Biology-Basel
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2023
·Vol. 12
·期 9
·1214
·
IF 4.2
Ferry Saputra,Yu-Heng Lai,Marri Jmelou M. Roldan,Honeymae C. Alos,Charlaine A. Aventurado,Ross D. Vasquez,Chung-Der Hsiao
Simple SummaryIn recent years, the human population on Earth has increased, leading to a higher demand for food sources. Pesticides have emerged as a breakthrough to enhance crop yields. However, the excessive use of pesticides has raised concerns regarding their potential impact on aquatic animals. Thus, this study aims to assess the potential cardiovascular toxicity of various pesticides, with a specific focus on fenpropathrin. When compared to other pesticides, fenpropathrin causes cardiomegaly, an increased heart rate, a significant rise in blood flow velocity, and an elevated metabolism rate. Furthermore, it has been found to bind to several ion channels, inducing alterations in cardiovascular-related markers. These findings indicate that fenpropathrin induces cardiotoxicity in the zebrafish larvae model.AbstractFenpropathrin, a pyrethroid insecticide, has been widely used for many years in agricultural fields. It works by disturbing the voltage-gated sodium channel, leading to paralysis and the death of the target animal. While past studies have focused on neurodegeneration following fenpropathrin poisoning in humans, relatively few pieces of research have examined its effect on other peripheral organs. This study successfully investigated the potential toxicity of fenpropathrin on the cardiovascular system using zebrafish as an animal model. Zebrafish larvae exposed to varying doses of fenpropathrin underwent an evaluation of cardiac physiology by measuring the heart rate, stroke volume, cardiac output, and shortening fraction. The blood flow velocity and the dorsal aorta diameter were also measured to assess the impact of fenpropathrin exposure on the vascular system. Furthermore, molecular docking was performed to evaluate the pesticide binding affinity to various proteins associated with the cardiovascular system, revealing the potential mechanism of the fenpropathrin cardiotoxic effect. The findings demonstrated a significant dose-dependent increase in the heart rate stroke volume, cardiac output, shortening fraction, and ejection fraction of zebrafish larvae after 24 h of acute treatment with fenpropathrin. Additionally, zebrafish treated at a concentration of 1 ppm exhibited significantly larger blood vessels in diameter and an increased blood flow velocity compared to the control group. According to molecular docking, fenpropathrin showed a high affinity for various voltage-gated sodium channels like scn1lab, cacna1sb, and clcn3. Finally, from the results, we found that fenpropathrin caused cardiomegaly, which may have been induced by the voltage-gated sodium channel disruption. This study highlights the significant disruption of fenpropathrin in the cardiovascular system and emphasizes the need for further research on the health implications of this pesticide.Keywords:fenpropathrin;zebrafish;cardiovascular toxicity;pesticide
研究领域:
毒理学
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环境科学
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心血管生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 19
·11711
·
IF 6.208
Huan-Chau Lin,Ferry Saputra,Gilbert Audira,Yu-Heng Lai,Marri Jmelou M. Roldan,Honeymae C. Alos,Charlaine A. Aventurado,Ross D. Vasquez,Guan-Jhe Tsai,Ken-Hong Lim,Chung-Der Hsiao
BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side effects related to cardiovascular events. Asciminib (ASC) was the first allosteric inhibitor approved to target the myristoyl pocket of BCR-ABL protein to inhibit protein activity. The different mechanism of inhibition opens the possibility of co-exposure with both medicines. Reports on cardiovascular side effects due to the combination use of PON + ASC in pre-clinical and clinical studies are minimal. Thus, this study aimed to observe the potential cardiovascular-related side effect after co-exposure to ASC and PON using zebrafish as an animal model. In this study, zebrafish were acutely exposed to both compounds. The cardiovascular physiology parameters and gene expression related to cardiovascular development were evaluated. We demonstrate that combining ASC with PON at no observed effect concentration (NOEC) did not cause any significant change in the cardiac performance parameter in zebrafish. However, a significant increase innkx2.5expression level and a substantial decrease in blood flow velocity were recorded, suggesting that combining these compounds at NOEC can cause mild cardiovascular-related side effects.Keywords:zebrafish;anti-cancer drug;asciminib;ponatinib;cardiovascular toxicity;molecular docking
研究领域:
药理学
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毒理学
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发育生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2019
·
IF 5.714
Rong Shen,Yichang Yu,Rong Lan,Ran Yu,Ze Yuan,Zhining Xia
As a new type of pollutant, fluoroquinolones (FQs) antibiotics are ubiquitous in environment and have some threat to human health and ecological environment. Their ecological toxicity to the environment urgently need to be assessed. Therefore, we firstly explored the toxic effects and possible mechanism of cardiovascular toxicity induced by gatifloxacin (GTFX) and ciprofloxacin (CPFX) using zebrafish model. After 24 h exposure, the zebrafish treated with GTFX showed pericardial edema which was further investigated by histopathological examination, while CPFX exposure did not induce morphological abnormalities. However, both of them induced cardiac dysfunction, such as decreased heart rate and cardiac output which was showed a positive correlation with the concentration. To better understand the possible molecular mechanisms underlying cardiovascular toxicity in zebrafish, we investigated the transcriptional level of genes related to calcium signaling pathway and cardiac muscle contraction . The results indicated that the expression of ATPase ( atp2a1l ) and cardiac troponin C ( tnnc1a ) genes were significantly inhibited, the expression of calcium channel ( cacna1ab ) gene showed slight promoted trend after CPFX exposure. For zebrafish treated with GTFX, the expression of atp2a1l genes was also significantly inhibited, while the expression of tnnc1a genes was slightly inhibited and cacna1ab genes expression had no obvious effect. The present study firstly revealed that GTFX exposure can induce morphological and functional abnormalities on the cardiovascular system of zebrafish. Though CPFX exposure did not induce morphological abnormalities, the function of cardiovascular system was still damaged. Mechanistically, this toxicity might result from the pressure of down-regulation of genes associated with calcium signaling pathway and cardiac muscle contraction. The results of this study can provide a valuable theoretical basis for the establishment of FQs environmental quality standards in water environment, environmental drug regulation and risk management.
研究领域:
环境科学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2017
·
IF 5.099
Hong-cui Liu,Tian-yi Chu,Li-li Chen,Wen-jun Gui,Guo-nian Zhu
The health risk of triadimefon (TF) to cardiovascular system of human is still unclear, especially to pesticide suicides population, occupational population (farmers, retailers and pharmaceutical workers), and special population (young children and infants, pregnant women, older people, and those with compromised immune systems) who are at a greater risk. Therefore, firstly we explored the toxic effects and possible mechanism of cardiovascular toxicity induced by TF using zebrafish model. Zebrafish at stage of 48 h post fertilization (hpf) exposed to TF for 24 h exhibited morphological malformations which were further confirmed by histopathologic examination, including pericardial edema, circulation abnormalities, serious venous thrombosis and increased distance between the sinus venosus (SV) and bulbus arteriosus (BA) regions of the heart. In addition to morphological changes, TF induced functional deficits in the heart of zebrafish, including bradycardia and a significant reduced cardiac output that became more serious at higher concentrations. To better understand the possible molecular mechanisms underlying cardiovascular toxicity in zebrafish, we investigated the transcriptional level of genes related to calcium signaling pathway and cardiac muscle contraction . Q-PCR (quantitative real-time polymerase chain reaction) results demonstrated that the expression level of genes related to ATPase ( atp2a1l , atp1b2b , atp1a3b ), calcium channel ( cacna1ab , cacna1da ) and cardiac troponin C ( tnnc1a ) were significantly decreased after TF exposure. For the first time, the present study revealed that TF exposure had observable morphological and functional negative impacts on cardiovascular system of zebrafish. Mechanistically, this toxicity might result from the pressure of down-regulation of genes associated with calcium signaling pathway and cardiac muscle contraction following TF exposure. These findings generated here can provide information for better pesticide poisoning treatments, occupational disease prevention, and providing theoretical foundation for risk management measures.
研究领域:
毒理学
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环境健康
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
·
IF 6.291
Mengying Yang,Jiaxing Huang,Shuhui Zhang,Xin Zhao,Daofu Feng,Xizeng Feng
As a highly effective plant hormone, the overuse of 6-benzylaminopurine (6-BA) may pose potential threats to organisms and the environment. Melatonin is widely known for its regulation of sleep rhythm, and it also shows a beneficial effect in a variety of adverse situations. In order to investigate the harm of 6-BA to vertebrates and whether melatonin can reverse the toxicity induced by 6-BA, we analyzed the circadian rhythm and cardiovascular system of zebrafish, and further clarified the role of the thyroid endocrine system. The exposure of well-developed embryos started at 2 hpf, then 6-BA and/or melatonin were carried out. The results indicated that 6-BA disturbed the rhythmic activities of the larvae, increased wakefulness, correspondingly reduced their rest, and induced disrupted clock gene expression. Video analysis and qRT-PCR data found that zebrafish under 6-BA exposure showed obvious cardiovascular morphological abnormalities and dysfunction, and the mRNA levels of cardiovascular-related genes ( nkx2.5 , gata4 , myl7 , vegfaa and vegfab ) were significantly down-regulated. In addition, altered thyroid hormone content and hypothalamus-pituitary-thyroid (HPT) axis-related gene expression were also clearly observed. 1umol/L of melatonin had little effect on zebrafish, but its addition could significantly alleviate the circadian disturbance and cardiovascular toxicity caused by 6-BA, and simultaneously played a regulatory role in thyroid system. Our research revealed the adverse effects of 6-BA on zebrafish larvae and the protective role of melatonin in circadian rhythm, cardiovascular and thyroid systems.
研究领域:
毒理学
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内分泌学
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心脏病学
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生物钟学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2015
·Vol. 35
·期 12
·1473-1480
·
IF 2.982
Bing Shen,Hong-Cui Liu,Wen-Bin Ou,Grant Eilers,Sheng-Mei Zhou,Fan-Guo Meng,Chun-Qi Li,Yong-Quan Li
Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC 50 value at 60.63 and 476.84 µg ml –1 , respectively, whereas the LC 50 of Acid Red 26 was between 2500 and 2800 µg ml –1 . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml –1 . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down-regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26. Copyright © 2015 John Wiley & Sons, Ltd.
研究领域:
毒理学
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分子生物学
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发育生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2017
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IF 6.402
Huiyun Zhang,Wenqian Xu,Emmanuel Omari-Siaw,Yingkun Liu,Baoding Chen,Deyu Chen,Jiangnan Yu,Ximing Xu
Periplocymarin (PPM), a cardiac glycoside, has a narrow therapeutic index, poor tumor selectivity and severe cardiovascular toxicity which hinder its wide clinical applications in cancer treatment. Herein, we report novel redox-responsive prodrug-nanoparticles (MPSSV-NPs) self-assembled by co-nanoprecipitation of PPM-vitamin E conjugate and a PEG derivative of linoleate (mPEG2000-LA) in water. It was found that the characteristics of PPM-vitamin E nanoparticles (PSSV-NPs) were improved through co-nanoprecipitation with increased percentages of mPEG2000-LA. Moreover, the MPSSV-NPs were optimized according to the in vitro release and cytotoxicity study. Furthermore, the optimized MPSSV-NPs dramatically enhanced the circulation time and tumor distribution of PSSV-NPs after single intravenous injection. The in vivo studies in malignant H22-bearing mice revealed that MPSSV-NPs could effectively suppress tumor growth without causing obvious systemic toxicity. Altogether, these results suggested that MPSSV-NPs could offer a safe, multifunctional and viable nanoplatform for cardiac glycosides in cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2018
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IF 6.434
Mengmeng Huang,Jingjing Jiao,Jun Wang,Zhidan Xia,Yu Zhang
Acrylamide (AA) is a high production volume chemical in industrial applications and widely found in baked or fried carbohydrate-rich foods. In this study, we unravelled that AA induced developmental toxicity associated with oxidative stress status and disordered lipid distribution in heart region of developing zebrafish. Treatment with AA caused a deficient cardiovascular system with significant heart malformation and dysfunction. We also found that AA could reduce the number of cardiomyocytes through the reduced capacity of cardiomyocyte proliferation rather than cell apoptosis. The cardiac looping and ballooning appeared abnormal though cardiac chamber-specific identity in the differentiated myocardium was maintained well after AA treatment through MF20/S46 immunofluorescence assay. Furthermore, treatment with AA disturbed the differentiation of atrioventricular canal, which was demonstrated by the disordered expressions of the atrioventricular boundary markers bmp4 , tbx2b and notch1b and further confirmed by the ectopic expressions of the cardiac valve precursor markers has2 , klf2a and nfatc1 through whole-mount in situ hybridization. Thus, our studies provide the evidence of cardiac developmental toxicity of AA in the cardiovascular system, and also raised health concern about the harm of trans-placental exposure to high level of AA for foetuses and the risk of high exposure to AA for the pregnant women.
研究领域:
毒理学
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发育生物学
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心血管科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
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IF 4.9
Yaxin Cheng,Jinsong Tao,Yaqi Zhang,Long Xi,Run Han,Meng Xu,Simon Ming-Yuen Lee,Wei Ge,Yong Gan,Ying Zheng
Mesoporous silica nanoparticles (MSNs) are widely used in the biomedical field because of their unique and excellent properties. However, the potential toxicity of different shaped MSNs via injection has not been fully studied. This study aims to systematically explore the impact of shape and shear stress on the toxicity of MSNs after injection. An in vitro blood flow model was developed to investigate the cytotoxicity and the underlying mechanisms of spherical MSNs (S-MSN) and rodlike MSNs (R-MSN) in human umbilical vein endothelial cells (HUVECs). The results suggested that the interactions between MSNs and HUVECs under the physiological flow conditions were significantly different from that under static conditions. Whether under static or flow conditions, R-MSN showed better cellular uptake and less oxidative damage than S-MSN. The main mechanism of cytotoxicity induced by R-MSN was due to shear stress-dependent mechanical damage of the cell membrane, while the toxicity of S-MSN was attributed to mechanical damage and oxidative damage. The addition of fetal bovine serum (FBS) alleviated the toxicity of S-MSN by reducing cellular uptake and oxidative stress under static and flow conditions. Moreover, the in vivo results showed that both S-MSN and R-MSN caused cardiovascular toxicity in zebrafish and mouse models due to the high shear stress, especially in the heart. S-MSN led to severe oxidative damage at the accumulation site, such as liver, spleen, and lung in mice, while R-MSN did not cause significant oxidative stress. The results of in vitro blood flow and in vivo models indicated that particle shape and shear stress are crucial to the biosafety of MSNs, providing new evidence for the toxicity mechanisms of the injected MSNs.
研究领域:
纳米技术
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生物医学工程
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毒理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2019
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IF 5.589
Shuang Liang,Yueyue Chen,Shiming Zhang,Yuanyuan Cao,Junchao Duan,Yapei Wang,Zhiwei Sun
Silica nanoparticles (SiNPs) have been widely used in human health related products, such as food additives, cosmetics and even drug delivery, gene therapy or bioimaging. Recently, a first-in-human clinical trial based on polyethylene glycol (PEG)-modified SiNPs had been approved by US FDA to trace melanoma. However, as a nano-based drug delivery system, its biocompatibility and vascular toxicity are still largely unknown. Thus, we synthesized the fluorescent SiNPs to explore the biocompatibility and vascular endothelial function, and compare different biological effects caused by PEG-modified and unmodified SiNPs in cells and zebrafish model. The characterizations of SiNPs and PEG-modified SiNPs were analyzed by TEM, SEM, AFM and DLS, which exhibited relatively good stable and dispersive. Compared with SiNPs, PEG-modified SiNPs had markedly reduced the inflammatory response and vascular damage in Tg (fli-1: EGFP) and Tg (mpo: GFP) transgenic zebrafish lines, respectively. Consistent with the in vivo results, the PEG-modified SiNPs had been found to significantly decline the levels of ROS, inflammatory cytokines and mitochondrial-mediated apoptosis in vascular endothelial cells compared to SiNPs, and the ROS scavenger NAC could effectively alleviate the above adverse effects induced by nanoparticles. Our results suggested that the PEG-modified SiNPs could become more safety via increasing the biocompatibility and decreasing cellular toxicities in living organisms.
研究领域:
纳米技术
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生物医学工程
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药理学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Xin Wang,Fan Chen,Jian Lu,Mengqi Wu,Jiagao Cheng,Wenping Xu,Zhong Li,Yang Zhang
Acetochlor (ACT) is a widely used pesticide, yet the environmental and health safety of its chiral isomers remains inadequately evaluated. In this study, we evaluated the toxicity of ACT and its chiral isomers in a zebrafish model. Our findings demonstrate that ACT and its chiral isomers disrupt early zebrafish embryo development, inducing oxidative stress, abnormal lipid metabolism, and apoptosis. Additionally, ACT and its chiral isomers lead to cardiovascular damage, including reduced heart rate, decreased red blood cell (RBC) flow rate, and vascular damage. We further observed that (+)- S -ACT has a significant impact on the transcription of genes involved in cardiac and vascular development, including tbx5 , hand2 , nkx2.5 , gata4 , vegfa , dll4 , cdh5 , and vegfc . Our study highlights the potential risk posed by different conformations of chiral isomeric pesticides and raises concerns regarding their impact on human health. Overall, our results suggest that the chiral isomers of ACT induce developmental defects and cardiovascular toxicity in zebrafish, with (+)- S -ACT being considerably more toxic to zebrafish than (−)- R -ACT.
研究领域:
环境毒理学
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发育生物学
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心血管科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Oncotarget
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2016
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IF 5.008
Hui-Yun Zhang,Wen-Qian Xu,Yuan-yuan Zheng,Emmanuel Omari-Siaw,Yuan Zhu,Xia Cao,Shan-Shan Tong,Jiang-nan Yu,Xi-ming Xu
Cardiac glycosides could increase intracellular Ca 2+ ion by inhibiting the Na + /K + ATPase to induce apoptosis in many tumor cells. However, narrow therapeutic index, poor tumor selectivity and severe cardiovascular toxicity hinder their applications in cancer treatment. To improve the safety profile and tumor targetablility of cardiac glycosides, we designed octreotide conjugated periplocymarin, a cardiac glycoside isolated from Cortex periplocae . The conjugate showed higher cytotoxicity on MCF-7 cells and HepG2 tumor cells (SSTRs overexpression) but much less toxicity in L-02 normal cells. Tissue distribution studies of the conjugate using H 22 tumor model in mice showed higher accumulation in tumor and lower distribution in heart and liver than periplocymarin. Furthermore, in vivo anticancer effects of the conjugate on mice bearing H 22 cancer xenografts confirmed enhanced anti-tumor efficacy and decreased systemic toxicity. Altogether, octreotide-conjugated periplocymarin demonstrated tumor selectivity and may be useful as a targeting agent to improve the safety profile of cardiac glycosides for cancer therapy.
研究领域:
药理学
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肿瘤学
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药物递送系统
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药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）