XENOBIOTICA
·
2017
·
IF 1.932
Hui Li,Dongju Lin,Ying Peng,Jiang Zheng
1. Nitrofurantoin (NFT), a 5-nitrofuran derivative, has been widely used for the treatment of specific urinary tract infections. It has been reported that exposure to NFT was associated with various adverse effects, particularly hepatotoxicity and pneumotoxicity. The objective of the study was to identify reactive metabolites of NFT and explore the mechanisms of the toxicities.2. An epoxide intermediate generated in microsomal incubations was trapped by glutathione (GSH) and 4-bromobenzyl mercaptan (BBM), and the resulting GSH and BBM conjugates were characterized by LC–MS/MS. A spontaneous denitration took place in the trapping reaction. 2-Nitrofuran and 2-hydroxyfuran as model compounds were employed to probe the mechanism of the denitration.3. The oxidative activation of NFT was P450-dependent, and P450 3A5 and P450 2A6 were the principal enzymes responsible for the bioactivation. The findings facilitate the understanding of the mechanisms of NFT-induced toxicities.
研究领域:
药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Environmental Science-Nano
·
2024
·Vol. 11
·期 5
·1817-1846
·
IF 5.8
Yiqun Mo,Yue Zhang,Qunwei Zhang
With the exponential growth of the nanotechnology field, the global nanotechnology market is on an upward track with fast-growing jobs. Nickel (Ni)-containing nanoparticles (NPs), an important class of transition metal nanoparticles, have been extensively used in industrial and biomedical fields due to their unique nanostructural, physical, and chemical properties. Millions of people have been/are going to be exposed to Ni-containing NPs in occupational and non-occupational settings. Therefore, there are increasing concerns over the hazardous effects of Ni-containing NPs on health and the environment. The respiratory tract is a major portal of entry for Ni-containing NPs; thus, the adverse effects of Ni-containing NPs on the respiratory system, especially the lungs, have been a focus of scientific study. This review summarized previous studies, published before December 1, 2023, on the cytotoxic, genotoxic, and carcinogenic effects of Ni-containing NPs on humans, lung cells in vitro, and rodent lungs in vivo, and the potential underlying mechanisms were also included. In addition, whether these adverse effects were induced by NPs themselves or Ni ions released from the NPs was also discussed. The extra-pulmonary effects of Ni-containing NPs were briefly mentioned. This review will provide us with a comprehensive view of the pulmonary effects of Ni-containing NPs and their underlying mechanisms, which will shed light on our future studies, including the urgency and necessity to produce engineered Ni-containing NPs with controlled and reduced toxicity, and also provide a scientific basis for developing nanoparticle exposure limits and policies.
研究领域:
毒理学
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环境健康
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纳米医学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Xionghua Sun,Xuelei Wan,Li Chen,Yadong Cui,Xihua Chen,Jian Zhang,Xiaogang Jiang
The senescence of alveolar epithelial cells is one of the characteristics of mitomycin pulmonary toxicity, but the direct target of mitomycin-induced alveolar epithelial cell senescence remains unclear. In this study, a method of small-molecule ligand–protein interaction by pulldown/mass spectrometry identified peroxiredoxin I (Prdx I) as the target of mitomycin-induced alveolar epithelial cell senescence, and mitomycin was shown to significantly inhibit the peroxidase activity of Prdx I. Consequently, the levels of cellular reactive oxygen species (ROS) increased, leading to the activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal-regulated protein kinases 1/2 (ERK 1/2) and, accordingly, to the increased expression of p53. Both a Prdx I activator and Prdx I overexpression alleviated mitomycin-induced alveolar cell senescence. A ROS scavenger inhibited MEK1/2-ERK1/2-p53 activation and then attenuated the senescence of alveolar epithelial cells triggered by mitomycin. Thus, Prdx I can serve as the first target of mitomycin-induced alveolar epithelial cell senescence, which might represent a promising approach to reduce mitomycin-induced lung toxicity.
研究领域:
药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2024
·
IF 5.9
Zijuan Qi,Xiaofeng Huang,Jiajun Jing,Wenya Feng,Ming Xu,Li Yan,Ming Gao,Sijin Liu,Xue-Feng Yu
Iron oxide nanoparticles (IONPs) have wide applications in the biomedical field due to their outstanding physical and chemical properties. However, the potential adverse effects and related mechanisms of IONPs in human organs, especially the lung, are still largely ignored. In this study, we found that group-modified IONPs (carboxylated, aminated and silica coated) induce slight lung cell damage (in terms of the cell cycle, reactive oxygen species (ROS) production, cell membrane integrity and DNA damage) at a sublethal dosage. However, aminated IONPs could release more iron ions in the lysosome than the other two types of IONPs, but the abnormally elevated iron ion concentration did not induce ferroptosis. Intriguingly, amino-modified IONPs aggravated the accumulation of intracellular peroxides induced by the ferroptosis activator RSL3 and thus caused ferroptosis in vitro , and the coadministration of amino-modified IONPs and RSL3 induced more severe lung injury in vivo. Therefore, our data revealed that the surface functionalization of IONPs plays an important role in determining their potential pulmonary toxicity, as surface modification influences their degradation behavior. These results provide guidance for the design of future IONPs and the corresponding safety evaluations and predictions.
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
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Yuanteng Zhang,Zizheng Gao,Zezheng Pan,Huangxi Fu,Feng Jiang,Hao Yan,Bo Yang,Qiaojun He,Peihua Luo,Zhifei Xu,Xiaochun Yang
Crizotinib is the first-line drug for advanced non-small cell lung cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo, which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased apoptosis rate. We proved that crizotinib-blocked autophagic flux caused apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity.
研究领域:
肿瘤学
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呼吸病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
·
IF 6.1
Yanzi Zhao,Yujing Niu,Xuefei Wang,Peng Wan,Zhanfei Ma,Jian Sun,Shoufang Jiang,Ling Xue,Nan Liu
Indium-tin oxide nanoparticles (Nano-ITO) are widely used in various applications as infrared shielding materials, which increase the risk of occupational exposure. According to reports, Nano-ITO can cause indium lung disease in occupational exposed workers, but the specific mechanism of Nano-ITO-induced pulmonary toxicity remains unclear. In this study, 50 8-week-old male Sprague-Dawley rats were divided into five groups (10 rats in each group) as follows: control group (physiological saline), 1.2 mg/kg Nano-ITO group, 6 mg/kg Nano-ITO group, N-Acetyl-L-Cysteine (NAC) control group (200 mg/kg), and NAC + Nano-ITO group (200 mg/kg NAC intraperitoneal injection, after 1.5 h, 6 mg/kg Nano-ITO intratracheal instillation), twice a week for 12 weeks. Pathological and ultrastructural changes in the rat lung tissue, immunofluorescence assays, immunohistochemistry, protein and mRNA levels of apoptosis- and autophagy-related genes were measured. The levels of ROS, MDA, H 2 O 2 , and LDH, and the activities of T-AOC and SOD, were determined using oxidative stress assay kits. The results showed that Nano-ITO caused strong pulmonary inflammation, pulmonary alveolar proteinosis, and pulmonary interstitial fibrosis. In addition, Nano-ITO-induced oxidative stress in rat lungs presented as increased levels of ROS and H 2 O 2 in the lungs, increased LDH and MDA levels, SOD and T-AOC activity in BALF, and activation of the Nrf2/NQO1/HO-1 signaling pathway. Intriguingly, Nano-ITO significantly increased the protein expression of microtubule-associated protein light chain 3 (LC3-II), the protein levels of autophagy-related genes 5 (ATG5), and Beclin-1 (BECN1), and reduced the protein levels of phosphatidylinositol 3-kinase (PI3K) in lung tissues. In addition, transmission electron microscopy (TEM) showed a significant increase in autophagic vesicles in the cytoplasm of lungs treated with Nano-ITO, indicating that Nano-ITO induces autophagy in rat lungs. Moreover, apoptosis also participates in Nano-ITO-induced pulmonary injury in a synchronous manner, as evidenced by the enhancement of TUNEL-positive signals and activation of the apoptosis pathway (Bax and Bcl-2 positive proportions). NAC supplementation restored most of the pathological structural features of rat lung tissue to their physiological range and effectively weakened apoptosis, as demonstrated by the notable reductions in TUNEL, Bax, and Bcl-2 protein expression levels in the lungs. Although autophagy was detected in the lungs of rats in the Nano-ITO and NAC + Nano-ITO groups, we discovered that NAC could rescue the expression of ATG5 and BECN1 induced by Nano-ITO, thus indicating that exposure to Nano-ITO promotes pulmonary apoptosis and autophagy by mediating oxidative stress. These results indicate that Nano-ITO can cause pulmonary injury by inducing oxidative stress, which activates apoptosis and autophagy, ultimately leading to alveolar proteinosis and interstitial fibrosis.
研究领域:
毒理学
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纳米技术
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呼吸医学
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分子生物学
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药理学
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病理学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Lulin Hu,Weiyan Yu,Yi Yang,Jingcheng Hao,Lu Xu
As a class of very common and important industrial liquid materials, metalworking fluids (MWFs) are easy to be vaporized into the air and cause pulmonary toxic effects. The inhaled MWF aerosols should first interact with the pulmonary surfactant (PS) film that plays an essential role in maintaining the normal respiratory mechanics and pulmonary immunology in a human body. Here, to probe any potential adverse impacts of airborne MWFs on the biophysical and physiological functions of PS film that may help achieve a deep and comprehensive understanding of the pulmonary toxicology of MWFs, a systematic study on the interaction between an animal-derived natural PS ( i.e. , Calsurf) film and the aerosols of water-based MWFs and their different constituents is conducted using constrained drop surfactometry (CDS) capable of closely simulating normal tidal breathing and lung-related physiological conditions in vitro . It was found that the airborne MWFs can induce strong PS inhibitions once their accumulated amount in the environment attains 0.2 mg/cm 3 . And their inhibitory effects are demonstrated to mainly originate from the surfactant additives such as polyethylene glycol monooleate (PEGMO) that can desorb PS film from the air/water interface via competitive interfacial adsorption, although it has normally been regarded as an eco-friendly commercial reagent.
研究领域:
工业毒理学
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肺生物学
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生物物理学
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环境卫生
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材料科学
·
职业健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 41
·期 6
·941-952
·
IF 2.997
Qinqing Qian,Yun Zhang,Yuan Chen,Chenqiao Ye,Qiang Feng,Jinqing Tu,Zhenbo Lu,Yilan Xu,Na Ran,Guiying Xing,Zhangsen Yu
Cerium oxide (CeO 2 ) nanoparticles have unique redox properties and exert excellent antioxidant effects in the biological environment. In recent years, many researchers have focused on the CeO 2 nanoparticles as an effective antioxidant drug in the prevention and treatment of various diseases. However, the toxicity of CeO 2 nanoparticles in vivo remains controversial and still needs intensive research. Therefore, the objective of this study is to investigate the pulmonary and systemic toxicity in rats after 14 days of exposure to the PEGylated CeO 2 nanoparticles (abbreviated as CNPs; exposure dose of 2, 10, or 20 mg/kg) through a single intratracheal instillation (IT). We assessed the indicators of lung injury and the pathological damage degree of lung tissue. The bronchoalveolar lavage fluid (BALF) analysis and lung histopathology revealed the occurrence of slight pulmonary inflammation in the 20-mg/kg experimental group rats. However, the inflammation factors in the lung tissue of every group rats did not significantly increase, and the levels of superoxide dismutase (SOD) and glutathione (GSH) in lung tissue homogenate rose considerably in the experimental groups. Collectively, these results indicated that pulmonary exposure by the high dose of CNPs could induce mild pulmonary inflammation but did not cause severe systemic toxicity. Moreover, we speculate that the mechanism of pulmonary toxicity of CNPs in rats was due to the autophagic death of healthy lung epithelial cells mediated by endoplasmic reticulum stress. Our results implicate that CNPs can be safely used as an antioxidant drug for the oxidative stress pulmonary diseases.
研究领域:
药理学
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毒理学
·
纳米技术
·
肺科学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yunxia Ji,Libang Chen,Yunqing Wang,Jinjin Zhang,Yue Yu,Meirong Wang,Xiaoyan Wang,Weili Liu,Bing Yan,Liang Xiao,Xiaodong Song,Changjun Lv,Lingxin Chen
The smaller size fraction of plastics may be more substantially existing and detrimental than larger-sized particles. However, reports on nanoplastics (NPs), especially their airborne occurrences and potential health hazards to the respiratory system, are scarce. Previous studies limit the understanding of their real respiratory effects, since sphere-type polystyrene (PS) nanoparticles differ from NPs occurring in nature with respect to their physicochemical properties. Here, we employ a mechanical breakdown method, producing NPs directly from bulk plastic, preserving NP properties in nature. We report that among four relatively high abundance NP materials PS, polyethylene terephthalate (PET), polyvinyl chloride (PVC), and polyethylene (PE) with a size of 100 nm, PVC induced slightly more severe lung toxicity profiles compared to the other plastics. The lung cytotoxicity of NPs is higher than that of commercial PS NPs and comparable to natural particles silicon dioxide (SiO2) and anatase titanium dioxide (TiO2). Mechanistically, BH3-interacting domain death agonist (Bid) transactivation-mediated mitochondrial dysfunction and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy or ferroptosis are likely common mechanisms of NPs regardless of their chemical composition. This study provides relatively comprehensive data for evaluating the risk of atmospheric NPs to lung health.
研究领域:
环境科学
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毒理学
·
材料科学
·
呼吸医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Baomei Zhang,Xiaoye Yang,Yang Wang,Guangxi Zhai
A novel nanocarrier of heparin (Hep) modified graphene oxide (GO) was fabricated via a linker (adipic dihydrazide) and used as a pH-sensitive drug delivery system for controlling the release of anticancer drug doxorubicin (DOX) for anti-tumor therapy. The finally obtained nanocarrier was GO-ADH-Hep with better stability, blood compatibility and biocompatibility confirmed by the hemolytic test and in vitro cytotoxicity study. Its safety issue was greatly improved via Hep modification. The amount of DOX loaded onto GO-ADH-Hep was significantly high and dependent on pH value. The release rate of DOX from GO- ADH-Hep/DOX was pH-sensitive and much-slower than that of free DOX solution suggesting the sustained drug-release capacity of this prepared nanocomplexes. In addition, the results of cytotoxicity study illustrated that this fabricated nanocomplexes displayed effective cytotoxicity to MCF-7 and HepG2 cells. What's more, the results of the in vivo pharmacokinetic study was also indicated that the GO-ADH-Hep/DOX nanocomplexes could significantly prolong the retention time of DOX in vivo and this was consistent with the in vitro drug release performance. And finally, according to the biodistribution study, DOX delivered by GO-ADH-Hep could reduce cardiotoxicity deriving from DOX solution and also decrease the pulmonary toxicity deriving from unmodified GO. Based on the in vitro and in vivo investigations, the fabricated GO-ADH-Hep could be a promising candidate as an ideal nano-carrier for drug delivery and anti-cancer therapy.
研究领域:
纳米技术
·
药学
·
生物医学工程
·
癌症研究
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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）