Investigating the Pharmacological Mechanisms of SheXiang XinTongNing Against Coronary Heart Disease Based on Network Pharmacology and Experimental Evaluation

SheXiang XinTongNing (XTN), which is composed of six traditional Chinese herbs, is a commercially available Chinese patent medicine that has been widely used as the treatment of coronary heart disease (CHD). Its mechanisms against coronary heart disease, however, remain largely unknown. This study aimed to investigate the pharmacological mechanisms of XTN against CHD via network pharmacology and experimental evaluation. In this study, GO enrichment and KEGG pathway enrichment were firstly performed for acquiring the potentially active constituents of XTN, the candidate targets related to coronary heart disease, the drug-components-targets network as well as the protein-protein interaction network and further predicting the mechanisms of XTN against coronary heart disease. Subsequently, a series of in vitro experiments, specifically MTT assay, flow cytometry and Real-time quantitative polymerase chain reaction analysis, and a succession of in vivo experiments, including Tunel staining and immunohistochemical staining were conducted for further verification. Results showed that Bcl-2, IGF1, CASP3 were the key candidate targets which significantly associated with multiple pathways, namely PI3K-Akt signaling pathway and MAPK signaling pathway. It indicated that the potential mechanism of XTN against CHD may be predominantly associated with cell apoptosis. The in vitro experimental results showed that XTN treatment remarkably decreased the apoptotic rate and Bax/Bcl-2 ratio of H9c2 cells. Histological results confirmed that XTN not only effectively alleviated oxidative damage caused by myocardial ischemia but inhibited cell apoptosis. Given the above, through the combined utilization of virtual screening and experimental verification, the findings suggest that XTN makes a significant contribution in protecting the heart from oxidative stress via regulating apoptosis pathways, which lays the foundations and offers an innovative idea for future research.

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A Multi-Scale Bioinformatics Study on Novel Mechanism of Xintong Granule for Treating Coronary Heart Disease by Network Pharmacology and Molecular Docking Verification

10.21203/rs.3.rs-116130/v1 ◽

2020 ◽

Author(s):

Zhihong Huang ◽

Siyu Guo ◽

Changgeng Fu ◽

Wei Zhou ◽

Jingyuan Zhang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Molecular Docking ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Signaling Pathway ◽

Chinese Herbs ◽

Network Pharmacology ◽

Pharmacological Mechanism ◽

Vascular Regulation

Abstract Background: Xintong Granule (XTG) is a Chinese patent medicine composed of 13 Chinese herbs, which is widely used in the treatment of coronary heart disease (CHD). However, there are few studies on it, and its potential pharmacological mechanism needs to be further elucidated.Methods: In this study, network pharmacology was employed to construct the drug-compounds-targets-pathways molecular regulatory network of the treatment of CHD to explore the effective compounds of XTG and its underlying pharmacological mechanism. First, we established the related ingredients and potential targets of these ingredients databases by Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and A Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM). Next, the CHD targets were obtained in DigSee, OMIM, DisGeNET, TTD, GeneCards and GenCLiP3 database. Then, protein-protein interaction (PPI) analysis, GO and KEGG pathway enrichment analysis were carried out and the core targets were filtered by topology. Moreover, molecular docking was performed to assess the binding potential of hub targets and key compounds.Results: The result reflected that 178 components of XTG and 669 putative therapeutic targets were screened out. After a systematic and comprehensive analysis, we identified 9 hub targets (TNF, MAPK1, STAT3, IL6, AKT1, INS, EGFR, EGF, TP53) primarily participated in the comprehensive therapeutic effect related to blood circulation, vascular regulation, cell membrane region, compound binding, receptor activity, signal transduction, AGE-RAGE signaling pathway in diabetic complications, JAK-STAT signaling pathway, PI3K-AKT signaling pathway and MAPK signaling pathway.Conclusion: The results of this study tentatively clarified the potential targets and signaling pathways of XTG against CHD, which may benefit to the development of clinical experimental research and application.

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Research on the Mechanism of Wuwei Yuganzi San in the Treatment of Coronary Heart Disease Based on Network Pharmacology

10.21203/rs.3.rs-360519/v1 ◽

2021 ◽

Author(s):

Qunhui Zhang ◽

Yimei Li ◽

Yang Guo ◽

Qiqin Lu ◽

Guoying Zhang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Signaling Pathway ◽

Protein Interaction ◽

Mapk Signaling ◽

Receptor Protein ◽

Network Pharmacology ◽

Ras Signaling ◽

Ppi Network ◽

Active Ingredients

Abstract Background: Coronary heart disease (CHD) is a chronic cardiovascular disease across the world, which poses numerous threats to mankind. Wuwei Yuganzi San (WYS) is a famous traditional Tibetan medicine prescription. It has been confirmed effective in the treatment of CHD, but its specific mechanism remains still unclear. Objective: To elucidate the main pharmacological action of WYS in treating CHD and investigate the underlying multiple mechanisms of its multi-ingredient-multi-target by network pharmacology.Methods: Firstly, active ingredients of WYS and connected targets of five herbs were retrieved by using traditional Chinese medicine systems pharmacology (TCMSP) and screening literature. Then, genome explanation databases (OMIM and GeneCards) were used to acquire targets related to CHD. The protein-protein interaction (PPI) network was built using the mutual targets filtering genes through protein interaction. Next, a network diagram could be established with the help of Cytoscape 3.8.2. And, STRING platform was used to construct a protein interaction network. Finally, GO and KEGG analyses were analyzed to further elucidate biological process enrichment.Results: After the screening, 36 active ingredients and 202 related targets in WYS in addition to 952 disease-related targets were acquired. A total of 37 key targets including AKT1, ESR1, and EGFR were screened in the PPI network. These targets were mostly concentrated on the transmembrane receptor protein tyrosine kinase signaling pathway, cellular response to growth factors stimulus, and response to growth factor. The KEGG enrichment demonstrated that the MAPK signaling pathway, P13K/AKT signaling pathway, Ras signaling pathway, and other corresponding signaling pathways were closely related to CHD.Conclusions. WYS plays a significant role in the treatment of CHD. And this study provides a novel approach to disclose the therapeutic mechanisms of WYS on CHD.

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A Network Pharmacology Analysis to Reveal the Molecular Mechanism of Zhizi-Danshen on Coronary Heart Disease

10.21203/rs.3.rs-85979/v1 ◽

2020 ◽

Author(s):

Yue-hong Shen ◽

Shu-lin Wang ◽

Na Wu ◽

Yu-chen Dai ◽

Qian Zhou ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Endothelial Function ◽

Signaling Pathway ◽

Target Genes ◽

Cardiac Fibrosis ◽

Fluid Shear Stress ◽

Network Pharmacology ◽

Vascular Endothelial ◽

Vascular Endothelial Function

Abstract ObjectiveOur study aimed to investigate the potential mechanisms of the herb pair Zhizi-Danshen (ZD) for coronary heart disease (CHD) using network pharmacological data mining technology.MethodsThe Traditional Chinese Medicine System Pharmacology (TCMSP) database was used to collect the active ingredients of ZD and predict ZD-related target proteins. Afterwards, we identified CHD-related targets from DisGeNET database, NCBI gene database, and TTD database. The common targets both from ZD and CHD were screened by Venny2.1, which were then imported into the String database for protein-protein interaction (PPI) analysis. Finally, the GO and KEGG enrichment analysis were performed by R software, and the network construction was established using Cytoscape3.7.2.ResultsWe obtained 199 possible targets from 62 candidate ingredients of ZD and 1033 CHD-ralated targets, with 83 overlapping common target genes. Then, 11 core targets were acquired from PPI network analysis. Further, GO analysis showed that these common targets mainly influenced receptor ligand activity，cytokine activity，cytokine receptor binding，steroid hormone receptor activity, and peptide binding. KEGG pathway analysis indicated that ZD affected CHD through seven important pathways linked to vascular endothelial function regulation (fluid shear stress and atherosclerosis，AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway), imflammatory effects (IL-17 signaling pathway, TNF signaling pathway，Toll-like receptor signaling pathway)，and hormone regulation (relaxin signaling pathway). ConclusionsThis study revealed the potential pharmacological mechanisms of ZD against CHD, which were mainly associated with regulation of vascular endothelial function and inflammatory effects, promotion of vasodilatation, and prevention of cardiac fibrosis. Moreover, it provided a novel conception for the development of alternative therapies on CHD.

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MDM2 inhibition improves cisplatin-induced renal injury in mice via inactivation of Notch/hes1 signaling pathway

Human & Experimental Toxicology ◽

10.1177/0960327120952158 ◽

2020 ◽

pp. 096032712095215

Author(s):

X Luo ◽

L Zhang ◽

G-D Han ◽

P Lu ◽

Y Zhang

Keyword(s):

Signaling Pathway ◽

Renal Injury ◽

Cell Apoptosis ◽

Renal Tissue ◽

Tunel Staining ◽

Acute Renal Injury ◽

Renal Tubular ◽

Injury Models

Objective: To explore the potential function of MDM2-mediated Notch/hes1 signaling pathway in cisplatin-induced renal injury. Methods: The acute renal injury models of mice after intraperitoneal injection of cisplatin in vivo, and the apoptotic models of human renal tubular epithelial (HK-2) cells induced by cisplatin in vitro, were conducted respectively. The renal function-related parameters were measured. The renal tissue pathological changes and apoptosis were observed by PAS staining and TUNEL staining, respectively. Cell viability and apoptosis were detected by MTT and flow cytometry. Notch/hes1 pathway-related proteins were tested by Western blotting. Results: After mice injected by cisplatin, the levels of Cr, BUN, urine cystatin C, urine NGAL and urine ACR were increased and GFR was decreased with the elevation of renal tubular injury scores, the upregulation of the expressions of MDM2, N1ICD, Hes1 and Cleaved caspase-3, as well as the enhancement of cell apoptosis accompanying decreased ratio of Bcl-2/Bax. However, these cisplatin-induced renal injuries of mice have been improved by MDM2 inhibition. Besides, the declined viability, increased cytotoxicity, and enhanced apoptosis were observed in cisplatin-induced HK-2 cells, with the activated Notch/hes1 pathway. Notably, the phenomenon was alleviated in cisplatin-induced HK-2 cells transfected with MDM2 shRNA, but was severer in those co-treated with AdMDM2. Moreover, Notch1 siRNA can reverse the injury of AdMDM2 on HK-2 cells. Conclusion: Inhibiting MDM2 could reduce cell apoptosis through blocking Notch/hes1 signaling pathway, thus alleviating the acute renal injury caused by cisplatin.

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A Network Pharmacology-Based Study on Active Ingredients of Corydalis Rhizoma on Coronary Heart Disease

10.21203/rs.3.rs-90765/v1 ◽

2020 ◽

Author(s):

Ying Li ◽

Guhang Wei ◽

Zhenkun Zhuang ◽

Mingtai Chen ◽

Changjian Yuan ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Signaling Pathway ◽

Network Pharmacology ◽

Active Ingredients ◽

Active Components

Abstract BackgroundCorydalis Rhizoma(CR) showed a high efficacy for coronary heart disease (CHD). However, the interaction between the active ingredients of CR and the targets of CHD has not been unequivocally explained in previous researches. To study the active components and potential targets of Corydalis Rhizoma and to determine the mechanism underlying the exact effect of Corydalis Rhizoma on coronary heart disease, a method of network pharmacology was used.Materials and MethodsThe active components of CR and targets corresponding to each component were scanned out from Traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and target genes of CHD were searched on GeneCards database and Online Mendelian Inheritance in Man(OMIM) database. The active components and common targets of CR and CHD were used to build the “CR-CHD” network through Cytoscape (version 3.2.1) software as well as protein-protein interaction(PPI) network on String database. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis was executed by clusterProfiler(version 3.8) and DOSE(version 3.6) package on R platform.Results49 active ingredients and 394 relevant targets of CR and the 7173 CHD-related genes were retrieved. 40 common genes were selected for subsequent analysis. Crucial biological processes and pathways were obtained and analyzed, including DNA-binding transcription activator activity, RNA polymerase II-specific, RNA polymerase II transcription factor binding, kinase regulator activity, ubiquitin-like protein ligase binding, fluid shear stress and atherosclerosis, TNF signaling pathway, apoptosis, MAPK signaling pathway and PI3K-Akt signaling pathway.ConclusionsOverall, CR could alleviate CHD through the mechanisms predicted by network pharmacology, laying the foundation for future development of new drugs from traditional Chinese medicine on CHD.

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A Network Pharmacology-Based Study on Active Ingredients of Corydalis Rhizoma on Coronary Heart Disease

10.21203/rs.3.rs-41449/v1 ◽

2020 ◽

Author(s):

Ying Li ◽

Guhang Wei ◽

Zhenkun Zhuang ◽

Mingtai Chen ◽

Haidan Lin ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Signaling Pathway ◽

Network Pharmacology ◽

Active Ingredients ◽

Active Components

Abstract Background. Corydalis Rhizoma(CR) showed a high efficacy for coronary heart disease (CHD). However, the interaction between the active ingredients of CR and the targets of CHD has not been unequivocally explained in previous researches. To study the active components and potential targets of Corydalis Rhizoma and to determine the mechanism underlying the exact effect of Corydalis Rhizoma on coronary heart disease, a method of network pharmacology was used. Materials and Methods. The active components of CR and targets corresponding to each component were scanned out from Traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and target genes of CHD were searched on GeneCards database and Online Mendelian Inheritance in Man(OMIM) database. The active components and common targets of CR and CHD were used to build the “CR-CHD” network through Cytoscape (version 3.2.1) software as well as protein-protein interaction(PPI) network on String database. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis was executed by clusterProfiler(version 3.8) and DOSE(version 3.6) package on R platform. Results. 49 active ingredients and 394 relevant targets of CR and the 7173 CHD-related genes were retrieved. 40 common genes were selected for subsequent analysis. Crucial biological processes and pathways were obtained and analyzed, including DNA-binding transcription activator activity, RNA polymerase II-specific, RNA polymerase II transcription factor binding, kinase regulator activity, ubiquitin-like protein ligase binding, fluid shear stress and atherosclerosis, TNF signaling pathway, apoptosis, MAPK signaling pathway and PI3K-Akt signaling pathway. Conclusions. Overall, CR could alleviate CHD through the mechanisms predicted by network pharmacology, laying the foundation for future development of new drugs from traditional Chinese medicine on CHD.

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MiR-218 Promotes Adriamycin-Induced H9C2 Apoptosis by Inhibiting Stress-Associated Endoplasmic Reticulum Protein 1

Disease Markers ◽

10.1155/2022/6881103 ◽

2022 ◽

Vol 2022 ◽

pp. 1-10

Author(s):

Qinghua Chen ◽

Gang Chen ◽

Shuofang Zhao

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Cell Apoptosis ◽

Cell Activity ◽

Mapk Signaling ◽

Luciferase Reporter ◽

Tunel Staining ◽

H9c2 Cell ◽

H9c2 Cells ◽

Gene Assay

Objective. Adriamycin is a clinically important chemotherapeutic drug, but its use is restricted due to its myocardial toxicity. Therefore, it is especially important to explore the toxicity mechanism of Adriamycin (ADR) to cardiomyocytes. Methods. The myocardial toxicity model of ADR was constructed in vitro, and the effect of miR-218 inhibitor and sh-Serp1 on the activity of H9C2 cells induced by ADR was detected by MTT method. Also, flow cytometry, real-time polymerase chain reaction (RT-PCR), and TUNEL staining were used to detect the cell apoptosis. The activity of LDH was detected by colorimetry, and the interaction of miR-218 with Serp1 was detected by double-luciferase reporter gene assay. Western blotting technique was used to detect the expression level of caspase3 and p38 MAPK signal pathway. Results. miR-218 inhibitor can obviously inhibit ADR-induced decrease in cell activity of H9C2 cells, inhibit cell apoptosis, and inhibit p38 MAPK signaling pathway activation. Conversely, sh-Serp1 aggravated the decrease in H9C2 cell activity and promoted cell apoptosis. Conclusion. Upregulation of miR-218 expression will promote ADR-induced apoptosis of H9C2 cells. At the same time, we confirmed that the mechanism by which miR-218 promotes myocardial apoptosis was through the Serp1/p38 MAPK/caspase-3 signaling pathway.

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Investigating the pharmacological mechanisms of SheXiang XinTongNing against coronary heart disease based on network pharmacology

10.21203/rs.3.rs-21814/v1 ◽

2020 ◽

Author(s):

Li-ying Jia ◽

Jia Li ◽

Gui-yun Cao ◽

Zhao-qing Meng ◽

Lu Gan ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Signaling Pathway ◽

Protein Interaction ◽

Protein Interaction Network ◽

Interaction Network ◽

Enrichment Analysis ◽

Network Pharmacology

Abstract Background SheXiang XinTongNing, a commercially available Chinese patent medicine, has been widely used in the treatment of coronary heart disease. However, the mechanisms of SheXiang XinTongNing are still unclear. The aim of this study was to investigate the pharmacological mechanisms of SheXiang XinTongNing against coronary heart disease via network analysis. Method The traditional Chinese medicine system pharmacology analysis platform was used to screen the potential active constituents of the six traditional Chinese medicines in SheXiang XinTongNing, and the potential targets were obtained from PharmMapper. The genome annotation database platform was used to screen the candidate targets related to coronary heart disease. Then the drug-components-targets network and protein interaction network were built by Cytoscape 3.6.0 software. Further, GO bio-functional enrichment analysis and KEGG pathway enrichment analysis were performed through annotation, visualization and integrated discovery database. Results Results showed that the drugs-components-targets network contains 104 targets and 62 key components. The protein interaction network consisted of 107 nodes; key targets included Bcl2l1, IGF1, SRC, CASP3, et al. Functionally, the candidate targets were significantly associated with multiple pathways such as PI3K-Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway, FoxO signaling pathway, Endocrine resistance. Given the above, the pharmacological activities of SheXiang XinTongNing may be predominantly related to several factors such as cell apoptosis, inflammation and angiogenesis. Conclusion XTN can effectively attenuate the symptoms of coronary heart disease through diverse pathways. The research proves that network pharmacology can successfully reveal the mechanisms of traditional Chinese medicine in a holistic view. Our systematic analysis lays a foundation for further studying.

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