SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Qiaoqiao Wang,Jingjing Miao,Anran Zhao,Manni Wu,Luqing Pan
Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non‑tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non‑tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.
研究领域:
环境毒理学
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分子生物学
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水生生态学
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产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2022
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IF 4.622
Xiaojing Li,Ruichen Bai,Yichen Bai,Xu Shi,Yuhong Yang,Shiwen Xu
Acetochlor is a high-volume herbicide whose widespread use threatens ecosystems and affects aquaculture. Apoptosis and autophagy are important causes of hepatotoxicity caused by toxicants, which can be mediated by oxidative stress and the inhibition of PPAR/RXR pathway. However, the mechanism of acetochlor on fish hepatocyte damage still needs to be further investigated. Therefore, we treated the Ctenopharyngodon idella hepatic cell line (L8824 cells) with different concentrations (10, 20, and 40 μM) of acetochlor and/or ROS scavenger NAC (1 mM) for 24 h. The results showed that acetochlor decreased the cell viability in a dose-dependent manner. AO/EB staining and flow cytometry verified the increased apoptotic rates . Quantitative analysis of gene expression levels or protein expression levels displayed that the expression levels of Beclin1, P62, LC3B, BAX, and cleaved Casp3 were increased, and the expression of BCL2 was reduced. Besides, we detected the increased ROS contents and decreased PPAR/RXR pathway expressions after acetochlor treatment. The clearance of ROS alleviated the inhibition of the PPAR/RXR pathway and lightened apoptosis and autophagy under acetochlor stress. Overall, these results revealed that acetochlor exposure triggered BCL2/BAX/Casp3-cascaded apoptosis and Beclin1-dependent autophagy through ROS-mediated PPAR/RXR inhibition. The results partially explain the toxicological mechanism of acetochlor and provide targets for the development of its antidote.
研究领域:
毒理学
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细胞生物学
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环境科学
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水产养殖
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产品关联
DOI
PubMed
高影响因子
MOLECULES
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2012
·Vol. 17
·期 9
·10994-11009
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IF 2.386
Yunxia Zhang,Yunlan Li,Qingshan Li
The specific aims of this study were to evaluate the inhibition effect on CYP3A of di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT), a tin-based complex with high antitumor activity, and the probable mechanism(s) of this action. Adult male SD rats were treated separately with natural saline (NS), lipopolysaccharide (LPS, 5 mg/kg), DBDCT (1.25, 2.5 and 5.0 mg/kg) intraperitoneally for 2 days after induction of CYP3A with dexamethasone (DEX, 100 mg/kg) for 4 days. Western blot analysis and fluorescent quantitation PCR (FQ-PCR) were conducted to determine the changes in expression of CYP3A, PXR, CAR and RXR. The biological accumulation of DBDCT and total Sn were determined by high-performance liquid chromatography (HPLC) and atomic fluorescence spectrometry (AFS). CYP450 content and CYP3A activities were significantly inhibited (p< 0.05) in DBDCT-treated rats compared with the control group, as was the expression of CYP3A (p< 0.05) at both protein and mRNA levels. In DBDCT-treated groups, the expression of PXR protein and mRNA increased, while the expression of CAR decreased. The biological accumulation of DBDCT and Sn in rat livers treated with DBDCT was high. The accumulation of DBDCT and Sn due to the inhibition of CYP3A may be involved in the mechanism of toxicity of DBDCT in rat liver.Keywords:cytochrome P450 3A (CYP3A);di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT);inhibition;rat
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2024
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IF 2.9
Yifei Shen,Jie Liu,Bingyi Yao,Yuanjin Zhang,Shengbo Huang,Chenmeizi Liang,Junze Huang,Yu Tang,Xin Wang
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, which can cause serious complications and gradually increase the mortality rate. However, the effects of NAFLD on drug-metabolizing enzymes and transporters remain unclear, which may cause some confusion regarding patient medication. In this study, a NAFLD rat model was constructed by feeding rats with methionine and choline deficiency diets for 6 weeks, and the mRNA and protein levels of drug-metabolizing enzymes and transporter were analyzed by real-time fluorescent quantitative PCR and Western blot, respectively. The activity of drug-metabolizing enzymes was detected by cocktail methods. In the NAFLD rat model, the mRNA expression of phase I enzymes, phase II enzymes, and transporters decreased. At the protein level, only CYP1A1, CYP1B1, CYP2C11, and CYP2J3 presented a decrease. In addition, the activities of CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP3A2, UGT1A1, UGT1A3, UGT1A6, and UGT1A9 decreased. These changes may be caused by the alteration of FXR, HNF4α, LXRα, LXRβ, PXR, and RXR. In conclusion, NAFLD changes the expression and activity of hepatic drug-metabolizing enzymes and transporters in rats, which may affect drug metabolism and pharmacokinetics. In clinical medication, drug monitoring should be strengthened to avoid potential risks.
研究领域:
药理学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Han Xiaoying,Zhang Yi,Qiao Ou,Ji Haixia,Zhang Xinyu,Wang Wenzhe,Li Xia,Wang Juan,Li Dekun,Ju Aichun,Liu Changxiao,Gao Wenyuan
Yiqi Fumai lyophilized injection (YQFM) is the recombination of Sheng mai san (SMS).YQFM has been applied clinically to efficaciously and safely treat chronic heart failure (CHF). However, the mechanism of YQFM is still not fully elucidated. The purpose of our study was to investigate the protective mechanism of YQFM against abdominal aortic coarctation (AAC) in rats by proteomic methods. After YQFM treatment, the cardiac function were obviously meliorated. One hundred and fifty-seven important differentially expressed proteins (DEPs) were identified, including 109 in model rat compared with that in control rat (M:C) and 48 in YQFM-treated rat compared with that in model rat (T:M) by iTRAQ technology to analyze the proteomic characteristics of heart tissue. Bioinformatics analysis showed that DEPs was mainly involved in the body’s energy metabolism and was closely related to oxidative phosphorylation. YQFM had also displayed efficient mitochondrial dysfunction alleviation properties in hydrogen peroxide (H2O2)-induced cardiomyocyte damage by Transmission Electron Microscope (TEM), Metabolic assay, and Mitotracker staining. What’s more, the levels of total cardiomyocyte apoptosis were markedly reduced following YQFM treatment. Furthermore, Western blot analysis showed that the expressions of peroxisome proliferator activated receptor co-activator-1α(PGC-1α) (p < 0.01 or p < 0.001), perixisome proliferation-activated receptor alpha (PPAR-α) (p < 0.001)and retinoid X receptor alpha (RXR-α) were upregulated (p < 0.001), PGC-1α as well as its downstream effectors were also found to be upregulated in cardiomyocytes after YQFM treatment(p < 0.001).These results provided evidence that YQFM could enhance mitochondrial function of cardiomyocytes to play a role in the treatment of CHF by regulating mitochondrial biogenesis-related proteins.
研究领域:
心脏病学
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药理学
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蛋白质组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
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2022
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IF 4.772
Zhang Yuying,Guo Kaimin,Zhang Pengfei,Zhang Mengying,Li Xiaoqiang,Zhou Shuiping,Sun He,Wang Wenjia,Wang Hui,Hu Yunhui
It is clinical reported that YangXue QingNao Wan (YXQNW) combined with donepezil can significantly improve the cognitive function of AD patients. However, the mechanism is not clear. A network pharmacology approach was employed to predict the protein targets and affected pathways of YXQNW in the treatment of AD. Based on random walk evaluation, the correlation between YXQNW and AD was calculated; while a variety of AD clinical approved Western drugs were compared. The targets of YXQNW were enriched and analyzed by using the TSEA platform and MetaCore. We proved that the overall correlation between YXQNW and AD is equivalent to clinical Western drugs, but the mechanism of action is very different. Firstly, YXQNW may promote cerebral blood flow velocity by regulating platelet aggregation and the vasoconstriction/relaxation signal pathway, which has been verified by clinical meta-analysis. Secondly, YXQNW may promote Aβ degradation in the liver by modulating the abnormal glucose and lipid metabolisms via the adiponectin-dependent pathway, RXR/PPAR-dependent lipid metabolism signal pathway, and fatty acid synthase activity signal pathway. We also verified whether YXQNW indeed promoted Aβ degradation in hepatic stellate cells. This work provides a novel scientific basis for the mechanism of YXQNW in the treatment of AD.
研究领域:
药理学
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神经病学
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临床研究
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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