BRITISH JOURNAL OF PHARMACOLOGY
·
2023
·
IF 7.3
Luyao Ma,Fangjun Yu,Di He,Lianxia Guo,Yu Yang,Wangchun Li,Tianpeng Zhang
Background and purpose The role of CLOCK in regulation of drug chronoefficacy and chronotoxicity remains elusive. Here, we aimed to uncover the impact of CLOCK and dosing time on clopidogrel efficacy and toxicity. Experimental Approach The antiplatelet effect, toxicity and pharmacokinetics experiments were conducted with Clock −/− and wild-type mice after gavage administration of clopidogrel at different circadian time points. The expression levels of drug metabolizing enzymes were determined by qPCR and Western blotting. Transcriptional gene regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. Key Results The antiplatelet effect and toxicity of clopidogrel in wild-type mice showed a dosing-time dependent variation. Clock ablation reduced the antiplatelet effect of clopidogrel, increased clopidogrel-induced hepatotoxicity, and blunted their rhythms. This was associated with attenuated rhythms of clopidogrel active metabolite (Clop-AM) and clopidogrel, respectively. We further found that Clock regulated the diurnal variation of Clop-AM formation by modulating the rhythmic expression of CYP1A2 and CYP3A11, and altered clopidogrel chronopharmacokinetics by circadian regulation of CES1D expression. Mechanistic studies revealed that CLOCK activated Cyp1a2 and Ces1d transcription by directly binding to the E-box elements in their promoters, and promoted Cyp3a11 transcription through enhancing the transactivation activity of DBP and TEF. Conclusion and implication CLOCK regulates the diurnal rhythmicity in clopidogrel efficacy and toxicity through regulation of CYP1A2, CYP3A11 and CES1D expression. The findings may contribute to the optimization of dosing schedule for clopidogrel, and deepen understanding of the connection between the circadian clock and chronopharmacology.
研究领域:
药理学
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生物节律学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
IF 4.872
Meiyu Lu,Wankui Jiang,Qinqin Gao,Mingliang Zhang,Qing Hong
Phthalate esters (PAEs), a class of toxic anthropogenic compounds, have been predominantly used as additives or plasticizers , and great concern and interests have been raised regarding its environmental behavior and degradation mechanism. In the present study, a bacterial consortium consisting of Microbacterium sp. PAE-1 and Pandoraea sp. PAE-2 was isolated by the enrichment method, which could degrade dibutyl phthalate (DBP) completely by biochemical cooperation. DBP was converted to phthalic acid (PA) via monobutyl phthalate (MBP) by two sequential hydrolysis steps in strain PAE-1, and then PA was further degraded by strain PAE-2. Strain PAE-1 could hydrolyze many dialkyl Phthalate esters (PAEs) including dimethyl, diethyl, dibutyl, dipentyl, benzyl butyl, dihexyl, di-(2-ethyhexyl) and their corresponding monoalkyl PAEs. Two esterase genes named dpeH and mpeH , located in the same transcription unit, were cloned from strain PAE-1 by the shotgun method and heterologously expressed in Escherichia. coli (DE3) . The K m and k cat values of DpeH for DBP were 9.60 ± 0.97 μM and (2.72 ± 0.06) × 10 6 s −1 , while those of MpeH for MBP were 18.61 ± 2.00 μM and (5.83 ± 1.00) × 10 5 s −1 , respectively. DpeH could only hydrolyze dialkyl PAEs to the corresponding monoalkyl PAEs, which were then hydrolyzed to PA by MpeH. DpeH shares the highest similarity (53%) with an alpha/beta hydrolase from Microbacterium sp. MED-G48 and MpeH shows only 25% identity with a secreted lipase from Trichophyton benhamiae CBS 112371, indicating that DpeH and MpeH are two novel hydrolases against PAEs.
研究领域:
环境科学
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微生物学
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生物降解
·
酶学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2021
·
IF 9.028
Haiyang Tang,Hongli Zhong,Yang Pan,Qing Zhou,Zongli Huo,Wenhai Chu,Bin Xu
pH adjustment prior to extraction is an important step in water sample pretreatment processes for exploration of new/unknown disinfection byproducts (DBPs) in drinking water. To achieve a better extraction efficiency, the pH of a water sample is usually adjusted to a low level (e.g., < 0.5) to ensure that target DBPs are in their neutral forms. However, such a practice may elude some amphoteric DBPs (especially those nitrogenous DBPs with multiple functional groups), which can accept protons at a low pH and lose protons at a high pH. In this study, with careful extraction pH selection and optimization, we first report the detection and identification of a new group of heterocyclic nitrogenous DBPs, halogenated pyridinols, in simulated drinking water using ultra performance liquid chromatography/electrospray ionization-triple quadrupole mass spectrometry and time-of-flight mass spectrometry, including 5-chloro-3-pyridinol, 2-bromo-3-pyridinol, 2,6-dichloro-4-pyridinol, 2,6-dibromo-3-pyridinol, 3-bromo-2-chloro-5-pyridinol, 5-bromo-2-chloro-3-pyridinol, 3,5,6-trichloro-2-pyridinol, and 2,4,6-tribromo-3-pyridinol. On the basis of the speciation of dissociated chemical species and recovery tests at different extraction pH values, it was found that, only at a pH of 3.0, all the eight new DBPs could achieve recoveries of >50%. With subsequent instrumental parameter optimization, the method detection and quantitation limits of the eight new DBPs were determined to be 0.04–1.58 and 0.15–4.11 ng/L, respectively. The optimized method enabled an accurate detection of the eight new DBPs in two real drinking water samples. Further aided with in vivo developmental and acute toxicity assays using zebrafish embryos, the developmental and acute toxicity of the new DBPs were found to be slightly lower than those of halogenated benzoquinones but dozens of times higher than those of commonly known DBPs such as tribromomethane and iodoacetic acid.
研究领域:
环境科学
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分析化学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2023
·
IF 13.6
Yimin Xie,Yihuai Huang,Zhiwei Liang,Hojae Shim
Waste scrap tyre as microbial immobilization matrix enhanced degradation of phthalate esters (PAEs), di (2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and diethyl phthalate (DEP). The hybrid (physical adsorption and microbial immobilization) degradation process performance of scrap tyres was examined for the PAEs degradation. The scrap tyre was shown with competitive adsorption capacity toward PAEs, influenced by pH, temperature, dosage of adsorbent (scrap tyre), and concentration of PAE. The primary adsorption mechanism for tyres toward PAEs was considered hydrophobic. The immobilization of previously isolated Bacillus sp. MY156 on tyre surface significantly enhanced PAEs degradation as well as bacterial growth. The enzymatic activity results implied immobilization promoted dehydrogenase activity and decreased esterase activity. The cell surface response during PAEs degradation, in terms of morphological observation, FTIR and XRD analyses, and extracellular polymeric substance (EPS) release, was further assessed to better understand the interactions between microorganisms and tyre surface. Waste scrap tyres could be a promising potential candidate to be reused for sustainable environmental management, including contaminants removal.
研究领域:
环境科学
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水处理
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微生物学
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材料科学
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可持续发展
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers of Environmental Science & Engineering
·
2024
·Vol. 18
·期 9
·1-14
·
IF 6.1
Liao Xiaobin,Liu Xinyue,He Yueyun,Tang Xueping,Xia Ruanjunjie,Huang Yongjun,Li Wenhua,Zou Jing,Zhou Zhenming,Zhuang Mazhan
During the COVID-19 pandemic, most sewage treatment plants increased disinfectant dosages to inactivate pathogenic viruses and microorganisms more effectively. However, this approach also led to the production of more disinfection by-products (DBPs). To ensure both disinfection efficiency and a reduction in DBP formation, new disinfection protocols are required. In this study, the disinfection efficiency, DBP amounts, and toxicity changes resulting from ozone (O 3 ), ultraviolet (UV), chlorine (Cl 2 ), and their combined processes were examined. The results demonstrated that the O 3 /UV/Cl 2 combination achieved the highest disinfection efficiency. Chlorination produced the most DBPs, whereas UV treatment reduced the formation of trihalomethane (THM), halogenated ketones (HKs), haloacetic acids (HAA), dichloroacetonitrile (DCAN) and N-nitrosodimethylamine (NDMA) by 45.9%, 52.6%, 82.0%, 67.95%, and 47%, respectively. O 3 also significantly reduced their production by 99.1%, 91.1%, 99.5%, 100%, and 35%. Intracellular organic matter (IOM) was identified as the primary DBP precursors, producing 2.94 times more DBPs than extracellular organic matter (EOM). The increased DBP formation during chlorination was attributed to IOM leakage and cell membrane damage, which was verified using scanning electron microscopy (SEM). The toxicities of DBPs were evaluated for six disinfection methods, revealing inconsistent results. The overall toxicities were assessed using zebrafish embryo experiments. Both evaluations indicated that chlorination alone was the least favorable method. In addition, the toxicities followed a sequence: Cl 2 ≈ O 3 /Cl 2 > O 3 > O 3 /UV/Cl 2 > UV > UV/Cl 2 . These findings can serve as a reference for sewage treatment plants in selecting appropriate disinfection methods to manage the COVID-19 epidemic from comprehensive perspective.
研究领域:
环境科学
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公共卫生
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毒理学
✓ 已验证
DOI
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2023
·
IF 11.4
Haoyue Tan,Pan Gao,Yiwen Luo,Xiao Gou,Pu Xia,Pingping Wang,Lu Yan,Shaoqing Zhang,Jing Guo,Xiaowei Zhang,Hongxia Yu,Wei Shi
Although previous studies have confirmed the association between phthalate esters (PAEs) exposure and endocrine disorders in humans, few studies to date have systematically assessed the threats of new PAE alternatives to endocrine disruptions. Herein, zebrafish embryos were continuously exposed to two PAEs [di-n-butyl phthalate (DBP) and diisobutyl phthalate (DiBP)], two structurally related alternatives [diiononyl phthalate (DINP) and diisononyl hexahydrophthalate (DINCH)], and two non-PAE substitutes [dipropylene glycol dibenzoate (DGD) and glyceryl triacetate (GTA)], and the endocrine-disrupting effects were investigated during the early stages (8–48 hpf). For five endogenous hormones, including progesterone, testosterone, 17β-estradiol, triiodothyronine (T3), and cortisol, the tested chemicals disturbed the contents of at least one hormone at environmentally relevant concentrations (≤3.9 μM), except DINCH and GTA. Then, the concentration-dependent reduced zebrafish transcriptome analysis was performed. Thyroid hormone (TH)- and androgen/estrogen-regulated adverse outcome pathways (AOPs) were the two types of biological pathways most sensitive to PAE exposure. Notably, six compounds disrupted four TH-mediated AOPs, from the inhibition of deiodinases (molecular initiating event, MIE), a decrease in T3 levels (key event, KE), to mortality (adverse outcome, AO) with the quantitatively linear relationships between MIE-KE (|r| = 0.96, p = 0.002), KE-AO (|r| = 0.88, p = 0.02), and MIE-AO (|r| = 0.89, p = 0.02). Multiple structural analyses showed that benzoic acid is the critical toxicogenic fragment. Our data will facilitate the screening and development of green alternatives.
研究领域:
环境科学
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毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
IF 4.872
Jiarong Qiu,Haiyan Yang,Yuting Shao,Longxiang Li,Shengwei Sun,Luyao Wang,Yuzhi Tan,Zhihong Xin
Our previous work has reported that EstJ6 was a phthalate-degrading hydrolase. In the study, a random mutant library was constructed by two rounds of error-prone PCR, three mutants (ET1.1, ET2.1, and ET2.2) with enhanced hydrolytic activity against dibutyl phthalate (DBP) were obtained. The best mutant ET2.2, accumulated three amino acid substitutions (Thr91Met, Ala67Val, and Val249Ile) and exhibited 2.8-fold increase enzyme activity and 2.3-fold higher expression level. Meanwhile, compared with EstJ6, ET2.2 showed over 50% improvement in thermostability (at 50 °C for 1 h) and 1.2-fold increase in 50% methanol tolerance. Kinetic parameters analysis revealed that the Km value for ET2.2 decreased by 60% and the kcat/Km value increased by 166%. The molecular docking indicated that the shortening of hydrogen bond between Ser146-OH and DBP-CO, which may led to an increase in enzyme activity and catalytic efficiency, the enhancement of hydrophobicity of hydrophobic pocket was related to the improvement of organic solvents tolerance, and three hydrophobic amino acid substitutions Thr91Met, Ala67Val, and Val249Ile facilitated to improve the thermal stability and organic solvents tolerance. These results confirmed that random mutagenesis was an effective tool for improving enzyme properties and lay a foundation for practical applications of phthalate-degrading hydrolase in biotechnology and industrial fields.
研究领域:
生物化学
·
酶工程
·
生物技术
·
环境科学
✓ 已验证
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2020
·
IF 6.551
Chenhui Duan,Yanjun Fang,Jingran Sun,Zhenxin Li,Qiangqiang Wang,Jialei Bai,Hui Peng,Jun Liang,Zhixian Gao
The health risks of exposure to plasticizers have received widespread attention, however, little is known about the effects of fast food packaging plasticizers on steroid hormone synthesis. In the present study, the types and migration of plasticizers in some commonly used fast-food packaging materials were detected by GC–MS, and the interference effects of these plasticizers and their metabolites on steroid hormone synthesis in the human body were evaluated by the H295R steroidogenesis assay. The GC–MS results showed that the main plasticizer compounds that migrated from fast food packaging into food were di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bis(2-ethylhexyl) adipate (DEHA). Exposure to these chemicals (100–1000 μM) can significantly reduce the viability of H295R cells in a dose-response manner, and these plasticizers and their metabolites that migrated into oily foods at high temperatures (0.25–25 μM) could significantly increase the E2 level and reduce the T level in H295R cells. According to the qRT-PCR data, 0.25 to 25 μM mono(2-ethylhexyl) phthalate (MEHP) significantly upregulated the expression levels of 17β-HSD1 and CYP19A1, and downregulated those of CYP17A1, CYP11A1 and StAR. The Western blot results were consistent with those of qRT-PCR. In summary, these results indicated that even exposure to low concentrations (≤1 mg/l or 2.5 μM) of these chemicals and their metabolites can cause significant endocrine-disrupting effects.
研究领域:
环境健康
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毒理学
·
内分泌学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2024
·
IF 3.3
Li-Lan Liu,Jun-Zhe Yue,Zhen-Yu Lu,Ru-Ya Deng,Can-Can Li,Ye-Na Yu,Wen-Jin Zhou,Min Lin,Hai-Tao Gao,Jiaming Liu,Ling-Zi Xia
Phthalates (PEs), such as di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) could cause reproductive and developmental toxicities , while human beings are increasingly exposed to them at low-doses. Phytochemical quercetin (Que) is a flavonoid that has estrogenic effect, anti-inflammatory and anti-oxidant effects. This study was conducted to assess the alleviative effect of Que. on male reproductive toxicity induced by the mixture of three commonly used PEs (MPEs) at low-dose in rats, and explore the underlying mechanism. Male rats were treated with MPEs (16 mg/kg/day) and/or Que. (50 mg/kg/d) for 91 days. The results showed that MPEs exposure caused male reproductive injuries, such as decreased serum sex hormones levels, abnormal testicular pathological structure, increased abnormal sperm rate and changed expressions of PIWIL1 and PIWIL2. Furthermore, MPEs also changed the expression of steroidogenic proteins in steroid hormone metabolism, including StAR, CYP11A1 , CYP17A1 , 17β-HSD, CYP19A1 . However, the alterations of these parameters were reversed by Que. MPEs caused male reproductive injuries in rats; Que. inhibited MPEs' male reproductive toxicity, which might relate to the improvement of testosterone biosynthesis.
研究领域:
毒理学
·
生殖生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Probiotics and Antimicrobial Proteins
·
2024
·
IF 4.4
Zhu Yuan-ting,Wang Xing-jie,Liu Shu-liang,Lai Jing-hui,Li Jian-long,Li Qin,Hu Kai-di,Liu Ai-ping,Yang Yong,He Li,Chen Shu-juan,Ao Xiao-lin,Zou Li-kou
Phthalate acid esters (PAEs) and their metabolites, such as di- n -butyl phthalate (DBP) and mono- n -butyl phthalate (MBP), are known to cause male reproductive damage. Lactiplantibacillus plantarum RS20D has demonstrated the ability to remove both DBP and MBP in vitro, suggesting its potential as a detoxifying agent against these compounds. This study aimed to investigate the protective effects of RS20D on DBP or MBP-induced male reproductive toxicity in adolescent rats. Oral administration of RS20D significantly mitigated the histological damage to the testes caused by MBP or DBP, restored sperm concentration, morphological abnormalities, and the proliferation index in MBP-exposed rats, and partially reversed spermatogenic damage in DBP-exposed rats. Furthermore, RS20D restored serum levels of estradiol (E2) and testosterone, and superoxide dismutase (SOD) activity in DBP-exposed rats, significantly increased testosterone levels in MBP-exposed rats, and restored copper (Cu) concentrations in the testes after exposure to DBP or MBP. Additionally, RS20D effectively modulated the intestinal microbiota in DBP-exposed rats and partially ameliorated dysbiosis induced by MBP, which may be associated with the alleviation of reproductive toxic effects induced by DBP or MBP. In conclusion, this study demonstrates that RS20D administration can alleviate male reproductive toxicity and gut dysbacteriosis induced by DBP or MBP exposure, providing a dietary strategy for the bioremediation of PAEs and their metabolites.
研究领域:
毒理学
·
生殖生物学
·
微生物学
·
营养科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYST
·
2021
·Vol. 146
·期 15
·4858-4864
·
IF 4.616
Shuling Xu,Hefu Li,Meng Guo,Lei Wang,Xia Li,Qingwang Xue
DBP, one of the phthalic acid esters (PAEs), is known as an endocrine disruptor and is toxic to humans in abnormal concentrations. Here, a high-density and ordered SERS substrate based on the self-assembly of triangular Ag nanoplate (TAgNP) arrays is developed for DBP detection. Benefiting from the ordered arrangement and sharp corners of TAgNPS, the arrays can provide sufficient and uniform hotspots for reproducible and highly active SERS effects. Using Rhodamine 6G (R6G) as a reporter molecule, the SERS enhancement factor (EF) of the TAgNP arrays was found to be as high as 1.2 × 107 and the relative standard deviation was 6.56%. As a trial for practical applications, the TAgNP array substrates were used for the detection of dibutyl phthalate (DBP) in edible oils. In this assay, edible oil samples were added to hexane as an organic phase for the formation of the TAgNP arrays, which caused DBP to be loaded at hotspots. DBP in edible oils could be identified at concentrations as low as 10−7 M. This SERS substrate based on the TAgNP arrays has great potential applications in the high sensitivity and reproducible detection of contaminants in food.
研究领域:
分析化学
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环境科学
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食品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Zhiqiang Li,Yating Hu,Wen Zhang,Qi Zhang,Peiwu Li,Xiaoqian Tang
Edible oils, a major source of dietary fat, are frequently contaminated with dibutyl phthalate (DBP) and benzo( a )pyrene (BaP), posing serious food safety risks. To enhance the accuracy of immunoassays in complex oil matrices, we developed a point-of-care testing platform that integrates bimetallic porous carbon nanomaterials as multifunctional signaling probes with a multi-algorithm framework driven by a voting model weighting algorithm. The porous carbon material Zn-CN was synthesized via organic solution coordination followed by high-temperature pyrolytic derivatization. Pt-Zn-CN was subsequently prepared by incorporating platinum nanoparticles into Zn-CN through reductive stirring at room temperature. This nanomaterial exhibits excellent photothermal properties and dispersibility, and its large surface area and porous architecture facilitate efficient antibody coupling and target enrichment. The resulting nanoprobes act as multifunctional signal transducers to enhance the recognition and amplification of antigen–antibody interactions. The multi-algorithm framework leverages bionic swarm intelligence and autonomous decision-making to perform high-precision image segmentation, attaining 97.6 % contour recognition and 95.7 % detection accuracy within 0.03 s. This platform enables ultra-fast early warning and achieves ultra-low detection limits of 0.184 ng/mL for DBP and 0.096 ng/mL for BaP. A user-friendly graphical user interface supports real-time quantification of BaP and DBP, providing intuitive safety warnings for edible oils.
研究领域:
食品安全
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纳米技术
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分析化学
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生物传感器
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机器学习
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环境科学
·
公共卫生
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）