape 3.9.2 software. The core target network was generated by topological analysis， while key pathways were selected by GO and KEGG pathway enrichment analysis， and protein interaction relationships were obtained from the String database， so as to construct drug-ingredient-target network and protein interaction network （PPI） relationship diagrams. Discovery Studio 2020 software was used to perform molecular docking， and the GROMACS program was used to perform molecular dynamics simulation.

Results

A total of 21 prescriptions were collected involving 121 herbs. There were 9 herbs with a frequency ≥10 times， which were Danshen （

Radix et Rhizoma Salviae Miltiorrhizae

）， Huangqi （

Radix Astragali

）， Baizhu （

Rhizoma Atractylodis Macrocephalae

）， Danggui （

Radix Angelicae Sinensis

）， Dangshen （

Radix Codonopsis

）， Gancao （

Radix et Rhizoma Glycyrrhizae

）， Baishao （

Radix Paeoniae Alba

）， Fuling （

Poria

） and Shudihuang （

Radix Rehmanniae Praeparata

） from high- to low-frequency. A total of 98 active ingredients and 1125 potential targets were obtained from 9 high-frequency CMH. GSE44426 and GSE124281 data sets screened out 24 gene samples， including 14 of the healthy control group and 10 of the PMF group， and identified 319 DEGs between the two groups， including 122 up-regulated genes and 197 down-regulated genes. WGCNA screened out 24 co-expression module genes and found that the five modules closely related to the onset of PMF were MEpink， MEdarkred， MEblack， MEgrey， and MEturquoise， involving 7112 key module hub genes. The GO and KEGG enrichment analyses indicated that lipids and the atherosclerosis pathways were mainly involved in the mechanism of above high-frequency CMH in treating PMF， which included six hub protein targets： HSP90AA1， HSP90AB1， SRC， MAPK1， IL1B and IL10. From the drug-ingredient-target network， seven active ingredients of CMH targeting at these six hub targets were found， including verb

ascoside， verbascos isoflavone， kaempferol， luteolin， naringenin， quercetin and pachymic acid. The molecular docking and molecular dynamics analyses showed that the key CMH were Shudihuang， Huangqi， Baishao， Danshen， Gancao and Fuling， and among the seven active ingredients， calycosin had the highest binding affinity with HSP90AB1.

Conclusion

The main CMH for the treatment of PMF may be Shudihuang， Huangqi， Baishao， Danshen， Gancao and Fuling， and the active ingredients include verbascoside， verbascos isoflavones， kaempferol， luteolin， naringenin， quercetin and pachymic acid. The relevant targets are HSP90AA1， HSP90AB1， SRC， MAPK1， IL-10， and IL-1β， and the most critical pathways are lipid and atherosclerosis pathways.

关键词

Keywords

references

MESA RA ， VERSTOVSEK S ， CERVANTES F ， et al . Primary myelofibrosis （PMF）， post polycythemia vera myelofibrosis （post-PV MF）， post essential thrombocythemia myelofibrosis （post-ET MF）， blast phase PMF （PMF-BP）： Consensus on terminology by the international working group for myelofibrosis research and treatment （IWG-MRT）［J］. Leuk Res ， 2007 ， 31 （ 6 ）： 737 - 740 .

TEFFERI A . Primary myelofibrosis：2023 update on diagnosis， risk-stratification， and management ［J］. Am J Hematol ， 2023 ， 98 （ 5 ）： 801 - 821 .

王梦亚，程志 . 原发性骨髓纤维化的中医药治疗探析［J］. 中医研究， 2016 ， 29 （ 8 ）： 9 - 11 .

UESAKA K ， OKA H ， KATO R ， et al . Bioinformatics in bioscience and bioengineering：recent advances， applications， and perspectives ［J］. J Biosci Bioeng ， 2022 ， 134 （ 5 ）： 363 - 373 .

DURRANT JD ， MCCAMMON JA . Molecular dynamics simulations and drug discovery ［J］. BMC Biol ， 2011 ， 9 ： 71 . doi： 10.1186/1741-7007-9-71 http://dx.doi.org/10.1186/1741-7007-9-71 .

LI W ， YUAN B ， ZHAO Y ， et al . Transcriptome profiling reveals target in primary myelofibrosis together with structural biology study on novel natural inhibitors regarding JAK2 ［J］. Aging （Albany NY）， 2021 ， 13 （ 6 ）： 8248 - 8275 .

国家药典委员会 . 中华人民共和国药典：一部［M］. 北京：中国医药科技出版社， 2020 ．

CHORZALSKA A ， MORGAN J ， AHSAN N ， et al . Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis ［J］. Blood ， 2018 ， 132 （ 19 ）： 2053 - 2066 .

WANG F ， ZHANG H ， HE B ， et al . Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis ［J］. Hematol Oncol ， 2023 ， 41 （ 3 ）： 474 - 486 .

刘清池，马传宝，李建英，等 . 鳖甲生血丸治疗原发性骨髓纤维化患者120例临床观察［J］. 中医杂志， 2014 ， 55 （ 8 ）： 677 - 680 .

MJAHED H ， GIRODON F ， FONTENAY M ， et al . Heat shock proteins in hematopoietic malignancies ［J］. Exp Cell Res ， 2012 ， 318 （ 15 ）： 1946 - 1958 .

MIAO Z ， ZHANG K ， BAO R ， et al . Th1/Th2 imbalance and heat shock protein mediated inflammatory damage triggered by manganese via activating NF-κB pathway in chicken nervous system in vivo and in vitro ［J］. Environ Sci Pollut Res Int ， 2021 ， 28 （ 32 ）： 44361 - 44373 .

XU P ， HUANG MW ， XIAO CX ， et al . Matairesinol suppresses neuroinflammation and migration associated with Src and ERK1/2-NF-κB pathway in activating BV2 mic-roglia ［J］. Neurochem Res ， 2017 ， 42 （ 10 ）： 2850 - 2860 .

FISHER DAC ， MINER CA ， ENGLE EK ， et al . Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT， MAP kinase， and NFκB signaling ［J］. Leukemia ， 2019 ， 33 （ 8 ）： 1978 - 1995 .

BARONE M ， CATANI L ， RICCI F ， et al . The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis ［J］. Oncoimmunology ， 2020 ， 9 （ 1 ）： 1782575 .

CÓRDOBA‐MORENO MO ， SANTOS GC ， MUXEL SM ， et al . IL‐10‐induced STAT3/NF‐κB crosstalk modulates pineal and extra‐pineal melatonin synthesis ［J］. J Pineal Res ， 2024 ， 76 （ 1 ）： e12923 .

BARBOSA LIMA LE ， MUXEL SM ， KINKER GS ， et al . STAT1‐NFκB crosstalk triggered by interferon gamma regulates noradrenaline‐induced pineal hormonal production ［J］. J Pineal Res ， 2019 ， 67 （ 3 ）： e12599 .

YANG CM ， LEE IT ， LIN CC . et al .c-Src-dependent MAPKs/AP-1 activation is involved in TNF-alpha-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells ［J］. Biochem Pharmacol ， 2013 ， 85 （ 8 ）： 1115 - 1123 .

WANG HW ， WU T ， QI JY ， et al . Salidroside attenuates LPS-stimulated activation of THP-1 cell-derived macrophages through down-regulation of MAPK/NF-κB signaling pathways ［J］. J Huazhong Univ Sci Technolog Med Sci ， 2013 ， 33 （ 4 ）： 463 - 469 .

查看原文

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Mechanism of Yishen Qubi Tongluo Formula （益肾祛痹通络方） in the Treatment of Rheumatoid Arthritis：Based on Network Pharmacology，Molecular Docking and Experimental Verification

Bioinformatics Analysis and Experimental Validation of the Mechanism of Leigongteng （Tripterygium wilfordii Hook. f.） in Treating Rheumatoid Arthritis

Analysis of the Current Status and Prospects of Multi-Omics Technologies in the Field of Traditional Chinese Medicine

Exploring the Mechanism of Action of Qizhu Kang'ai Formula （芪术抗癌方） for the Treatment of Colorectal Cancer based on Network Pharmacology and Experimental Validation

Potential Mechanism of Action of Qiangxin Decoction （强心汤） for Chronic Heart Failure Based on Network Pharmacology and Molecular Docking

Related Author

QIU Mingliang

LIU Shuijuan

XIA Yuan

CHI Qiang

MO Lisha

LU Ying

YANG Canyu

XU Liuping

Related Institution

Clinical Medical College of Jiangxi University of Chinese Medicine

Affiliated Hospital of Jiangxi University of Chinese Medicine

The Second Affiliated Hospital of Guizhou University of Chinese Medicine

Guizhou University of Chinese Medicine

Guangdong Provincial Research Center for Metabolic Diseases， Guangdong Pharmaceutical University （Institute of Traditional Chinese Medicine）

Address：No.16, Nanxiao street, Dongzhimen, Dongcheng District, Beijing Postal code：100700
Tel：010-64035632 Email：jtcmcn@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19 京公网安备11010102007558号
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰