Potential Molecular Mechanisms and Drugs for Aconitine-Induced Cardiotoxicity in Zebrafish through RNA Sequencing and Bioinformatics Analysis

Abstract

Background:Accumulating evidence suggests that cardiotoxicity is one of the main manifestations of aconitine (AC) poisoning. However, the molecular mechanism of AC-induced cardiotoxicity remains unclear, there is little direct evidence for therapeutic targets and drugs of AC-induced cardiotoxicity. Material/Methods:Zebrafish were exposed to AC to evaluate cardiotoxicity by calculating the heart rates and observing the changes of cardiac and vascular structure. RNA-seq (RNA sequencing) and bioinformatics analysis were used to obtain differentially expressed genes (DEGs). The anti-AC cardiotoxicity compound was identified via connectivity map (CMAP) analysis and molecular docking. Results:AC-induced cardiotoxicity in zebrafish predominantly included arrhythmias, extended sinus venous and bulbus arteriosus (SV-BA) distance, and larger pericardial edema aera. A total of 1380 DEGs were identified by RNA-seq and bioinformatics analysis. cyclin-dependent kinase-1 (CDK1) was screened as the hub gene and the most potential therapeutic target due to its significant downregulation in cardiotoxicity based on protein-protein interaction (PPI) and drug-gene interaction (DGIdb) network analysis. Cell cycle signal pathway was the most significant pathways identified in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, the expression of CDK1 was validated in the Gene Expression Omnibus (GEO) database GSE71906, GSE65705, and GSE95140. Finally, heptaminol was identified as a novel anti-AC cardiotoxicity compound via CMAP analysis and molecular docking. Conclusions:Totally, hub genes and key pathways identified in this study can aid in the understanding of the molecular changes in AC-induced cardiotoxicity. Meanwhile, we provide a systematic method to explore drug toxicity prevention and treatment.

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos

“…Furthermore, an increase in coiling frequency, also a sign of embryotoxicity, has been reported recently. Wang et al found that AC-induced cardiotoxicity in zebrafish predominantly included arrhythmias, extended sinus venous and bulbus arteriosus (SV-BA) distance, and larger pericardial edema aera ( Wang et al, 2020 ). So far only one report had been published and showed that AC had direct embryotoxic effects during the rat organogenetic period ( Xiao et al, 2007 ).…”

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

“…The heart rate of SD rats was seen in clear rising in one study ( Zhang et al, 2012 ). Conformably, aconitine-evoked a remarkable rise in heart rate was also demonstrated in zebrafish embryo models compared with the control group in a dose-response relationship ( Fang et al, 2012 ; Cui et al, 2018 ; Wang M. et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ). A meta-analysis of two studies ( Fang et al, 2012 ; Wang S. et al, 2020 ) for the increased heart rate in zebrafish embryos [ n = 56, SMD = 2.42, 95% CI (1.56 to 3.27), p < 0.00001; heterogeneity: χ 2 = 30.32, df = 1 ( p < 0.00001), I 2 = 97%] ( Figure 3E ).…”

“…Moreover, 21 studies were deleted because the outcome measurement was not of interest. Ultimately, 32 eligible articles ( Liang et al, 1991 ; Meng, 2006 ; Fu, 2007 ; Liu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Deng, 2010 ; Fang et al, 2012 ; Zhang et al, 2012 ; Wang, 2013 ; Zhou et al, 2013 ; Sun et al, 2014 ; Yu, 2015 ; Cui et al, 2018 ; Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Li et al, 2018 ; Zhang et al, 2018 ; Liu et al, 2019 ; Wang M. et al, 2020 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Zhou et al, 2020 ; Xia et al, 2021 ; Yang et al, 2021 ; Ye et al, 2021 ; Wang S. et al, 2022 ) were identified for further evaluation, data extraction, and analysis ( Figure 2 ).…”

“…Through a holistic and comprehensive evaluation of the included literature, 13 studies had a quality assessment range of 2/10 to 9/10 with an average of 5.92 in Table 2 . Of which, one study ( Sun et al, 2014 ) got nine points, one study ( Peng et al, 2020 ) got eight points and four studies ( Wang M. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ) got seven points, two studies ( Cui et al, 2018 ; Liu et al, 2019 ) got six points, two studies ( Fang et al, 2012 ; Wang, 2013 ) got five points, two studies ( Liang et al, 1991 ; Zhang et al, 2012 ) got four points, and the rest of the study ( Deng, 2010 ) got two points. All studies were published in peer-reviewed journals.…”

“…Eight studies ( Liang et al, 1991 ; Fang et al, 2012 ; Zhang et al, 2012 ; Wang, 2013 ; Sun et al, 2014 ; Cui et al, 2018 ; Peng et al, 2020 ; Xia et al, 2021 ) were randomly assigned to treatment or control groups. Six studies ( Sun et al, 2014 ; Cui et al, 2018 ; Wang M. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ) described allocation concealment. All studies declared that the outcome assessment was blinded.…”