EXPERIMENTAL CELL RESEARCH
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2025
·
IF 3.5
Xiaofeng Ma,Wang chen,Zhihao Hu,Like Xie,Zhaobing Li,Huan Liu,Zili Li,Zhentao Jiang,Jiangwei Huang,Changrong Jiang,Ke Huang,Sujun Xiao
Background and aims The anthracycline chemotherapeutic agent doxorubicin (DOX) is widely used to treat cancer. However, DOX carries a high risk of adverse effects such as cardiovascular events. The aim of this study was to explore the role of Trim65 in DOX-induced cardiotoxicity (DIC) and its underlying mechanisms. Methods and Results Cellular studies were performed by exposing H9c2 cells (rat cardiomyocytes) to DOX. H9c2 cells were infected with lentivirus encoding negative control (LV-NC) or Trim65 (LV-Trim65). C57BL/6J mice were exposed to adeno-associated virus 9 (AAV9) containing cTnT promoter-encoded Trim65 sequence (AAV-Trim65) or AAV9 negative control sequence (AAV-NC) via tail vein injection. Furthermore, the following analysis were performed: cell viability, intracellular ROS production and lipid peroxidation. Echocardiography was used to measure the heart function of the mice. qPCR and western blotting were used to assess the expression of Trim65, p53, SLC7A11, and GPX4. According to our study, Trim65 expression was significantly downregulated in DIC. Overexpression of Trim65 exhibited considerable protection against to DIC, confirmed by both in vitro and in vivo experiments. In DOX-treated mice, mitochondria deformation was observed in the heart, as well as a high level of lipid peroxidation (signs of ferroptosis) and iron content, which were mitigated by overexpression of Trim65. Mechanistically, our study confirmed that DOX reduced the Trim65-mediated ubiquitination of p53, ultimately inhibiting the degration of p53. We also found that Trim65 mitigated DOX-induced ferroptosis via p53. Conclusion Collectively, our data demonstrated that Trim65 inhibits ferroptosis by degrading p53, thereby alleviating DIC. Therefore, Trim65 could be a promising target for the treatment of DIC.
研究领域:
分子生物学
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心血管病学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2021
·Vol. 24
·期 4
·1-8
·
IF 2.952
Hongwei Shi,Qingfu Zeng,Yunjie Wei,Hong Yang,Heng Tang,Dan Wang,Peng Pu,Rui Feng
Pirarubicin (THP), one of the anthracycline anticancer drugs, is widely used in the treatment of various types of cancer, but its cardiotoxicity cannot be ignored. Canagliflozin, the first sodium‑glucose co‑transporter‑2 inhibitor approved by the USA FDA, has been shown to have a significant effect on cardiovascular damage caused by diabetes. However, it has not been reported whether it can resist THP‑induced cardiotoxicity. The aim of the present study was to investigate the effect of canagliflozin on THP‑induced cardiotoxicity and its mechanism. A rat model of cardiotoxicity induced by THP was established and canagliflozin treatment was performed at the same time. The changes of electrocardiography, cardiac coefficient and echocardiogram were observed. The levels of lactate dehydrogenase, brain natriuretic peptide, creatine kinase MB, cardiac troponin T, superoxide dismutase (SOD) and malondialdehyde were detected. The expression of SOD2, NADPH oxidase 2, pro/cleaved‑caspase‑ and Bcl‑2/Bax were evaluated by western blotting. The primary culture of cardiomyocytes was prepared to explore the effect in vitro. After eight weeks, a series of cardiotoxicity manifestations were observed in THP rats. However, canagliflozin treatment had no significant effect on the above adverse reactions. Similarly, further studies showed that canagliflozin had no significant effect on THP‑induced cardiomyocyte injury in vitro. The present study showed that there was no significant protective effect of canagliflozin on THP‑induced cardiotoxicity and cardiomyocyte injury.
研究领域:
药理学
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心脏病学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Rongzhe Zhu,Xiaochen Liu,Qiupeng Xue,Xiaoru Dong,Tianyi Zhang,Yan Jiang
Previous surveys have revealed that mirtazapine (MIR), one of the most commonly prescribed antidepressants, is associated with a higher risk of adverse cardiac events compared with other newer antidepressants. Chronic ethanol (EtOH) abuse could also lead to myocardial injuries. Concerning the common comorbidity of major depression and alcohol dependence, combined consumption of MIR and EtOH might be prevalent in patients with depression, resulting in an additive or synergistic cardiotoxic effect. To this end, the present study evaluated cardiotoxicity induced by MIR-plus-EtOH in vivo (male C57BL/6J mice) and in vitro (H9c2 cardiomyoblasts), Further research on the role of autophagy and underlying signaling pathway were carried out in H9c2 cells. We found that EtOH exacerbated MIR-induced cardiotoxicity both in vivo and in vitro . Furthermore, EtOH significantly potentiated MIR-induced dysfunctional autophagy as reflected by upregulated protein levels of LC3-II, p62, Beclin1 and LAMP-1. Pharmacological inhibition of autophagy by 3-methyladenine alleviated MIR-plus-EtOH-induced myocardial injury. High mobility group box 1 (HMGB1) is a positive regulator of autophagy. In our work, HMGB1 knockdown decreased autophagosome accumulation and boosted viability in H9c2 cells. Additionally, HMGB1 blockage markedly upregulated p-Akt/Akt and p-mTOR/mTOR levels which were suppressed in MIR-plus-EtOH treated cells. In general, the present study demonstrates that EtOH potentiates MIR-induced cardiotoxicity which might be attributed to dysfunctional autophagy via inhibiting Akt/mTOR signaling pathway, while HMGB1 knockdown might contribute to improve autophagy flux.
研究领域:
药理学
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心脏病学
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2018
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IF 6.383
Doudou Hu,Ting Li,Zongpu Xu,Di Liu,Mingying Yang,Liangjun Zhu
A variety of colloid stabilizers and cryoprotectants confer improved nanoparticle (NP) colloidal stability and redisperability. However, discounted tumor targetability, delivery efficacy and possible side effects limit the application in vascular delivery of NPs. Here we present water-soluble silk sericin (SS) not only as a material for the preparation of NPs, but also both a dispersion stabilizer and a cryoprotectant. In the absence of any stabilizers, SS-based NPs (SSC@NPs) can resist the adsorption of serum proteins , preventing the formation of particle agglomerates. Following freeze-drying without addition of cryoprotectants, SSC@NPs powder can be easily resuspended into NP dispersion with a nearly monodispersed distribution. Additionally, SSC@NPs do not result in acute toxicity in mice at a dose of 400 mg/kg with a slow injection. Moreover, doxorubicin (DOX)-loaded SSC@NPs (DOX-SSC@NPs) diminish the biodistribution of DOX in the heart, mitigating DOX-induced cardiotoxicity of mice without compromising therapeutic efficacy. Our results suggest that the self-stabilized SSC@NPs could be a secure and effective drug carrier for intravenous administration when deprived of protective agents. Statement of Significance During manufacturing process such as freeze-drying, or interaction with complex fluids like blood, NPs for systemic drug delivery need to be highly dispersible and structurally intact. In this work, we have demonstrated the self-stability of SSC@NPs subjected to biological media and freeze-drying. This study represents the first work showing water-soluble SS could both act as a dispersion stabilizer and a cryoprotectant due to its hydrophilicity . Plus, good in vivo biocompatibility of SSC@NPs has been confirmed. Therefore, it may be promising that water-soluble SS can be generally used as a safe biomaterial against serum adsorption.
研究领域:
药剂学
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生物医学工程
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材料科学
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DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
·
2025
·
IF 7.7
Yuanzhao Wu,Fengjun Fan,Lu Zhou,Yihang Shen,Anli Wang,Yazhou Qin,Jiye Wang,Weixuan Yao
As an emerging pollutant, the synthetic cannabinoid N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA) is widely abused and frequently detected in metropolitan wastewater. However, its effect on aquatic organisms remains unexplored. In this study, embryonic and larval zebrafish were exposed to sublethal concentrations of ADB-FUBINACA to assess its toxic effects via behavioral, biochemical, and metabolomic analyses. The observed morphological defects included reduced heartbeat, shorter body length, spinal deformation, and pericardial edema. Transgenic zebrafish exhibited cardiac developmental defects and apoptosis, indicating that cardiotoxicity is associated with dysregulated gene expression. Impaired motor activity and disrupted neuronal development suggested neurotoxicity. Elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels indicate oxidative stress, whereas transcriptional changes in immune-related genes reflect a dysregulated inflammatory response. Metabolomic analyses revealed disruptions in pathways related to alanine, purine, and pyrimidine metabolism, and arginine biosynthesis, which correlated with oxidative damage, cardiotoxicity, and neurodevelopmental effects. In conclusion, ADB-FUBINACA induces developmental toxicity in zebrafish embryos via oxidative stress and metabolic disruption, highlighting the potential environmental risks posed by this emerging pollutant.
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
POWDER TECHNOLOGY
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2024
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IF 4.5
Han Hao,Tiantian Ren,Cuilu Quan,Jing Wang
Arginine (ARG) is a precursor for producing NO, which can relax vascular smooth muscle. We herein report cocrystals screened by powder grinding using chiral ARG to improve the bioavailability of 5-fluorouracil (5-FU) and alleviate 5-FU induced cardiotoxicity. The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) inferred the formation of new solid phases. Hydrogen bonding interactions between C=O group and N-H were supported by Fourier transform infrared (FTIR) spectroscopy. The spectra intensity of circular dichroism (CD) of cocrystals were higher than that of ARG after combined with non-optically active 5-FU. The bioavailability and cytotoxicity of 5-FU were enhanced by cocrystallization. Notably, L-cocrystal prepared using biologically active L-ARG released lower dose NO in human umbilical vein endothelial cells (HUVEC) cells than that of D-cocrystal. D-cocrystal performed higher NO release ability by non-enzymatic pathway, indicating a greater potential to alleviate cardiotoxicity. 5-FU-induced cardiotoxicity in rats was effectively alleviated, proved by the least increased LDH, cTnI and CK-MB level induced by D-cocrystal.
研究领域:
药学
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肿瘤学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 15
·8438
·
IF 6.208
Mengying Yang,Jialu Luan,Yixin Xu,Chengtian Zhao,Mingzhu Sun,Xizeng Feng
6-BA is a common plant growth regulator, but its safety has not been conclusive. The heart is one of the most important organs of living organisms, and the cardiogenesis process of zebrafish is similar to that of humans. Therefore, based on wild-type and transgenic zebrafish, we explored the development of zebrafish heart under 6-BA exposure and its mechanism. We found that 6-BA affected larval cardiogenesis, inducing defective expression of key genes for cardiac development (myl7,vmhc, andmyh6) and AVC differentiation (bmp4,tbx2b, andnotch1b), ultimately leading to weakened cardiac function (heart rate, diastolic speed, systolic speed). Acridine orange staining showed that the degree of apoptosis in zebrafish hearts was significantly increased under 6-BA, and the expression of cell-cycle-related genes was also changed. In addition, HPA axis assays revealed abnormally expressed mRNA levels of genes and significantly increased cortisol contents, which was also consistent with the observed anxiety behavior in zebrafish at 3 dpf. Transcriptional abnormalities of pro- and anti-inflammatory factors in immune signaling pathways were also detected in qPCR experiments. Collectively, we found that 6-BA induced cardiotoxicity in zebrafish, which may be related to altered HPA axis activity and the onset of inflammatory responses under 6-BA treatment.Keywords:zebrafish;6-benzylaminopurine;cardiotoxicity;HPA axis activity;inflammation
研究领域:
毒理学
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发育生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Toxics
·
2025
·Vol. 13
·期 2
·122
·
IF 4.1
Yixiao Wu,Wenjing Yu,Zhenyan Song,Jiawei He,Ze Li,Qi Chen,Shiwei Wang,Ping Li,Shaowu Cheng
Emerging contaminants refer to chemical substances that have not been widely regulated but possess the potential to cause adverse effects on both the environment and human health. Antibiotics, as emerging contaminants, pose significant threats to ecosystems and human health due to their widespread use and persistence in the environment. Levofloxacin, a broad-spectrum fluoroquinolone antibiotic, is commonly employed in the treatment of bacterial infections, and has been frequently detected in environmental matrices and freshwater systems. In this study, we assessed the effects of levofloxacin on hatchability, mortality rates, malformations, behavioral changes, and cardiac development in zebrafish embryos by exposing them to varying concentrations of levofloxacin (0, 0.5, 1, 2, 4, and 8 mM). Our results demonstrate that levofloxacin exposure significantly impaired the growth and development of zebrafish larvae, particularly at higher concentrations. Notable effects included reduced body length, abnormal yolk sac and swim bladder development, pericardial edema, prolonged distances between the sinus venosus and arteriolar bulb (SV-BA), and disruptions in heart rate. Quantitative PCR analysis further revealed that levofloxacin exposure significantly upregulated the expression of key cardiac development genes in zebrafish larvae, includingnppa,myh6,cacna1ab,myl7,gata4,nkx2.5,tbx2b, andtbx5b. These findings indicate that levofloxacin exposure exerts significant toxic effects on both embryonic and larval growth as well as heart development and gene expression in zebrafish. This study provides critical insights into the potential ecological risks posed by levofloxacin along with other antibiotics while laying a foundation for further investigation into their toxicological mechanisms.
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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2018
·Vol. 19
·期 11
·3658
·
IF 3.687
Zhi-Meng Xu,Cheng-Bin Li,Qing-Ling Liu,Ping Li,Hua Yang
Ginsenoside Rg1, a saponin that is a primary component of ginseng, has been demonstrated to protect hearts from diverse cardiovascular diseases with regulating multiple cellular signal pathways. In the present study, we investigated the protective role of ginsenoside Rg1 on doxorubicin-induced cardiotoxicity and its effects on endoplasmic reticulum stress and autophagy. After pre-treatment with ginsenoside Rg1 (50 mg/kg i.g.) for 7 days, male C57BL/6J mice were intraperitoneally injected with a single dose of doxorubicin (6 mg/kg) every 3 days for four injections. Echocardiographic and pathological findings showed that ginsenoside Rg1 could significantly reduce the cardiotoxicity induced by doxorubicin. Ginsenoside Rg1 significantly inhibited doxorubicin-induced formation of autophagosome. At the same time, ginsenoside Rg1 decreased the doxorubicin-induced cardiac microtubule-associated protein-light chain 3 and autophagy related 5 expression. Ginsenoside Rg1 can reduce endoplasmic reticulum dilation caused by doxorubicin. Compared with the doxorubicin group, the expression of cleaved activating transcription factor 6 and inositol-requiring enzyme 1 decreased in group ginsenoside Rg1. Treatment with ginsenoside Rg1 reduces the expression of TIF1 and increases the expression of glucose-regulated protein 78. In the ginsenoside Rg1 group, the expression of p-P70S6K, c-Jun N-terminal kinases 1 and Beclin1 declined. These results indicate that ginsenoside Rg1 may improve doxorubicin-induced cardiac dysfunction by inhibiting endoplasmic reticulum stress and autophagy.Keywords:ginsenoside Rg1;doxorubicin;cardiotoxicity;autophagy;endoplasmic reticulum stress
研究领域:
药理学
·
心脏病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 19
·11932
·
IF 6.208
Xue Han,Xiaowen Xu,Tingting Yu,Meifeng Li,Yulong Liu,Jingli Lai,Huiling Mao,Chengyu Hu,Shanghong Wang
Diflubenzuron is an insecticide that serves as a chitin inhibitor to restrict the growth of many harmful larvae, including mosquito larvae, cotton bollworm and flies. The residue of diflubenzuron is often detected in aquaculture, but its potential toxicity to aquatic organisms is still obscure. In this study, zebrafish embryos (from 6 h to 96 h post-fertilization, hpf) were exposed to different concentrations of diflubenzuron (0, 0.5, 1.5, 2.5, 3.5 and 4.5 mg/L), and the morphologic changes, mortality rate, hatchability rate and average heart rate were calculated. Diflubenzuron exposure increased the distance between the venous sinus and bulbar artery (SV-BA), inhibited proliferation of myocardial cells and damaged vascular development. In addition, diflubenzuron exposure also induced contents of reactive oxygen species (ROS) and malondialdehyde (MDA) and inhibited the activity of antioxidants, including SOD (superoxide dismutase) and CAT (catalase). Moreover, acridine orange (AO) staining showed that diflubenzuron exposure increased the apoptotic cells in the heart. Q-PCR also indicated that diflubenzuron exposure promoted the expression of apoptosis-related genes (bax, bcl2, p53, caspase3 and caspase9). However, the expression of some heart-related genes were inhibited. The oxidative stress-induced apoptosis damaged the cardiac development of zebrafish embryos. Therefore, diflubenzuron exposure induced severe cardiotoxicity in zebrafish embryos. The results contribute to a more comprehensive understanding of the safety use of diflubenzuron.Keywords:diflubenzuron;zebrafish embryo;cardiotoxicity;oxidative stress;apoptosis
研究领域:
毒理学
·
环境科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Toxics
·
2023
·Vol. 11
·期 1
·84
·
IF 4.6
Tianyi Chen,Haoze Chen,Anli Wang,Weixuan Yao,Zhongshi Xu,Binjie Wang,Jiye Wang,Yuanzhao Wu
Methyl parathion (MP) has been widely used as an organophosphorus pesticide for food preservation and pest management, resulting in its accumulation in the aquatic environment. However, the early developmental toxicity of MP to non-target species, especially aquatic vertebrates, has not been thoroughly investigated. In this study, zebrafish embryos were treated with 2.5, 5, or 10 mg/L of MP solution until 72 h post-fertilization (hpf). The results showed that MP exposure reduced spontaneous movement, hatching, and survival rates of zebrafish embryos and induced developmental abnormalities such as shortened body length, yolk edema, and spinal curvature. Notably, MP was found to induce cardiac abnormalities, including pericardial edema and decreased heart rate. Exposure to MP resulted in the accumulation of reactive oxygen species (ROS), decreased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, elevated malondialdehyde (MDA) levels, and caused cardiac apoptosis in zebrafish embryos. Moreover, MP affected the transcription of cardiac development-related genes (vmhc,sox9b,nppa,tnnt2,bmp2b,bmp4) and apoptosis-related genes (p53,bax,bcl2). Astaxanthin could rescue MP-induced heart development defects by down-regulating oxidative stress. These findings suggest that MP induces cardiac developmental toxicity and provides additional evidence of MP toxicity to aquatic organisms.Keywords:methyl parathion;cardiotoxicity;oxidative damage;zebrafish;apoptosis
研究领域:
毒理学
·
水生生物学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2023
·
IF 4.5
Qiang Luo,Liping Ai,Shuqiong Tang,Hua Zhang,Jinze Ma,Xiaoping Xiao,Keyuan Zhong,Guiyou Tian,Bo Cheng,Cong Xiong,Xiaobei Chen,Huiqiang Lu
Ethyl 3-(N-butylacetamido) propanoate (EBAAP) is one of the most widely used mosquito repellents worldwide, and is also commonly used to produce cosmetics. Residues have recently been detected in surface and groundwater in many countries, and their potential to harm the environment is unknown. Therefore, more studies are needed to fully assess the toxicity of EBAAP. This is the first investigation into the developmental toxicity and cardiotoxicity of EBAAP on zebrafish embryos. EBAAP was toxic to zebrafish, with a lethal concentration 50 (LC50) of 140 mg/L at 72 hours post fertilization (hpf). EBAAP exposure also reduced body length, slowed the yolk absorption rate, induced spinal curvature and pericardial edema, decreased heart rate, promoted linear lengthening of the heart, and diminished cardiac pumping ability. The expression of heart developmental-related genes ( nkx2.5, myh6, tbx5a, vmhc, gata4, tbx2b ) was dysregulated, intracellular oxidative stress increased significantly, the activities of catalase (CAT) and superoxide dismutase (SOD) decreased, and malondialdehyde (MDA) content increased significantly. The expression of apoptosis-related genes ( bax/bcl2, p53, caspase9, caspase3 ) was significantly upregulated. In conclusion, EBAAP induced abnormal morphology and heart defects during the early stages of zebrafish embryo development by potentially inducing the generation and accumulation of reactive oxygen species (ROS) in vivo and activating the oxidative stress response. These events dysregulate the expression of several genes and activate endogenous apoptosis pathways, eventually leading to developmental disorders and heart defects.
研究领域:
毒理学
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环境科学
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发育生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）