l-selenomethionine induces zebrafish embryo cardiovascular defects via down-regulating expression of lrp2b

Zhao, Guang; Zhu, Yuejie; Hu, Jun; Gao, Meng; Hong, Yiguo

doi:10.1016/j.chemosphere.2021.133351

Cited by 7 publications

(1 citation statement)

References 59 publications

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“…Compared to N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin T (troponin T), which are the classic predictive biomarkers for heart failure, cf-Hb in blood could be more sensitive in predicting heart damage in very early stages (OR, 1.31; 95% CI, 1.05–1.63; P = 0.02) [ 25 ]. Additionally, clinical trials have also revealed that cf-Hb is directly related to vascular damage and drug cardiotoxicity [ 26 , 27 ]. In a recent study using multiomics sequencing to comprehensively explore the mechanism of cardiotoxicity caused by doxorubicin, it was found that the reduction in Hb oxygen-carrying capacity and the increase in DNA breakage are the two main pathways responsible for doxorubicin-induced cardiotoxicity, and the increased release of cf-Hb is a prerequisite for toxicity prior to DNA damage [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis

Guo,

Yao,

Guo

et al. 2024

Acta Pharmacol Sin

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The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg−1 ·d−1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%–53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

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