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1.
Anne-Margarethe Enge Florian Kaltner Christoph Gottschalk Albert Braeuning Stefanie Hessel-Pras 《International journal of molecular sciences》2021,22(8)
1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na+/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics. 相似文献
2.
介绍了用单根光纤传输测量信号和功率信号的光功率推动液体压力测量仪及其工作原理。该仪器以电容式压力传感器的δ元件作为压力检测元件,采用低功耗前置器电路和简单直杆结构,实现了便携式测量。测量范围为O~100kPa,精度为O.01kPa。 相似文献
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在顺丁橡胶后处理生产线上,用处行开发的新型交替运输取代原有运输机。试用结果表明,采用新型交替运输机后,胶块的导向到位率由70%提高到98%;减轻了劳动强度,提出了生产开工率,运行周期可达1a以上。 相似文献
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简要叙述了研究电动机械负载模拟系统的必要性,介绍了国外目前在电动机械负载模拟系统方面的一些情况及该系统的一些典型控制策略,并分析了它们的优缺点,最后进行了总结. 相似文献
7.
液压支架设计及制作过程中的优化 总被引:1,自引:1,他引:0
主要介绍液压支架设计和使用过程中局部结构上的缺陷,经过优化设计从而实现安装、拆卸方便,维护量减少,检修便利。制作过程中部分零部件改变工艺过程实现通用化、系列化。 相似文献
8.
Amir Mohammadzadeh Pter P. Lakatos Mihly Balogh Ferenc Zdor Dvid rpd Kardi Zoltn S. Zdori Kornl Kirly Anna Rita Galambos Szilvia Barsi Pl Riba Sndor Benyhe Lszl Kles Tams Tbi va Szk Laszlo G. Harsing Jr. Mahmoud Al-Khrasani 《International journal of molecular sciences》2021,22(5)
The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. 相似文献
9.
Eleni Papakonstantinou Dimitrios Vlachakis Trias Thireou Panayiotis G. Vlachoyiannopoulos Elias Eliopoulos 《International journal of molecular sciences》2021,22(6)
Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy. 相似文献
10.
James I. Mitchell-White Thomas Stockner Nicholas Holliday Stephen J. Briddon Ian D. Kerr 《International journal of molecular sciences》2021,22(6)
The five members of the mammalian G subfamily of ATP-binding cassette transporters differ greatly in their substrate specificity. Four members of the subfamily are important in lipid transport and the wide substrate specificity of one of the members, ABCG2, is of significance due to its role in multidrug resistance. To explore the origin of substrate selectivity in members 1, 2, 4, 5 and 8 of this subfamily, we have analysed the differences in conservation between members in a multiple sequence alignment of ABCG sequences from mammals. Mapping sets of residues with similar patterns of conservation onto the resolved 3D structure of ABCG2 reveals possible explanations for differences in function, via a connected network of residues from the cytoplasmic to transmembrane domains. In ABCG2, this network of residues may confer extra conformational flexibility, enabling it to transport a wider array of substrates. 相似文献