ENVIRONMENT INTERNATIONAL
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2022
·
IF 13.352
Chen Wang,Lingjun Zeng,Yeyong Li,Chongli Shi,Yi Peng,Ruolin Pan,Mengyan Huang,Susu Wang,Jin Zhang,Hui Li
As a major alternative to traditional brominated flame retardants (BFRs), decabromodiphenyl ethane (DBDPE) is widely used and has been commonly detected in various environmental media and organisms. Few previous studies have focused on DBDPE-induced locomotion neurotoxicity, and the exact molecular mechanisms and related health risks remain unclear. In this study, we first analyzed the locomotion indicators of nematodes following DBDPE exposure, demonstrated that DBDPE caused locomotion neurotoxicity, and identified that a series of the transthyretin (TTR)-like genes participated in the regulation of nematode motility by transcriptomic analysis, gene transcription validation and TTR-like mutant verification. Subsequently, this study demonstrated that DBDPE exacerbated amyloid-beta (Aβ) deposition by repressing TTR/TTR-like gene transcription based on Alzheimer’s disease (AD) model nematodes and human SH-SY5Y cells following DBDPE exposure and further revealed that DBDPE reduced the binding between TTR and Aβ by competing with the strand G region sites on the TTR/TTR-like protein, ultimately exacerbating Aβ deposition and the risk of AD. In short, our study demonstrated that DBDPE induced locomotion neurotoxicity and potential AD risks through intensifying Aβ deposition by inhibiting TTR/TTR-like proteins, providing reference support for risk management and policy formulation related to DBDPE and similarly structured novel BFRs.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meng You,Xinxin Zhang,Yanli Zhang,Jialu Sun,Qiuyan Sha,Mengdie Wang,Huaiyue Zhang,Di Shen,Yunlong Zhang,Ning Wang,Ying Liu,Yu Liu
Transthyretin (TTR), a human blood circulating protein, undergoes misfolding and fibrillation, leading to transthyretin amyloidosis (ATTR), such as amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN). While previous studies induced TTR fibrillation under acidic conditions, the role of mechanical shear stress raising from blood flow remains unclear. Herein, we explored how circular shear force affects TTR protein fibrillation using peristaltic pump as an in vitro model mimicking blood flow in pH-neutral buffer. We discovered that TTR mutant proteins causing ATTR-CM (e.g. V122I and WT) were more susceptible to shear force induced fibrillization than ATTR-PN mutant proteins (V30M). In contrast, such differential fibrillation propensity was not observed under the conventional acidic conditions measured by the turbidity assay. Transmission electron microscopy (TEM) revealed distinct fibril morphologies. The impact of mechanical stress on TTR protein fibrillization kinetics was examined according Poiseuille's law. Notably, shear-induced fibrillation was specific to circulation and less obvious under stirring or sonication conditions. Finally, the commercial kinetic stabilizers of TTR proteins Tafamidis and Diflunisal effectively inhibited fibrillation under shear stress. Together, our results highlight ATTR-CM mutants are sensitive to shear force mimicking blood circulation, implying differential etiologies between ATTR-CM and ATTR-PN.
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SENSORS AND ACTUATORS B-CHEMICAL
·
2017
·
IF 5.401
Yanying Wang,Fang Chen,Xiaoxue Ye,Tsunghsueh Wu,Kangbing Wu,Chunya Li
Dodecahedral gold nanocrystals (AuNCs) were synthesized by using a 1-(10-bromodecyl)-3-methylimidazolium bromide ionic liquid as functional monomer and protectant. AuNCs were self-assembled onto molybdenum disulfite (MoS 2 ) nanosheets to fabricate AuNCs/MoS 2 nanocomposite, which was drop-coated onto a glassy carbon electrode surface to generate an interface for transthyretin (TTR) immobilizing. With a similar chemical structure to thyroxine, tetrabromobisphenol A (TBBPA) was specifically recognized by transthyretin and the TTR/AuNCs/MoS 2 /GCE provides a sensing platform for TBBPA. Its sensing performance towards TBBPA was found significantly improved by the integration of AuNCs onto MoS 2 nanosheets. Three conditions for assay development, such as incubation time, incubation temperature, and pH value, were investigated and found the optimum conditions were 200 s, 35 °C, and pH 7.0 respectively. Under these conditions, the ratio [ R i = ( i 0 − i )/ i 0 ] between the photocurrent variation (△ i = i 0 − i ) and the original photocurrent ( i 0 ) is linearly related to the logarithm of TBBPA concentration ( c TBBPA ) from 0.1 nM to 1.0 μM. The linear relationship can be described by the following equation: R i = 0.09092 log c TBBPA (M) + 0.8976 (R = 0.993). The detection limit is calculated to be 0.045 nM (S/N = 3). The photoelectrochemical immunosensor was used to accurately determine TBBPA concentration in South-Lake spiked water samples.
研究领域:
分析化学
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环境科学
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生物医学工程
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高影响因子
CHEMOSPHERE
·
2019
·
IF 5.108
Quan Chi,Wenxiang Zhang,Lang Wang,Juan Huang,Ming Yuan,Huaming Xiao,Xian Wang
Brominated flame retardants (BFRs) are found at quantifiable levels in both humans and wildlife and may potentially cause a health risk. For BFRs and their derivatives, limited information regarding the relationship among the structure, binding affinity to the target protein and toxicity is currently available. In the present work, representative BFRs with different hydroxyl- or bromo-substituents, namely 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47), 3-hydroxy-2, 2′, 4, 4′-tetrabromodiphenyl ether (3-OH-BDE-47) and tetrabromobisphenol A (TBBPA), were selected to investigate the interactions with transthyretin (TTR) by electrospray ionization mass spectrometry (ESI-MS) and cytotoxicity on HepG2 cells. It was noted that BDE-47 had a weak binding affinity to TTR, while 3-OH-BDE-47 and TBBPA had a stronger binding affinity than BDE-47 and thyroxine (T4). Hence, 3-OH-BDE-47 and TBBPA could affect the binding of TTR with its native ligand T 4 by competitive binding to TTR, even at equal concentrations, which might be associated with BFR toxicity of endocrine disruption. Negative cooperativity was found for 3-OH-BDE-47 and TBBPA binding to TTR, similar to T 4 with a well-established negatively cooperative binding mechanism. The tendency of toxic effects on HepG2 cells for these three BFRs was, 3-OH-BDE-47 > TBBPA > BDE-47, and this order was in good agreement with the binding ability explored by ESI-MS experiments and molecular docking simulation. The observations obtained by this study demonstrate that the binding properties of these BFRs to TTR and their cytotoxicity are correlated with structure differentials and functional substituents.
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高影响因子
MOLECULES
·
2024
·Vol. 29
·期 21
·5023
·
IF 4.2
Xiaoding Lin,Ting Xu,Wenqi Hou,Xiaoyan Dong,Yan Sun
The deposition of amyloid β-protein (Aβ) in the brain is the main pathogenesis of Alzheimer’s disease (AD). The development of potent inhibitors against Aβ aggregation is one of the effective strategies to combat AD. Endogenous transthyretin (TTR) can inhibit Aβ fibrillization via hydrophobic interactions, but its weak inhibitory potency hinders its application in AD therapy. Here, different recombinant TTRs were designed by cationic surface charge engineering. Compared with TTR, all positively charged recombinant TTRs showed enhanced capability in inhibiting Aβ aggregation, especially the recombinant protein obtained by mutating the acidic amino acid in TTR to arginine (TTR-nR) exhibited excellent inhibitory effect. Among them, TTR-7R remarkably increased the inhibitory potency against Aβ, which could effectively inhibit Aβ40fibrillization at a very low concentration (0.5 μM). In addition, TTR-7R increased cultured cell viability from 62% to 89%, scavenged amyloid plaques in AD nematodes, and prolonged nematode lifespan by 5 d at 2 μM. Thermodynamic studies demonstrated that TTR-7R, enriching in positive charges, presented hydrophobic interactions and enhanced electrostatic interactions with Aβ40, leading to a significantly enhanced inhibitory capacity of TTR-7R. The research provided insights into the development of efficient recombinant protein inhibitors for AD treatment.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2020
·
IF 7.864
Kai Huang,Xiu Wang,Hongxing Zhang,Lingshuai Zeng,Xiu Zhang,Bingmao Wang,Yikai Zhou,Tao Jing
Exposure to thyroid-disrupting chemicals (TDCs) poses a great threat to human health. However, the screening and analysis of TDCs in environmental samples remain a tough work. In this study, we reported a structure-directed strategy for analyzing TDCs targeting transthyretin (TTR) based on molecular imprinting and chromatographic separation. The imprinted composites were prepared using l-thyroxine (T4) as a template and a tryptophan-like monomer screened from the amino acid library. The imprinted composites exhibited an adsorption capacity of 22.2 μmol g–1 for T4 and an imprinting factor of 2.1. Chromatographic testing was then conducted among 72 chemicals using the imprinted composites-packed column. High retention factors were observed for chemicals that were structurally similar to T4. The chromatographic results were compared with a data set of 45 chemicals with known activities toward TTR. The results suggested that chemicals can be distinguished as TTR binders and nonbinders by retention factors, with a predictive accuracy of more than 90%. Moreover, the retention factors of chemicals were highly correlated with the reported relative potencies obtained from TTR assays. Thus, screening of TTR-binding chemicals can be realized through this simple chromatographic method. The imprinted composites were applied for target analysis and nontarget analysis of TTR-binding chemicals in dust samples. Three new TTR binders were successfully identified and verified by this method. The combination of molecular imprinting and chromatography opens up a new approach for screening TDCs targeting TTR.
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高影响因子
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