Network pharmacology and experimental verification-based strategy for exploring the mechanisms of luteolin in the treatment of osteosarcoma.
Network pharmacology and experimental verification-based strategy for exploring the mechanisms of luteolin in the treatment of osteosarcoma.
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DOI：
10.1186/s12935-023-03046-x
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发表时间：
2023-09-25
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
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作者：
木犀草素是多种中药治疗多发性肿瘤的有效成分。然而，其抑制骨肉瘤增殖和转移的机制尚不清楚。基于网络药理学和实验验证，阐明木犀草素抗骨肉瘤的作用机制。整合网络药理学预测，scRNA-seq分析，分子对接和实验验证。木黄素相关靶点和骨肉瘤相关靶点从几个公共数据库中收集。筛选木犀草素抗骨肉瘤的靶点，并构建PPI网络来鉴定中心靶点。对骨肉瘤相关靶点和木犀草素对骨肉瘤靶点的GO和KEGG富集进行了研究。通过scRNA-seq分析确定核心靶蛋白在OS组织中的表达分布。通过分子对接、细胞生物学实验和骨肉瘤原位小鼠模型验证木犀草素对骨肉瘤增殖转移的抑制作用及其机制。网络药理学结果显示，251个木草素靶向骨肉瘤靶点和8个枢纽靶点，包括AKT1、ALB、CASP3、IL6、JUN、STAT3、TNF、VEGFA，以及PI3K-AKT信号通路可能在木草素抗骨肉瘤中发挥重要作用。公开数据分析显示，骨肉瘤组织中AKT1、IL6、JUN、STAT3、TNF和VEGFA的表达明显高于正常骨，并且随着时间的推移，VEGFA对总生存和转移的诊断价值增加。scRNA-seq分析显示，在MYC+成骨OS细胞中，尤其是在原代样品中，AKT1、STAT3和VEGFA的表达显著升高。此外，木犀草素与枢纽靶点之间的对接活性很好，这一点通过分子对接得到了验证。实验结果显示木犀草素能抑制细胞活力，显著降低AKT1、STAT3、IL6、TNF、VEGFA的表达，并能抑制骨肉瘤原位小鼠模型骨肉瘤的增殖和转移。本研究表明木犀草素可能通过靶向AKT1、STAT3、IL6、TNF、VEGFA等多种基因调控多种信号通路，抑制骨肉瘤的增殖和转移。在线版本包含补充材料，可在10.1186/s12935-023-03046-x获得。
Luteolin is an active ingredient in various traditional Chinese medicines for the treatment of multiple tumors. However, the mechanisms of its inhibitory effect on osteosarcoma proliferation and metastasis remain unclear. To elucidate the anti-osteosarcoma mechanisms of luteolin based on network pharmacology and experimental verification. Integrate network pharmacology predictions, scRNA-seq analysis, molecular docking, and experimental validation. Luteolin-related targets and osteosarcoma-associated targets were collected from several public databases. The luteolin against osteosarcoma targets were screened and a PPI network was constructed to identify the hub targets. The GO and KEGG enrichment of osteosarcoma-associated targets and luteolin against osteosarcoma targets were performed. And scRNA-seq analysis was performed to determine the distribution of the core target expression in OS tissues. Molecular docking, cell biological assays, and osteosarcoma orthotopic mouse model was performed to validate the inhibitory effect and mechanisms of luteolin on osteosarcoma proliferation and metastasis. Network pharmacology showed that 251 luteolin against osteosarcoma targets and 8 hub targets including AKT1, ALB, CASP3, IL6, JUN, STAT3, TNF, and VEGFA, and the PI3K-AKT signaling pathway might play an important role in anti-osteosarcoma of luteolin. Analysis of public data revealed that AKT1, IL6, JUN, STAT3, TNF, and VEGFA expression in OS tissue was significantly higher than that in normal bones, and the diagnostic value of VEGFA for overall survival and metastasis was increased over time. scRNA-seq analysis revealed significantly higher expression of AKT1, STAT3, and VEGFA in MYC+ osteoblastic OS cells, especially in primary samples. Moreover, the docking activity between luteolin and the hub targets was excellent, as verified by molecular docking. Experimental results showed that luteolin could inhibit cell viability and significantly decrease the expression of AKT1, STAT3, IL6, TNF, and VEGFA, and luteolin could also inhibit osteosarcoma proliferation and metastasis in osteosarcoma orthotopic mouse model. This study shows that luteolin may regulate multiple signaling pathways by targeting various genes like AKT1, STAT3, IL6, TNF, and VEGFA to inhibit osteosarcoma proliferation and metastasis. The online version contains supplementary material available at 10.1186/s12935-023-03046-x.
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DOI：
10.1186/s13046-021-02146-8
发表时间：
2021-10-27
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Li H;Shen X;Ma M;Liu W;Yang W;Wang P;Cai Z;Mi R;Lu Y;Zhuang J;Jiang Y;Song Y;Wu Y;Shen H
通讯作者：
Shen H
影响因子：
5.6
作者：
Crupi, Rosalia;Impellizzeri, Daniela;Esposito, Emanuela
通讯作者：
Esposito, Emanuela
影响因子：
3.8
作者：
Duan, Z;Lamendola, DE;Seide, MV
通讯作者：
Seide, MV
影响因子：
20.3
作者：
Amaya, Maria L.;Inguva, Anagha;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
14.9
作者：
Davis AP;Grondin CJ;Johnson RJ;Sciaky D;Wiegers J;Wiegers TC;Mattingly CJ
通讯作者：
Mattingly CJ