Bioinformatics identification based on causal association inference using multi-omics reveals the underlying mechanism of Gui-Zhi-Shao-Yao-Zhi-Mu decoction in modulating rheumatoid arthritis.

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2025-01-01 Epub Date: 2024-12-19 DOI:10.1016/j.phymed.2024.156332
Jiayue Yang, Heng Yang, Fumin Wang, Yao Dai, Yuxuan Deng, Kaiyun Shi, Zehua Zhu, Xinkun Liu, Xiao Ma, Yongxiang Gao
{"title":"Bioinformatics identification based on causal association inference using multi-omics reveals the underlying mechanism of Gui-Zhi-Shao-Yao-Zhi-Mu decoction in modulating rheumatoid arthritis.","authors":"Jiayue Yang, Heng Yang, Fumin Wang, Yao Dai, Yuxuan Deng, Kaiyun Shi, Zehua Zhu, Xinkun Liu, Xiao Ma, Yongxiang Gao","doi":"10.1016/j.phymed.2024.156332","DOIUrl":null,"url":null,"abstract":"<p><strong>Object: </strong>Rheumatoid arthritis (RA) is a prevalent and currently incurable autoimmune disease. Existing conventional medical treatments are limited in their efficacy, prolonged disease may lead to bone destruction, joint deformity, and loss of related functions, which places a huge burden on RA patients and their families. For millennia, the use of traditional Chinese medicine (TCM), exemplified by the Gui-Zhi-Shao-Yao-Zhi-Mu decoction (GZSYZM), has been demonstrated to offer distinct therapeutic advantages in the management of RA. Exploring the potential mechanism of GZSYZM in the treatment of RA is a hot topic in the field of TCM.</p><p><strong>Method: </strong>High-throughput sequencing data of RA at bulk level and single cell level and Chinese Materia Medica target-related databases were used as data sources. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was employed for the identification of the most relevant compounds to the active ingredients present in the GZSYZM granules. Potential disease genes were identified using a combination of differential expression analysis and weighted gene co-expression network analysis, and the \"Chinese Materia Medica-Ingredient-Target\" network was constructed to obtain candidate drug target genes. The GZSYZM-RA hub genes were then identified based on Molecular Complex Detection algorithm. To explore the associations and potential mechanisms between the GZSYZM-RA hub gene set and RA, Mendelian randomization (MR) analysis and Bayesian co-localization analysis were used to further identify the GZSYZM-RA core genes that were causally associated with RA. A nomogram was constructed based on a multifactorial logistic regression model using the GZSYZM-RA core genes as predictors of RA. To evaluate its diagnostic value, receiver operating characteristic (ROC) curves, calibration curves, and decision curves were plotted. The potential downstream regulatory mechanisms of the gene of interest in GZSYZM in RA therapy were finally investigated using single- gene set enrichment analysis and molecular docking. The aim was to model the optimal conformation of its target protein receptor binding to the small molecule ligand in GZSYZM to identify the key constituents.</p><p><strong>Result: </strong>Functional enrichment analysis revealed that the GZSYZM-RA hub gene set is enriched in several autoimmune-related mechanistic pathways, with a particular emphasis on the phosphoinositide 3 kinase (PI3K)‑serine/threonine kinase (AKT) signaling pathway. AUCell scores demonstrated active expression of the GZSYZM-RA hub gene set with the PI3K-AKT signaling pathway on monocytes, especially non-classical monocytes. Immunol infiltration analysis based on the CIBERSORT algorithm also showed a strong correlation between several genes in the GZSYZM-RA hub gene set and monocytes by calculating Spearman's rank correlation coefficients. MR analysis with co-localization analysis further identified seven core genes (CASP8, PPARG, IKBKB, PPARA, IFNG, MYC, and STAT3) causally associated with RA. Diagnostic value for clinical decision making was demonstrated by a multivariable logistic regression model constructed with GZSYZM-RA core genes. Molecular docking analysis indicates that CASP8 and GZSYZM have high docking scores, with three key constituents (quercetin, kaempferol, and diosmetin) exhibiting strong binding affinities.</p><p><strong>Conclusion: </strong>GZSYZM may regulate the abnormal over-proliferation and apoptotic imbalance of fibroblast-like synoviocytes in RA patients by inhibiting signaling of the PI3K-AKT signaling pathway while activating CASP8-mediated pro-apoptotic effects. And it may be effective in directly or indirectly inhibiting monocyte-to-osteoclast differentiation, ultimately improving the poor prognosis of joint destruction in RA patients.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156332"},"PeriodicalIF":6.7000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.phymed.2024.156332","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Object: Rheumatoid arthritis (RA) is a prevalent and currently incurable autoimmune disease. Existing conventional medical treatments are limited in their efficacy, prolonged disease may lead to bone destruction, joint deformity, and loss of related functions, which places a huge burden on RA patients and their families. For millennia, the use of traditional Chinese medicine (TCM), exemplified by the Gui-Zhi-Shao-Yao-Zhi-Mu decoction (GZSYZM), has been demonstrated to offer distinct therapeutic advantages in the management of RA. Exploring the potential mechanism of GZSYZM in the treatment of RA is a hot topic in the field of TCM.

Method: High-throughput sequencing data of RA at bulk level and single cell level and Chinese Materia Medica target-related databases were used as data sources. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was employed for the identification of the most relevant compounds to the active ingredients present in the GZSYZM granules. Potential disease genes were identified using a combination of differential expression analysis and weighted gene co-expression network analysis, and the "Chinese Materia Medica-Ingredient-Target" network was constructed to obtain candidate drug target genes. The GZSYZM-RA hub genes were then identified based on Molecular Complex Detection algorithm. To explore the associations and potential mechanisms between the GZSYZM-RA hub gene set and RA, Mendelian randomization (MR) analysis and Bayesian co-localization analysis were used to further identify the GZSYZM-RA core genes that were causally associated with RA. A nomogram was constructed based on a multifactorial logistic regression model using the GZSYZM-RA core genes as predictors of RA. To evaluate its diagnostic value, receiver operating characteristic (ROC) curves, calibration curves, and decision curves were plotted. The potential downstream regulatory mechanisms of the gene of interest in GZSYZM in RA therapy were finally investigated using single- gene set enrichment analysis and molecular docking. The aim was to model the optimal conformation of its target protein receptor binding to the small molecule ligand in GZSYZM to identify the key constituents.

Result: Functional enrichment analysis revealed that the GZSYZM-RA hub gene set is enriched in several autoimmune-related mechanistic pathways, with a particular emphasis on the phosphoinositide 3 kinase (PI3K)‑serine/threonine kinase (AKT) signaling pathway. AUCell scores demonstrated active expression of the GZSYZM-RA hub gene set with the PI3K-AKT signaling pathway on monocytes, especially non-classical monocytes. Immunol infiltration analysis based on the CIBERSORT algorithm also showed a strong correlation between several genes in the GZSYZM-RA hub gene set and monocytes by calculating Spearman's rank correlation coefficients. MR analysis with co-localization analysis further identified seven core genes (CASP8, PPARG, IKBKB, PPARA, IFNG, MYC, and STAT3) causally associated with RA. Diagnostic value for clinical decision making was demonstrated by a multivariable logistic regression model constructed with GZSYZM-RA core genes. Molecular docking analysis indicates that CASP8 and GZSYZM have high docking scores, with three key constituents (quercetin, kaempferol, and diosmetin) exhibiting strong binding affinities.

Conclusion: GZSYZM may regulate the abnormal over-proliferation and apoptotic imbalance of fibroblast-like synoviocytes in RA patients by inhibiting signaling of the PI3K-AKT signaling pathway while activating CASP8-mediated pro-apoptotic effects. And it may be effective in directly or indirectly inhibiting monocyte-to-osteoclast differentiation, ultimately improving the poor prognosis of joint destruction in RA patients.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
基于多组学因果关联推理的生物信息学鉴定揭示了桂枝少药直木汤调节类风湿关节炎的潜在机制。
目的:类风湿关节炎(RA)是一种常见病和目前无法治愈的自身免疫性疾病。现有的常规药物治疗效果有限,病程延长可能导致骨破坏、关节畸形和相关功能丧失,给RA患者及其家属带来巨大负担。几千年来,中药(TCM)的使用,如桂枝少药直目汤(GZSYZM),已被证明在治疗类风湿性关节炎方面具有明显的治疗优势。探讨GZSYZM治疗类风湿关节炎的潜在机制是目前中医学研究的热点。方法:以RA整体水平和单细胞水平的高通量测序数据及中药靶点相关数据库为数据源。采用超高效液相色谱-高分辨率质谱联用技术鉴定了GZSYZM颗粒中与有效成分最相关的化合物。采用差异表达分析和加权基因共表达网络分析相结合的方法鉴定潜在疾病基因,构建“中药-成分-靶点”网络,获得候选药物靶点基因。然后基于分子复合体检测算法对GZSYZM-RA枢纽基因进行鉴定。为了探究GZSYZM-RA枢纽基因集与RA的关联及其潜在机制,我们采用孟德尔随机化(Mendelian randomization, MR)分析和贝叶斯共定位分析进一步鉴定与RA有因果关系的GZSYZM-RA核心基因。以GZSYZM-RA核心基因作为RA的预测因子,构建多因素logistic回归模型。为评价其诊断价值,绘制受试者工作特征(ROC)曲线、校正曲线和决策曲线。最后通过单基因集富集分析和分子对接研究了GZSYZM中感兴趣基因在RA治疗中的潜在下游调控机制。目的是模拟其靶蛋白受体与GZSYZM中小分子配体结合的最佳构象,以确定关键成分。结果:功能富集分析显示,GZSYZM-RA枢纽基因集在几个自身免疫相关的机制通路中富集,特别强调磷酸肌肽3激酶(PI3K) -丝氨酸/苏氨酸激酶(AKT)信号通路。AUCell评分显示GZSYZM-RA枢纽基因集与PI3K-AKT信号通路在单核细胞,特别是非经典单核细胞上活跃表达。基于CIBERSORT算法的免疫浸润分析也通过计算Spearman秩相关系数显示GZSYZM-RA枢纽基因集中的多个基因与单核细胞之间存在较强的相关性。MR分析和共定位分析进一步确定了与RA有因果关系的7个核心基因(CASP8、PPARG、IKBKB、PPARA、IFNG、MYC和STAT3)。以GZSYZM-RA核心基因构建多变量logistic回归模型,验证其对临床决策的诊断价值。分子对接分析表明,CASP8与GZSYZM具有较高的对接得分,其中三个关键成分(槲皮素、山奈酚和薯蓣皂苷)具有较强的结合亲和力。结论:GZSYZM可能通过抑制PI3K-AKT信号通路,激活casp8介导的促凋亡作用,调控RA患者成纤维细胞样滑膜细胞异常过度增殖和凋亡失衡。并可能直接或间接抑制单核细胞向破骨细胞的分化,最终改善RA患者关节破坏的不良预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
期刊最新文献
GelMA@APPA microspheres promote chondrocyte regeneration and alleviate osteoarthritis via Fgfr2 activation. Intervention effects of Er Miao san on metabolic syndrome in Bama miniature pigs. Shenghui decoction inhibits neuronal cell apoptosis to improve Alzheimer's disease through the PDE4B/cAMP/CREB signaling pathway. Synergistic antimicrobial efficacy of glabrol and colistin through micelle-based co-delivery against multidrug-resistant bacterial pathogens. 4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1