CHEMICO-BIOLOGICAL INTERACTIONS
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2019
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IF 3.407
Wen-Jing Wu,Wei-Feng Tang,Ming-Hui Xiang,Jianshe Yan,Xiumei Cao,Chang-Hui Zhou,Yan Chang,Jing Xi,Yi-Yi Cao,Yang Luan,Xin-Yu Zhang
1-Chloro-2-hydroxy-3-butene (CHB) is a possible metabolite of 1,3-butadiene, a carcinogenic air pollutant . To demonstrate its formation in vivo, it is desirable to develop a practical biomarker and the corresponding analysis method. CHB can undergo alcohol dehydrogenase- and cytochromes P450 enzymes (P450)-mediated oxidation to yield 1-chloro-3-buten-2-one (CBO), which readily forms glutathione conjugates. We hypothesized that CBO-derived mercapturic acids , which are the expected biotransformed products of CBO-glutathione conjugates, could be used as CHB biomarkers. Thus, in the present study, we investigated the in vivo biotransformation of CHB into CBO-derived mercapturic acids. Because the reaction of CBO with N -acetyl- l -cysteine yields two products, 1,4- bis ( N -acetyl- S -cysteinyl)-2-butanone (NC1) and 1-chloro-4-( N -acetyl- S -cysteinyl)-2-butanone (NC2), we first developed an isotope dilution LC/ESI − -MS-MS method to quantitate urinary NC1 and NC2, and then determined their concentrations in urine of C57BL/6 mice and Sprague-Dawley rats administered CHB. Since no NC2 was detected in samples, the LC/ESI − -MS-MS method was optimized specifically for NC1. NC1 was enriched through solid phase extraction with the recovery being 75–82%. The limits of detection and quantitation were 6.8 and 34 fmol/0.1 mL for mouse urine, and 4.5 and 7.1 fmol/0.1 mL for rat urine, respectively. In urine of animals before CHB administration, no NC1 was detected; in mice administered CHB at 10 and 30 mg/kg, and rats at 5 and 15 mg/kg, NC1 was detected and its concentrations in urine from animals given higher doses were 3–6 fold higher than those given lower doses. Moreover, the NC1 concentrations in urine during 0–8 h were 4–6 fold and 10–11 fold higher than those during 8–24 h for mice and rats, respectively. The results demonstrated that CHB could be in vivo biotransformed into NC1, which could be used as a practical CHB biomarker.
研究领域:
毒理学
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分析化学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Jinzhi Ren,Ying Peng,Luhang She,Lu Yan,Jianjun Li,Caixia Gao,Chao Wang,Yimeng Wang,Xiangping Nie,Xiaowei Zhang
The estuarine ecological environment faces significant threats from contaminants of emerging concern (CECs); yet, the risk posed by CECs to resident organisms remains poorly understood. Here, we employed tiered toxicity testing to investigate the adverse effects and potential mechanisms of tris (1-chloro-2-propyl) phosphate (TCPP) on the early life stages of an estuarine fish, Mugilogobius chulae . TCPP affected the development of M. chulae embryos, including survival, morphology, hatching, and behavior. A concentration-dependent transcriptomic analysis showed that TCPP disrupted 12 neurodevelopment-related KEGG pathways in M. chulae embryos, with five of the 30 % top-ranked pathways related to neurotransmitter signaling. Besides the cholinergic synapse signaling pathway, the glutamatergic signaling pathway (including NMDAR and AMPAR subtypes) may also mediate TCPP-induced neurodevelopmental toxicity. The NMDAR subtype GRIN2B was downregulated at high concentrations. Molecular dynamics simulations revealed a strong interaction between TCPP and GRIN2B, with TCPP binding to the residues Ile153 and Ile188. The results suggest that NMDARs play a crucial role in TCPP-induced neurodevelopmental toxicity toward M. chulae. AOP network analysis predicted that TCPP may impact cognitive functions and memory. Our study provides a novel testing strategy for identifying the mechanisms of toxicity of CECs, a crucial component of ecological risk assessment.
研究领域:
环境毒理学
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水生生态学
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分子生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2020
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IF 6.551
Min Xia,Xuedong Wang,Jiaqi Xu,Qiuhui Qian,Ming Gao,Huili Wang
The organophosphate flame retardant, tris (1-chloro-2-propyl) phosphate (TCPP), is ubiquitous in environmental matrices; however, there is a paucity of information concerning its systemic toxicity. Herein, we investigated the effects of TCPP exposure on zebrafish neurodevelopment and swimming behavior to elucidate the underlying molecular mechanisms of neurotoxicity. Under TCPP gradient concentration exposure, the hatching rates were declined by up to 33.3% in 72 hpf, and the malformation rates increased from 15% to 50%. Meanwhile, TCPP led to abnormal behaviors including decreased locomotive activity in the dark and slow/insensitive responses to sound and light stimulation of larvae. TCPP caused excessive apoptosis and ROS accumulation in early embryonic development, with hair cell defects and structural deformity of neuromast. Abnormal expression of neurodevelopment ( pax6a , nova1 , sox11b , syn2a , foxo3a and robo2 ) and apoptosis-related genes ( baxa , bcl2a and casp8 ) revealed molecular mechanisms regarding abnormal behavioral and phenotypic symptoms. Chronic TCPP exposure led to anxiety-like behavior and excessive panic, lower capacity for discrimination and risk avoidance, and conditioned place preference in adults. Social interaction tests demonstrated that long-term TCPP stress resulted in unsociable, eccentric, lonely and silent behaviors in adults. Zebrafish memory and cognitive function were severely reduced as concluded from T-maze tests. Potential mechanisms triggering behavioral abnormality were attributed to histopathological injury of diencephalon, abnormal changes in nerve-related genes at transcription and expression levels, and inhibited activity of AChE by TCPP stress. These findings provide an important reference for risk assessment and early warning to TCPP exposure, and offer insights for prevention/mitigation of pollutant-induced nervous system diseases.
研究领域:
毒理学
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神经科学
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环境科学
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发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Zhi-Feng Chen,Ying-Tao Tang,Xiao-Liang Liao,Jie-Ru Jiang,Zenghua Qi,Zongwei Cai
Organophosphate flame retardants (OPFRs) have been widely used in consumer products to prevent fire spread. However, once released into the atmospheric environment, they may accumulate in humans and undergo metabolic transformation and excretion by urine. In order to clarify the human exposure to OPFRs, a quick, easy, cheap, effective, rugged, and safe method for the simultaneous determination of urinary OPFRs and their metabolites by ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry was developed. After the optimization by a single-factor or orthogonal experiment, the satisfactory recovery (87.8–119%), matrix effect (−8.88–9.29%), method quantitation limit (3.66–159 ng/L), and inter-day repeatability (1.24 − 10.6%) of most analytes were achieved in artificial urine samples. Based on a monitoring test by the developed method, we propose that urinary bis(1-chloro-2-propyl) phosphate and di- p -cresyl phosphate could be used to trace human exposure to tris(1-chloro-2-propyl) phosphate and tricresyl phosphate, respectively. Most importantly, this is the first study to reveal that 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP) was dominantly presented in its conjugated form rather than its free form in urine ( p = 0.037). Overall, the obtained results contribute a relatively rapid method to help conduct large-scale urine monitoring for revealing the human exposure and risk of OPFRs.
研究领域:
分析化学
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环境科学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
·
IF 4.4
Huiyuan Zhang,Quanbin Li,Yaxing Li,Jianhua Guan,Kaidi Li,Yunlong Chen
Background: Atopic dermatitis (AD) is among the most frequently encountered skin diseases, bothering a considerable number of patients. Today, corticosteroids and antihistamines are among the numerous drugs applied for the therapy of AD. However, lengthy use of them contributes to side effects, such as physiological changes in skin. As an alternative and supplementary therapy, traditional Chinese medicine has become a trend for AD treatment. Huang-Lian-Jie-Du decoction (HLJDD), a renowned herbal formula has been employed to treat inflammatory diseases such as AD. However, its role in regulating immunity in AD remains unclear. The object of this study was to elucidate the efficacy of HLJDD and reveal the implicit mechanism from an immunological perspective in AD-like mice.Methods: In brief, 1-chloro-2,4-dinitrobenzene (DNCB) for the sensitization phase (1% DNCB) and stimulation phase (1.5% DNCB) were applied for BALB/c mice. HLJDD and dexamethasone (DXMS) were administered orally to the mice. Mice skin and spleens were collected to evaluate the efficacy of HLJDD. 16S rRNA sequencing was applied to evaluate the commensal microbiota changes in skin and fecal. In vitro, spleen CD4+ T cells and bone marrow-derived mast cells (BMMCs) were co-cultured to explore the modulation of HLJDD in T helper (Th) cells phenotyping.Results: HLJDD showcased a substantial amelioration in skin through the upregulation of FLG, LOR, AQP3, and reducing scratching behaviors in AD-like mice, Also, the quantity of infiltrated mast cells (MCs), pruritus-related mRNA were decreased. In addition, the expression of OX40/OX40L was decreased by HLJDD, which was critical in Th-cell phenotyping. With the treatment of HLJDD, Th1/Th2 and Th17/Treg ratios in AD-like mice became balanced. The structure of commensal microbiota in AD-like mice was affected by HLJDD. HLJDD could also improve the imbalance of Th17/Treg in vitro.Conclusion: HLJDD could improve the symptoms of AD-like mice by alleviating the scratching behaviors via decreased Th2 and pruritus-related mRNA expression. HLJDD also enhanced the relative diversity of skin microbiota and changed the structure of intestinal microbiota. An in-depth study found that HLJDD could balance the ratio of Th1/Th2, Th17/Treg in AD-like mice, and Th17/Treg in vitro by regulating the OX40/OX40L signaling pathway.
研究领域:
免疫学
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皮肤病学
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中医
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Traditional Chinese Medicine
·
2023
·Vol. 43
·期 5
·887-896
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IF 2.6
Yiding ZHAO,Xiaoning YAN,Shanshan JIANG,Yong LIU,Chun DONG,Huiyan CHI,Chaoyi MAO
Objective To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) signalling pathway in mice and . Methods AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. BALB/c mice were divided into five groups: normal control, model control, cetirizine, low-, medium-, and high-dose of ZXAS. After ZXAS in-tervention, the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines. Immun-oglobulin E (IgE), interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP) were de-tected by Enzyme-linked immunosorbent assay (ELISA). The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor (GRPR), TRPV1, and TRPA1 by using immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. In addition, 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, ELISA, and Western blotting were conducted for analysis of primary dorsal root ganglia (DRG) neurons . Results ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score, number of scratching and epidermal thickness, accompanied by the de-creased IgE and Th2 inflammatory cytokines. ZXAS also supressed the mRNA and protein expression of GRPR, TRPV1, and TRPA1 in the spinal cord. The medicated sera of ZXAS decreased capsaicin-induced Ca influx and downregulated the expression of TRPV1, TRPA1, and phospholipase C in DRG neurons. Conclusions The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca2+ signals in neurons.
研究领域:
药理学
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免疫学
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神经科学
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皮肤病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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