TOXICOLOGY
·
2021
·
IF 4.221
Yujie Huang,Jie Zhang,Yizhou Tao,Cheng Ji,Stanley Aniagu,Yan Jiang,Tao Chen
Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an aryl hydrocarbon receptor (AHR) inhibitor, or N-acetyl- l -cysteine (NAC), a reactive oxygen species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.
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高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2021
·Vol. 36
·期 8
·1674-1682
·
IF 4.119
Jun Shi,Xueting Wang,Lulu Chen,Huiping Deng,Min Zhang
Brominated flame retardants (BFRs), such as, 1,2,5,6-tetrabromocyclooctane (HBCD), 1,2-dibromo-4-(1,2-dibromopropyl)cyclohexane (TBECH), and 1 1,2-bis-(2,4,6-tribromophenoxy)ethane (BTBPE), have garnered increasing attention due to their potent biological effects. In the present study, the toxicity of HBCD, TBECH, and BTBPE in human vascular endothelial cells (ECs) was explored. The data showed that HBCD, TBECH, and BTBPE induced cytotoxicity, namely dose–dependent cell viability reduction, cell membrane permeability and apoptosis increase, migration, and lumen formation inhibition. Moreover, HBCD was found to be more toxic than BTBPE or TBECH. Exposure to HBCD, TBECH, and BTBPE led to the production of reactive oxygen species, mitochondrial superoxide generation, and mitochondrial membrane potential collapse, implying that reactive stress caused the cytotoxicity. The ATP content, glutathione content, superoxide dismutase, and MDA activities were reduced, indicating that mitochondrial dysfunction may be the key mechanisms responsible for apoptosis. The present study suggested that mitochondria are a new target of BFRs in ECs and further deepened our understanding of the developmental toxicity of BFRs.
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Biomaterials Science
·
2020
·Vol. 8
·期 21
·5931-5940
·
IF 6.183
Xiang Zhan,Xuan Nie,Fan Gao,Cong Zhang,Ye-Zi You,Yue Yu
Nanomedicine has attracted growing attention due to its designability and functionality, as well as its excellent pharmacokinetics with limited side effects, and recently, combined therapies have become desirable as they can obtain enhanced therapeutic efficacy by using nanomedicine. Herein, we have reported a functional drug delivery system with a dual response to temperature and reactive oxygen species to efficiently eliminate pancreatic cancer cells in a combined therapy strategy. Functional micelles with camptothecin (CPT) in the core and indocyanine green (ICG) on the surface could effectively accumulate in tumor sites through the EPR effect. The ROS in the tumor microenvironment trigger the conversion of an amino-based copolymer to a carboxy based copolymer, releasing the loaded ICG to reduce the size of the micelles with high penetration in tumor tissue. On the one hand, under 808 nm light irradiation, the micelles will produce the heat to kill tumor cells via photothermal therapy. On the other hand, the generated heat could further trigger the transition of a copolymer from a hydrophobic to a hydrophilic state, releasing the loaded CPT into the deep tumor cells to achieve chemotherapy. The in vitro and in vivo experiments revealed that this combined therapy could combat pancreatic cancer cells with an enhanced therapeutic effect.
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ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Jun Li,Yun-Jie Wei,Xian-Ling Yang,Wan-Xia Wu,Meng-Qian Zhang,Meng-Yang Li,Zu-E Hu,Yan-Hong Liu,Na Wang,Xiao-Qi Yu
To maximize the utilization and response to the high oxidative stress environment of tumor sites while avoiding the dilemma of enhancing reactive oxygen species (ROS) response in a single way, mitochondrial targeting combined with fluorescent self-reporting polymeric nanocarriers (1K-TPP and 2K-TPP) with grafted structures were synthesized via a chemoenzymatic method in a high yield to simultaneously enhance the drug delivery of endogenous ROS responses. 1K-TPP and 2K-TPP loaded doxorubicin (DOX) at a high content over 12% and formed homogeneous spherical micelles. In vitro, both of them showed promising high sensitivity (detection limit below 200 nM H2O2), fast response, and ratiometric fluorescent self-reporting properties (fluorescent enhancement more than 200 times) to ROS and excellent stability under physiological conditions, while achieving a rapid release of the DOX in response to 1 mM H2O2. Cell co-localization experiments exhibited that they had favorable mitochondrial targeting, and mitochondrial isolation experiments also confirmed that the TPP-modified 1K-TPP selectively accumulated nearly three times in mitochondria than that in total cells. The internalization of 1K-TPP and 2K-TPP into cancer cells was greatly improved by nearly 200% compared to that of unmodified control (1K-OH and 2K-OH) and also explored a unique energy-dependent endocytosis. Furthermore, stimulation of endogenous ROS enhanced the green fluorescence intensity (up to 51.4%) of the linked probe so as to destroy the internal structure of the nanocarriers, achieving self-reporting of the drug’s intracellular release and tracking of the intracellular location of nanocarriers. The cytotoxicity of DOX-loaded 1K-TPP and 2K-TPP in tumor cells with a higher ROS content showed statistical superiority to that of 1K-OH and 2K-OH, benefiting from the extremely good endogenous ROS response sensitivity leading to the differential selective release of drugs. These results demonstrate the potential of 1K-TPP and 2K-TPP, especially for 1K-TPP, as mitochondria-targeted, fluorescent self-reporting nanocarriers for combined enhancement of endogenous ROS responsiveness.
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高影响因子
Food & Function
·
2020
·Vol. 11
·期 6
·5156-5165
·
IF 4.171
Yu-Sheng Shi,Xiao-Xing Li,Hao-Tian Li,Yan Zhang
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
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ACS Applied Bio Materials
·
2021
·
IF 0
Ning Zhang,Daquan Wang,Xunan Jing,Tingting Yang,Hongbo Yang,Lingjie Meng
In the past decades, polymer–drug conjugates of anticancer agents have gained much attention due to their enhanced aqueous solubility, improved pharmacokinetics, and better drug utilization than their conventional insoluble counterparts. Several polymer–drug conjugates have entered the third phase of clinical trials yet suffer from inherent deficiencies, including uncontrolled drug release and unclear degradation mechanisms. In this study, a pH/reactive oxygen species (ROS) dual-responsive PEG-doxorubicin (DOX) conjugate (denoted as TPD) was synthesized through acyl alkynyl-amine click reaction by PEG dipropiolate (PEGB), amine-terminated thioketal (TKL), and doxorubicin (DOX). Due to the generated ene-amine and thioketal in the backbone, the prepared amphiphilic TPD not only has a high drug loading ratio for photosensitizer chlorin e6 (Ce6) but also has the sensitivity to the acidic tumor microenvironment (TME) and ROS. Considering the complex conditions of TME, the prepared TPD@Ce6 nanoparticles (NPs) might respond to the relatively low pH and release Ce6 initially, and upon laser radiation, Ce6 produces abundant singlet oxygen (1O2) to achieve a programmable accelerated release of DOX and more Ce6 at the tumor site. In addition, the NIR fluorescence of DOX could monitor drug delivery and controlled release. The developed TPD@Ce6 NPs can realize the targeted tumor in combination therapy with negligible cytotoxicity on normal tissues.
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MOLECULAR PHARMACEUTICS
·
2019
·
IF 4.396
Mengting Lin,Wangwei Guo,Zhentao Zhang,Yi Zhou,Jiejian Chen,Tiantian Wang,Xincheng Zhong,Yiying Lu,Qiyao Yang,Qichun Wei,Min Han,Donghang Xu,Jianqing Gao
Nitrogen mustard (NM) is among the earliest drugs used to treat malignant tumors and it kills tumor cells by cross-linking DNA. Unfortunately, because of the short half-life and unfavorable selectivity, NM causes significant damage to normal tissues. As NM can increase the levels of reactive oxygen species (ROS) in tumor cells, a ROS-activated nitrogen mustard prodrug (NM-Pro) was synthesized and mixed with NM at a specific ratio to obtain an “NM-ROS-NM-Pro-NM” positive feedback system, which ultimately achieves a specific lethal effect on hematological neoplasms. The further encapsulation of NM/NM-Pro in liposomes allows the sustained release of the drug and prolongs the residence time in vivo. Here, we prepared stable liposomes with a uniform particle size of 170.6 ± 2.2 nm. The optimal ratio of NM to NM-Pro in this study was 2:1. The active drug NM in the NM/NM-Pro system continuously stimulated ROS production by the cells, which in turn further activated the NM-Pro to continuously generate NM. The positive feedback pathway between the NM and NM-Pro resulted in the specific death of tumor cells. Furthermore, the K562 hematological neoplasm model was utilized to evaluate the therapeutic effect of NM/NM-Pro liposomes in vivo. After encapsulation in liposomes, the targeting of tumor cells was increased approximately two times compared with that of normal cells, and NM/NM-Pro liposomes exhibited reduced toxicity, without an increase in drug activity compared to the NM/NM-Pro combination. The NM/NM-Pro delivery system exerts a positive feedback effect on ROS production in tumor cells and displays good potential for the specific killing of hematoma cells.
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高影响因子
Advanced Healthcare Materials
·
2019
·Vol. 8
·期 18
·1900720
·
IF 6.27
Pengying Wu,Wei Dong,Xuyan Guo,Xiaoyang Qiao,Shifang Guo,Lei Zhang,Mingxi Wan,Yujin Zong
Sonodynamic therapy (SDT) not only has greater tissue-penetrating depth compared to photo-stimulated therapies, but also can also trigger rapid drug release to achieve synergistic sonochemotherapy. Here, reactive oxygen species (ROS)-responsive IR780/PTL- nanoparticles (NPs) are designed by self-assembly, which contain ROS-cleavable thioketal linkers (TL) to promote paclitaxel (PTX) release during SDT. Under ultrasound (US) stimulation, IR780/PTL-NPs produce high amounts of ROS, which not only induces apoptosis in human glioma (U87) cells but also boosts PTX released by decomposing the ROS-sensitive TL. In the U87 tumor-bearing mouse model, the IR780/PTL-NPs releases the drug at the target sites in a controlled manner upon US irradiation, which significantly inhibits tumor growth and induces apoptosis in the tumor tissues with no obvious toxicity. Taken together, the IR780/PTL-NPs are a novel platform for sonochemotherapy, and can control the spatio-temporal release of chemotherapeutic drugs during SDT.
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高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Yuejun Yao,Jie Ding,Zhaoyi Wang,Haolan Zhang,Jieqi Xie,Yingchao Wang,Liangjie Hong,Zhengwei Mao,Jianqing Gao,Changyou Gao
Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous diseases including atherosclerosis, diabetes, inflammation and myocardial infarction (MI). In this study, a ROS-responsive biodegradable elastomeric polyurethane containing thioketal (PUTK) linkages was synthesized from polycaprolactone diol (PCL-diol ), 1,6-hexamethylene diisocyanate (HDI), and ROS-cleavable chain extender . The PUTK was electrospun into fibrous patches with the option to load glucocorticoid methylprednisolone (MP), which were then used to treat MI of rats in vivo . The fibrous patches exhibited suitable mechanical properties and high elasticity. The molecular weight of PUTK was decreased significantly after incubation in 1 mM H 2 O 2 solution for 2 weeks due to the degradation of thioketal bonds on the polymer backbone . Both the PUTK and PUTK/MP fibrous patches showed good antioxidant property in an oxidative environment in vitro . Implantation of the ROS-responsive polyurethane patches in MI of rats in vivo could better protect cardiomyocytes from death in the earlier stage (24 h) than the non ROS-responsive ones. Implantation of the PUTK/MP fibrous patches for 28 days could effectively improve the reconstruction of cardiac functions including increased ejection fraction , decreased infarction size, and enhanced revascularization of the infarct myocardium.
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高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Gang-Gang Yang,Hang Zhang,Dong-Yang Zhang,Qian Cao,Jing Yang,Liang-Nian Ji,Zong-Wan Mao
A promising theranostic nanosystem VK3-CPT@Ru-CD is designed and fabricated by the host-guest driven self-assembly between the fluorescent adamantine-functionalized Ru(II) complexes and the ROS-labile-cyclodextrin modified thioketal linkers, in which anticancer drug camptothecin (CPT) and vitamin K3 (VK3) are effectively co-encapsulated. On account of the generative feedback between the intracellular redox cycling of VK3 and the high degree of ROS-triggered collapse of nanoparticles , VK3-CPT@Ru-CD can facilitate cancer-specific ROS amplification and drug release selectively in cancer cells, thus realizing the selective killing of tumor with minimal side-effects both in vitro and in vivo , the therapeutic effect of which is more prominent than the free anti-cancer drugs. More interestingly, the menadione structure of encapsulated VK3 can effectively quench the inherent fluorescence of Ru-CD, and a fluorescence lightening up phenomenon is observed accompanied with the ROS-triggered drug release, which can be utilized for real-time tracking of drug release in vitro and in vivo.
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WATER AIR AND SOIL POLLUTION
·
2015
·Vol. 226
·期 11
·1-12
·
IF 1.554
Ahmad Ayyaz,Gu Xiaogang,Li Li,Lu Shuguang,Xu Yisheng,Guo Xuhong
In this study, nanosized zero-valent iron-reduced graphene oxide (nZVI-rGO)-activated persulfate (PS) was used to investigate the generation of reactive oxygen species (ROS) for the degradation of trichloroethylene (TCE) in the aqueous solution. More than 98 % of TCE was degraded within 2 min under experimental conditions. The generation of ·OH increased when the pH was shifted toward the basic region while ·SO 4
− radicals’ intensity increased in the acidic pH. Different scenarios have been observed in ·O 2
− generation in the neutral and strong basic pH and decreased in acidic or slightly basic pH. In addition, the intensity of ·OH was increased with the addition of HCO 3
− (10 mM) and NO 3
− (100 mM) but decreased in the presence of Cl − (10 and 100 mM), HCO 3
− (100 mM), and NO 3
− (10 mM). The degradation of anisole, probe for both ·OH and ·SO 4
− , was slightly enhanced by 10 mM NO 3
− anions but decreased in 100 mM salt solution. ·O 2
− intensity was increased while HCO 3
− (10 and 100 mM) and NO 3
− (100 mM) anions were used. nZVI-rGO-activated PS process could remove TCE in aqueous effectively, and the ROS generation and intensity were influenced by solution pH values and anions.
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ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Tianhu Wang,Yabin Wang,Yingjie Zhang,Zhiyi Fang,Sulei Li,Zhenghui Gu,Yan Ma,Linghuan Wang,Dong Han,Changyong Wang,Jin Zhou,Feng Cao
In this study, we synthesized mesoporous polydopamine nanoparticles (MPDA NPs) using an emulsion-induced interface assembly strategy and loaded epigallocatechin gallate (EGCG) into MPDA NPs via electrostatic attraction to form EGCG@MPDA NPs. In the post myocardial infarction (MI) environment, these interventions specifically aimed to eliminate reactive oxygen species (ROS) and facilitate the repair of MI. We further combined them with a thermosensitive chitosan (CS) hydrogel to construct an injectable composite hydrogel (EGCG@MPDA/CS hydrogel). Utilizing in vitro experiments, the EGCG@MPDA/CS hydrogel exhibited excellent ROS-scavenging ability of H9C2 cells under the oxidative stress environment and also could inhibit their apoptosis. The EGCG@MPDA/CS hydrogel significantly promoted left ventricular ejection fraction (LVEF) in infarcted rat models post injection for 28 days compared to the PBS group (51.25 ± 1.73% vs 29.31 ± 0.78%, P < 0.05). In comparison to the PBS group, histological analysis revealed a substantial increase in left ventricular (LV) wall thickness in the EGCG@MPDA/CS hydrogel group (from 0.58 ± 0.03 to 1.39 ± 1.11 mm, P < 0.05). This work presents a novel approach to enhance MI repair by employing the EGCG@MPDA/CS hydrogel. This hydrogel effectively reduces local oxidative stress by ROS and stimulates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.
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