Eucommia ulmoides Oliver-Tribulus terrestris L. Drug Pair Regulates Ferroptosis by Mediating the Neurovascular-Related Ligand-Receptor Interaction Pathway- A Potential Drug Pair for Treatment Hypertension and Prevention Ischemic Stroke.

Qian Zhang,Xuesong Yang,Chuanhua Yang,Jie Yang,Yongzhi Chen

doi:10.3389/fneur.2022.833922

Qian Zhang, Xuesong Yang + Show 3 more

Open Access

https://doi.org/10.3389/fneur.2022.833922

Copy DOI

Abstract

BackgroundIn this study, we used the network pharmacology approach to explore the potential disease targets of the Eucommia ulmoides Oliver (EUO)-Tribulus terrestris L. (TT) drug pair in the treatment of hypertension-associated neurovascular lesions and IS via the ferroptosis pathway.MethodsWe used the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform to search for the key active compounds and targets of the drug pair. Based on the GeneCards database, the relevant targets for the drug pair were obtained. Then, we performed the molecular docking of the screened core active ingredients and proteins using the DAVID database and the R AutoDock Vina software. Based on the GSE22255 dataset, these screened target proteins were used to build random forest (RF) and support vector machine (SVM) models. Finally, a new IS nomogram prediction model was constructed and evaluated.ResultsThere were 36 active compounds in the EUO-TT drug pair. CHRM1, NR3C1, ADRB2, and OPRD1 proteins of the neuroactive ligand-receptor interaction pathway interacted with the proteins related to the ferroptosis pathway. Molecular docking experiments identified 12 active ingredients of the drug pair that may tightly bind to those target proteins. We constructed a visual IS nomogram prediction model using four genes (CHRM1, NR3C1, ADRB2, and OPRD1). The calibration curve, DCA, and clinical impact curves all indicated that the nomogram model is clinically applicable and diagnostically capable. CHRM1, NR3C1, ADRB2, and OPRD1, the target genes of the four effective components of the EUO-TT drug pair, were considered as risk markers for IS.ConclusionsThe active ingredients of EUO-TT drug pair may act on proteins associated with the neuroactive ligand-receptor interaction pathway to regulate ferroptosis in vascular neurons cells, ultimately affecting the onset and progression of hypertension.

Highlights

Ischemic stroke (IS), one of the neurovascular disorders, is a common complication of hypertension, the second most common cause of death worldwide, and has become a major public health problem
30 compounds were found to correspond to 114 genes, and the gene names of each target were obtained from Uniprot (Table 1)
Network pharmacology was used to screen the active compounds of Eucommia ulmoides Oliver (EUO)-terrestris L. (TT) L. drug pair and found that the target genes were mainly enriched in the neuroactive ligand-receptor interaction pathway in this research

Summary

Introduction

Ischemic stroke (IS), one of the neurovascular disorders, is a common complication of hypertension, the second most common cause of death worldwide, and has become a major public health problem. A study based on the Global Burden of Disease, Injuries and Risk Factors (GDB2010) showed that stroke mortality has increased by 26% since 1990 [2]. A prospective observational study of 61 populations worldwide (∼1 million people aged 40–89 years) found a positive association between stroke risk and blood pressure levels [3]. The effect of western medicine in the treatment of hypertension is precise, it is mainly based on the control of blood pressure. This treatment regimen has several disadvantages, such as high dependence on medicines, numerous side effects, and heavy economic burden due to long-term use. We used the network pharmacology approach to explore the potential disease targets of the Eucommia ulmoides Oliver (EUO)-Tribulus terrestris L. (TT) drug pair in the treatment of hypertension-associated neurovascular lesions and IS via the ferroptosis pathway

Methods

Results

Discussion

Conclusion