CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
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2017
·Vol. 33
·期 3
·378-383
·
IF 1.024
Liang Guangping,Chung Tseyu,Guo Jinhua,Zhang Rongrong,Xü Wei,Tzen Jason T. C.,Jiang Renwang
Some cinobufagin oxime ether derivatives as potential Na + /K + -ATPase inhibitors were synthesized by following the side chain of istaroxime. These compounds inhibit Na + /K + -ATPase in a dose-dependent manner. Compound 3 c with an oxyethylamine side chain that is the same as that of istaroxime showed the most potent inhibition, which was stronger than compound 3 a with only hydroxyoxime moiety at C-3 and compound 3 b with a methylated hydroxyoxime moiety. Molecular docking was used to explore the binding modes of the target compounds with Na + /K + -ATPase, which suggested that the longer ethyl amine group at C-3 oxime moiety of compound 3 c could make stronger interaction with Na + /K + -ATPase via intermolecular charge-charge and H-bond interaction as compared with other derivatives.
研究领域:
药理学
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有机化学
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计算生物学
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DOI
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-9
·
IF 5.228
Wang Jun,Zhu Xuexia,Huang Xin,Gu Lei,Chen Yafen,Yang Zhou
Obscure puffer Takifugu obscurus , a species of anadromous fish, experiences several salinity changes in its lifetime. Cadmium (Cd) is a toxic heavy metal that can potentially induce oxidative stress in fish. The present study aimed to detect the combined effects of Cd (0, 5, 10, 20 and 50 mg L −1 ) and salinity (0, 15 and 30 ppt) on juvenile T. obscurus . Results showed the juveniles could survive well under different salinities; however, with Cd exposure, the survival rates significantly decreased at 0 and 30 ppt. At 15 ppt, tolerance to Cd increased. Cd exposure clearly induced oxidative stress and the responses among different tissues were qualitatively similar. Salinity acted as a protective factor which could reduce the reactive oxygen species and malondialdehyde levels. In addition, salinity could enhance the antioxidant defense system, including superoxide dismutase, catalase and glutathione. Na + /K + –ATPase activity significantly decreased under Cd exposure in gill, kidney and intestine. These findings indicated that Cd could moderate the adaptability of juvenile T. obscurus to high salinity and low salinity played a protective role upon Cd exposure. Thus, the role of salinity should be considered when evaluating the effect of heavy metals on anadromous and estuarine fishes.
研究领域:
环境毒理学
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鱼类生理学
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产品关联
DOI
PubMed
高影响因子
BIOPHYSICAL JOURNAL
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2021
·
IF 4.033
Erika Aloi,Jin-Hua Guo,Rita Guzzi,Ren-Wang Jiang,Lucy Kate Ladefoged,Derek Marsh,Mikael Esmann,Rosa Bartucci,Natalya U. Fedosova
Spin labels based on cinobufagin, a specific inhibitor of the Na,K-ATPase, have proved valuable tools to characterize the binding site of cardiotonic steroids (CTSs), which also constitutes the extracellular cation pathway. Because existing literature suggests variations in the physiological responses caused by binding of different CTSs, we extended the original set of spin-labeled inhibitors to the more potent bufalin derivatives. Positioning of the spin labels within the Na,K-ATPase site was defined and visualized by molecular docking. Although the original cinobufagin labels exhibited lower affinity, continuous-wave electron paramagnetic resonance spectra of spin-labeled bufalins and cinobufagins revealed a high degree of pairwise similarity, implying that these two types of CTS bind in the same way. Further analysis of the spectral lineshapes of bound spin labels was performed with emphasis on their structure (PROXYL vs. TEMPO), as well as length and rigidity of the linkers. For comparable structures, the dynamic flexibility increased in parallel with linker length, with the longest linker placing the spin label at the entrance to the binding site. Temperature-related changes in spectral lineshapes indicate that six-membered nitroxide rings undergo boat-chair transitions, showing that the binding-site cross section can accommodate the accompanying changes in methyl-group orientation. D 2 O-electron spin echo envelope modulation in pulse-electron paramagnetic resonance measurements revealed high water accessibilities and similar polarity profiles for all bound spin labels, implying that the vestibule leading to steroid-binding site and cation-binding sites is relatively wide and water-filled.
研究领域:
生物物理学
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药理学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2013
·Vol. 29
·期 12
·1460-1470
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IF 2.708
Mingbao Feng,Ruijuan Qu,Ying Li,Zhongbo Wei,Zunyao Wang
Hexabromobenzene (HBB) is a novel brominated flame retardant (BFR) with ample evidence of its ubiquitous existence in the aquatic ecosystems. However, to date, the toxicological effects of this BFR on fish have been inadequately researched. The present study was conducted, based on an in vivo model, to investigate HBB-induced biochemical changes in liver and gill tissues of Carassius auratus after medium-term exposure to different concentrations (10, 150, and 300 mg/kg) for 7, 14, and 25 days. Oxidative stress was evoked evidently for the prolonged exposure, demonstrated by significant inhibition in antioxidant enzymes activities including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, and a decrease in reduced glutathione level, as well as simultaneous elevation in malondialdehyde content. Moreover, Na + , K + -ATPase activity, and protein level were remarkably reduced in fish tissues. Based on the integrated biomarker response, the toxic potency in each treatment was distinguished, and the more severe stress was mainly noted with the increasing concentrations and the extending durations. It was also observed that liver exhibited more pronounced alterations in biochemical parameters than gill, probably indicating the vulnerability of liver to HBB-triggered oxidative stress. Taken together, the results of this study clearly showed that HBB was capable of inducing oxidative stress and inhibiting Na + , K + -ATPase activity in different tissues of C. auratus after medium-term exposure. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1460–1470, 2014.
研究领域:
环境毒理学
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水生生态学
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生物化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2017
·
IF 2.896
Cheng-yuan Li,Mei Su,Yun-yi Yan,Lin Zhou,Lu-yao Ao,Wei-rong Fang,Yun-man Li
1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008)，a novel and potent potassium-competitive acid blocker for the treatment of acid secretion related diseases, has not been reported previously. In this study, we demonstrated that KFP-H008 inhibits basal acid secretion, 2-deoxy- D -glucose- (2DG-) stimulated gastric acid secretion in rats. KFP-H008 blocked histamine-stimulated acid secretion in rats and heidenhain pouch dogs and reversed acid output in isolated gastric perfusion under histamine stimulation. In all the animal experiments, KFP-H008 exerted a more effective, potent and longer-lasting inhibitory action in comparison with lansoprazole , a proton pump inhibitor (PPI) commonly used in clinic. KFP-H008 inhibited H + -K + -ATPase activity both at pH 6.5 and pH 7.5, and was unaffected by pH. The inhibitory action was reversible and was achieved in a K + -competitive manner. Furthermore, KFP-H008 did not affect Na + -K + -ATPase activity, thus exhibiting high selectivity, which is different from PPIs. In all, KFP-H008, a novel potassium-competitive acid blocker, may provide new option for the patients with acid-related diseases and provide longer-lasting inhibitory action than drugs commonly used in clinical treatment.
研究领域:
药理学
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胃肠病学
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药物开发
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产品关联
DOI
PubMed
高影响因子
TECHNOLOGY IN CANCER RESEARCH & TREATMENT
·
2021
·
IF 3.399
Yayan Yang,Qian Feng,Chuanfeng Ding,Wei Kang,Xiufeng Xiao,Yongsheng Yu,Qian Zhou
Although Epirubicin (EPI) is a commonly used anthracycline for the treatment of breast cancer in clinic, the serious side effects limit its long-term administration including myelosuppression and cardiomyopathy. Nanomedicines have been widely utilized as drug delivery vehicles to achieve precise targeting of breast cancer cells. Herein, we prepared a DSPE-PEG nanocarrier conjugated a peptide, which targeted the breast cancer overexpression protein Na+/K+ ATPase α1 (NKA-α1). The nanocarrier encapsulated the EPI and grafted with the NKA-α1 targeting peptide through the click reaction between maleimide and thiol groups. The EPI was slowly released from the nanocarrier after entering the breast cancer cells with the guidance of the targeting NKA-α1 peptide. The precise and controllable delivery and release of the EPI into the breast cancer cells dramatically inhibited the cells proliferation and migration in vitro and suppressed the tumor volume in vivo. These results demonstrate significant prospects for this nanocarrier as a promising platform for numerous chemotherapy drugs.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
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DOI
PubMed
高影响因子
FEBS Journal
·
2018
·Vol. 285
·期 12
·2292-2305
·
IF 4.53
Jin-Hua Guo,Ren-Wang Jiang,Jacob Lauwring Andersen,Mikael Esmann,Natalya U. Fedosova
The information obtained from crystallized complexes of the Na + ,K + -ATPase with cardiotonic steroids (CTS) is not sufficient to explain differences in the inhibitory properties of CTS such as stereoselectivity of CTS binding or effect of glycosylation on the preference to enzyme isoforms. The uncertainty is related to the spatial organization of the hydrophilic cavity at the entrance of the CTS-binding site. Therefore, there is a need to supplement the crystallographic description with data obtained in aqueous solution, where molecules have significant degree of flexibility. This work addresses the applicability of the electron paramagnetic resonance (EPR) method for the purpose. We have designed and synthesized spin-labeled compounds based on the cinobufagin steroid core. The length of the spacer arms between the steroid core and the nitroxide group determines the position of the reporting group (N-O) confined to the binding site. High affinity to Na + ,K + -ATPase is inferred from their ability to inhibit enzymatic activity. The differences between the EPR spectra in the absence and presence of high ouabain concentrations identify the signature peaks originating from the fraction of the spin labels bound within the ouabain site. The degree of perturbations of the EPR spectra depends on the length of the spacer arm. Docking of the compounds into the CTS site suggests which elements of the protein structure might be responsible for interference with the spin label (e.g., steric clashes or immobilization). Thus, the method is suitable for gathering information on the cavity leading to the CTS-binding site in Na + ,K + -ATPase in all conformations with high affinity to CTS .
研究领域:
生物化学
·
药理学
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DOI
高影响因子
ENVIRONMENTAL POLLUTION
·
2023
·
IF 8.9
Lin Zhang,Yin Lin,An-Xin Lu,Jun-Xia Liu,Jing Li,Chong-Huai Yan
Today's women of childbearing age with a history of high lead (Pb) exposure in childhood have large Pb body burdens, which increases Pb release during pregnancy by promoting bone Pb mobilisation. The purpose of this study was to investigate the metabolic mechanisms underlying bone Pb mobilisation and explore the bone metabolism-related pathways during pregnancy. Drinking water containing 0.05% sodium acetate or Pb acetate was provided to weaned female rats for 4 weeks followed by a 4-week washout period, and then rats were co-caged with healthy males of the same age until pregnancy. Blood and bone tissues of the female rats were collected at gestational day (GD) 3 (early pregnancy), GD 10 (middle pregnancy), and GD 17 (late pregnancy), respectively. Pb and calcium concentrations, biomarkers for bone turnover, bone microstructure, serum metabolomics, and metabolic indicators were intensively analyzed. The results demonstrated that pre-pregnancy Pb exposure elevated blood lead levels (BLLs) at GD17, accompanied by a negative correlation between BLLs and trabecular bone Pb levels. Meanwhile, Pb-exposed rats had low bone mass and aberrant bone architecture with a larger number of mature osteoclasts (OCs) compared to the control group. Moreover, the metabolomics uncovered that Pb exposure caused mitochondrial dysfunction, such as enhanced oxidative stress and inflammatory response, and suppressed energy metabolism. Additionally, the levels of ROS , MDA, IL-1β, and IL-18 involved in redox and inflammatory pathways of bone tissues were significantly increased in the Pb-exposed group, while antioxidant SOD and energy metabolism-related indicators including ATP levels, Na + -K + -ATPase, and Ca 2+ -Mg 2+ -ATPase activities were significantly decreased. In conclusion, pre-pregnancy Pb exposure promotes bone Pb mobilisation and affects bone microstructure in the third trimester of pregnancy, which may be attributed to OC activation and mitochondrial dysfunction.
研究领域:
毒理学
·
生殖生物学
·
代谢组学
·
骨生物学
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产品关联
DOI
PubMed
高影响因子
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