Abstract
Oxidative stress initiates harmful cellular responses, such as DNA damage and protein denaturation, triggering a series of cardiovascular disorders. Systematic investigations of the transcription factors (TFs) involved in oxidative stress can help reveal the underlying molecular mechanisms and facilitate the discovery of effective therapeutic targets in related diseases. In this study, an integrated strategy which integrated RNA-seq-based transcriptomics techniques and a newly developed concatenated tandem array of consensus TF response elements (catTFREs)-based proteomics approach and then combined with a network pharmacology analysis, was developed and this integrated strategy was used to investigate critical TFs in the protection of Yixin-shu (YXS), a standardized medical product used for ischaemic heart disease, against hydrogen peroxide (H2O2)-induced damage in cardiomyocytes. Importantly, YXS initiated biological process such as anti-apoptosis and DNA repair to protect cardiomyocytes from H2O2-induced damage. By using the integrated strategy, DNA-(apurinic or apyrimidinic site) lyase (Apex1), pre B-cell leukemia transcription factor 3 (Pbx3), and five other TFs with their functions involved in anti-oxidation, anti-apoptosis and DNA repair were identified. This study offers a new understanding of the mechanism underlying YXS-mediated protection against H2O2-induced oxidative stress in cardiomyocytes and reveals novel targets for oxidative stress-related diseases.
Highlights
Oxidative stress initiates harmful cellular responses, such as DNA damage and protein denaturation, triggering a series of cardiovascular disorders
An integrated strategy which integrated transcription factors (TFs) activity quantified by catTFRE method and their downstream genes by RNA-seq technology firstly and combined with a network pharmacology analysis was developed and used to identify critical TFs in the protection of Yixin-shu (YXS), a Chinese standardized medical product used for the treatment of ischaemic heart disease, against H2O2-induced oxidative stress
The activity of oxidative stress-related biochemical enzymes such as total-antioxygen capacity (T-AOC) and total superoxide dismutase (T-SOD) increased and metabolites such as MDA decreased in a dose-dependent manner with the increasing concentrations of YXS (Fig. 1C,D and E)
Summary
Oxidative stress initiates harmful cellular responses, such as DNA damage and protein denaturation, triggering a series of cardiovascular disorders. An integrated strategy which integrated RNA-seq-based transcriptomics techniques and a newly developed concatenated tandem array of consensus TF response elements (catTFREs)-based proteomics approach and combined with a network pharmacology analysis, was developed and this integrated strategy was used to investigate critical TFs in the protection of Yixin-shu (YXS), a standardized medical product used for ischaemic heart disease, against hydrogen peroxide (H2O2)-induced damage in cardiomyocytes. Considering the binding activity of TFs to a specific DNA sequence and their downstream genes expression levels at the same time could reflect the activity and functions of the transcription factors more accurately and systematically. An integrated strategy which integrated TFs activity quantified by catTFRE method and their downstream genes by RNA-seq technology firstly and combined with a network pharmacology analysis was developed and used to identify critical TFs in the protection of Yixin-shu (YXS), a Chinese standardized medical product used for the treatment of ischaemic heart disease, against H2O2-induced oxidative stress. Rather than focusing on a single or a few molecular pathways, a whole-transcriptome analysis and large-scale TF investigation, and combined a network pharmacology approach help to ensure a comprehensive and accurate analysis
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