Cardiotoxicity evaluation and comparison of diterpene alkaloids on zebrafish

Ye, Qiang; Li, Hongmei; Fang, Chengxin; Liu, Yushi; Liu, Xiaomei; Liu, Juanru; Zhang, Cunyan; Tingmo, Zhang; Peng, Cheng; Guo, Li

doi:10.1080/01480545.2019.1586916

Cited by 29 publications

(23 citation statements)

References 27 publications

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“…Also, AC could induce cardiomyocyte damage by mitigating BNIP3-dependent mitophagy and the TNFα-NLRP3 signaling axis ( Peng et al, 2019 ). Ye et al suggested that AC might induce cardiotoxicity in zebrafish by activating Na + channel and inhibiting K + channel ( Ye et al, 2019 ). Liu et al reported that AC induced cardiotoxicity and apoptosis in embryonic zebrafish by influencing the expression of cardiovascular relative genes, such as Tbx5 , Gata4 , and Nkx2.5 ( Liu et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from Aconitum plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (Nrf2, HO-1, Cat, and Sod-1) Erk1/2 and Bcl-2 were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (Bad, Bax, Cyto C, Casp-9, and Casp-3) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Even so, acute or chronic cardiac toxic effects often have still followed later, when AC‐containing herb medicines were improperly used nowadays. As reported in previous articles, up to 88.2% of patients with AC poisoning suffered polymorphous ventricular arrhythmias, including ventricular ectopics, ventricular tachycardia, torsade de points , and ventricular fibrillation, all of which are the commonest fatal cardiac side‐effects induced by AC 30‐33 . Besides, myocarditis or severe myocardial injuries were observed in some autopsy cases of AC poisoning.…”

Section: Introductionmentioning

confidence: 61%

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

Zhou¹,

Liu

Qiu

et al. 2021

Medicinal Research Reviews

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Aconitine (AC) is well‐known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti‐inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC‐containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC‐related cardiotoxicity, as well as the issues before the development of AC‐based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.

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“…These Na+ channels were believed to activate to increase the heart rate. Then, the increase in heart rate made the myocardium overloaded and finally resulted in functional and organic damage on the zebrafish heart [45].…”

Section: Resultsmentioning

confidence: 99%

Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review

Jayasinghe

Jayawardena

2019

Evidence-Based Complementary and Alternative Medicine

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Herbal remedies have been practiced by humans over centuries and therefore possess time-proven safety. However, it is imperative to evaluate the toxic effects of herbal medicine to confirm their safety, particularly when developing therapeutic leads. Use of laboratory animals such as rats, mice, and rabbits was considered as gold standard in herbal toxicity assessments. However, in the last few decades, the ethical consideration of using higher vertebrates for toxicity testing has become more contentious. Thus, possible alternative models entailing lower vertebrates such as zebrafish were introduced. The zebrafish embryotoxicity model is at the forefront of toxicology assessment due to the transparent nature of embryos, low cost, short cycle, higher fecundity, and genetic redundancy to the humans. Recently, its application has been extended to herbal toxicology. The present review intends to provide a comprehensive assembly of studies that applied the zebrafish embryo model for the assessment of herbal toxicity. A systematic literature survey was carried out in popular scientific databases. The literature search identified a total of 1014 articles in PubMed = 12, Scopus SciVerse® = 623, and Google Scholar = 1000. After screening, 25 articles were included in this review, and they were categorized into three groups in which the zebrafish embryotoxicity assay has been applied to investigate the toxicity of (1) polyherbal formulae/medical prescription (2 full texts), (2) crude extracts (12 full texts), and (3) phytocompounds/isolated constituents (11 full texts). These studies have investigated the toxicity of 6 polyherbal formulae, 16 crude extracts, and more than 30 phytocompounds/isolated constituents using the zebrafish embryotoxicity model. Moreover, this model has explicated the teratogenic effects and specific organ toxicities such as the kidney, heart, and liver. Furthermore, in some studies, the molecular mechanisms underlying the toxicity of herbal medicine have been elucidated. This comprehensive collection of scientific data solidifies the zebrafish embryo model as an effective model system for studying toxicological effects of a broad spectrum of herbal remedies. Henceforth, it provides a novel insight into the toxicity assessment of herbal medicine.

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Cardiotoxicity evaluation and comparison of diterpene alkaloids on zebrafish

Cited by 29 publications

References 27 publications

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

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

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review

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