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- Behr, A. C., et al.
(författare)
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Impairment of bile acid metabolism by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in human HepaRG hepatoma cells
- 2020
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 94, s. 1673-1686
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are man-made chemicals that are used for the fabrication of many products with water- and dirt-repellent properties. The toxicological potential of both substances is currently under debate. In a recent Scientific Opinion, the European Food Safety Authority (EFSA) has identified increased serum total cholesterol levels in humans as one major critical effect being associated with exposure to PFOA or PFOS. In animal studies, both substances induced a decrease of serum cholesterol levels, and the underlying molecular mechanism(s) for these opposed effects are unclear so far. In the present study, we examined the impact of PFOA and PFOS on cholesterol homoeostasis in the human HepaRG cell line as a model for human hepatocytes. Cholesterol levels in HepaRG cells were not affected by PFOA or PFOS, but both substances strongly decreased synthesis of a number of bile acids. The expression of numerous genes whose products are involved in synthesis, metabolism and transport of cholesterol and bile acids was strongly affected by PFOA and PFOS at concentrations above 10 mu M. Notably, both substances led to a strong decrease of CYP7A1, the key enzyme catalyzing the rate-limiting step in the synthesis of bile acids from cholesterol, both at the protein level and at the level of gene expression. Moreover, both substances led to a dilatation of bile canaliculi that are formed by differentiated HepaRG cells in vitro. Similar morphological changes are known to be induced by cholestatic agents in vivo. Thus, the strong impact of PFOA and PFOS on bile acid synthesis and bile canalicular morphology in our in vitro experiments may allow the notion that both substances have a cholestatic potential that is connected to the observed increased serum cholesterol levels in humans in epidemiological studies.
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- Godoy, Patricio, et al.
(författare)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
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Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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- Stoehlker, Th., et al.
(författare)
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APPA at FAIR : From fundamental to applied research
- 2015
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Ingår i: Nuclear Instruments and Methods in Physics Research Section B. - : Elsevier BV. - 0168-583X .- 1872-9584. ; 235, s. 680-685
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Tidskriftsartikel (refereegranskat)abstract
- FAIR with its intense beams of ions and antiprotons provides outstanding and worldwide unique experimental conditions for extreme matter research in atomic and plasma physics and for application oriented research in biophysics, medical physics and materials science. The associated research programs comprise interaction of matter with highest electromagnetic fields, properties of plasmas and of solid matter under extreme pressure, density, and temperature conditions, simulation of galactic cosmic radiation, research in nanoscience and charged particle radiotherapy. A broad variety of APPA-dedicated facilities including experimental stations, storage rings, and traps, equipped with most sophisticated instrumentation will allow the APPA community to tackle new challenges. The worldwide most intense source of slow antiprotons will expand the scope of APPA related research to the exciting field of antimatter.
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- Gorda, O., et al.
(författare)
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Ion-optical design of CRYRING@ESR
- 2015
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Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T166
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Tidskriftsartikel (refereegranskat)abstract
- In 2012 the CRYRING storage ring was delivered from Stockholm to Darmstadt as a part of the Swedish in-kind contribution to the FAIR project. The ring lattice has been slightly changed for optimal injection and to provide additional space for experiment equipment. For the injection from the experimental storage ring (ESR), a new transfer line has been designed. The local injector line has been significantly modified compared to the previous one in Stockholm taking into account the geometry of the existing GSI building. In this paper we present the ion-optical properties of CRYRING@ESR after the described modifications. Single-turn injection from the ESR and multi-turn injection from the local injector are discussed. Ion-optical calculations of fast and slow extraction from CRYRING are also presented. The closed orbit correction scheme is considered taking into account the future arrangement of the beam position monitors and correction magnets. Based on the results of the calculations the requirements for the magnet alignment are finally discussed.
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| 8. |
- Lestinsky, M., et al.
(författare)
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CRYRING@ESR: present status and future research
- 2015
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Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T166
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Tidskriftsartikel (refereegranskat)abstract
- The former storage ring CRYRING has been shipped from the Manne Siegbahn Laboratory in Stockholm to Darmstadt as a Swedish in-kind contribution to FAIR. At its new location downstream of ESR all ion species presently accessible in ESR can be transferred to CRYRING, in which ions with rigidities between 1.44 and 0.054 Tm can be stored. The original Swedish layout has been modified by reconfiguring the sequence of straight sections and by slightly increasing the circumference to ESR/2. Ions can be injected from ESR or from an independent 300 keV/u RFQ test injector. The instrumentation of the ring includes an RF drift tube system for acceleration and deceleration (1 T s(-1), with a possibility for an upgrade to 7 T s(-1)), electron cooling, a free experimental section, and both fast and slow extraction of ions. We report on the present progress of this project, give a prospective timeline, and summarize the new research which will be enabled by this project. First beam for commissioning of the storage ring is expected for 2015, final bakeout to restore ultrahigh vacuum conditions in 2016 and ion beams injected through ESR in similar to 2017.
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| 9. |
- Gluck, J., et al.
(författare)
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The Food Contaminants Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis Structure-Dependently in the Human Hepatoma Cell Line HepaRG
- 2021
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Ingår i: Foods. - : MDPI AG. - 2304-8158. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Pyrrolizidine alkaloids (PAs) are a group of secondary plant metabolites being contained in various plant species. The consumption of contaminated food can lead to acute intoxications in humans and exert severe hepatotoxicity. The development of jaundice and elevated bile acid concentrations in blood have been reported in acute human PA intoxication, indicating a connection between PA exposure and the induction of cholestasis. Additionally, it is considered that differences in toxicity of individual PAs is based on their individual chemical structures. Therefore, we aimed to elucidate the structure-dependent disturbance of bile acid homeostasis by PAs in the human hepatoma cell line HepaRG. A set of 14 different PAs, including representatives of all major structural characteristics, namely, the four different necine bases retronecine, heliotridine, otonecine and platynecine and different grades of esterification, was analyzed in regard to the expression of genes involved in bile acid synthesis, metabolism and transport. Additionally, intra- and extracellular bile acid levels were analyzed after PA treatment. In summary, our data show significant structure-dependent effects of PAs on bile acid homeostasis. Especially PAs of diester type caused the strongest dysregulation of expression of genes associated with cholestasis and led to a strong decrease of intra- and extracellular bile acid concentrations.
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| 10. |
- Krebs, Alice, et al.
(författare)
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Template for the Description of Cell-Based Toxicological Test Methods to Allow Evaluation and Regulatory Use of the Data
- 2019
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 36:4, s. 682-699
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests.
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