| 1. |
|
|
| 2. |
|
|
| 3. |
- Hendriks, DFG, et al.
(författare)
-
Mechanisms of Chronic Fialuridine Hepatotoxicity as Revealed in Primary Human Hepatocyte Spheroids
- 2019
-
Ingår i: Toxicological sciences : an official journal of the Society of Toxicology. - : Oxford University Press (OUP). - 1096-0929. ; 171:2, s. 385-395
-
Tidskriftsartikel (refereegranskat)abstract
- Drug hepatotoxicity is often delayed in onset. An exemplar case is the chronic nature of fialuridine hepatotoxicity, which resulted in the deaths of several patients in clinical trials as preclinical studies failed to identify this human-specific hepatotoxicity. Conventional preclinical in vitro models are mainly designed to evaluate the risk of acute drug toxicity. Here, we evaluated the utility of 3D spheroid cultures of primary human hepatocytes (PHHs) to assess chronic drug hepatotoxicity events using fialuridine as an example. Fialuridine toxicity was only detectable after 7 days of repeated exposure. Clinical manifestations, including reactive oxygen species formation, lipid accumulation, and induction of apoptosis, were readily identified. Silencing the expression or activity of the human equilibrative nucleoside transporter 1 (ENT1), implicated in the mitochondrial transport of fialuridine, modestly protected PHH spheroids from fialuridine toxicity. Interference with the phosphorylation of fialuridine into the active triphosphate metabolites by silencing of thymidine kinase 2 (TK2) provided substantial protection, whereas simultaneous silencing of ENT1 and TK2 provided near-complete protection. Fialuridine-induced mitochondrial dysfunction was suggested by a decrease in the expression of mtDNA-encoded genes, which correlated with the onset of toxicity and was prevented under the simultaneous silencing of ENT1 and TK2. Furthermore, interference with the expression or activity of ribonucleotide reductase (RNR), which is critical to deoxyribonucleoside triphosphate (dNTP) pool homeostasis, resulted in selective potentiation of fialuridine toxicity. Our findings demonstrate the translational applicability of the PHH 3D spheroid model for assessing drug hepatotoxicity events which manifest only under chronic exposure conditions.
|
|
| 4. |
- Hilty, Florentine M., et al.
(författare)
-
Incorporation of Mg and Ca into Nanostructured Fe2O3 Improves Fe Solubility in Dilute Acid and Sensory Characteristics in Foods
- 2011
-
Ingår i: Journal of Food Science. - : Wiley. - 0022-1147 .- 1750-3841. ; 76:1, s. N2-N10
-
Tidskriftsartikel (refereegranskat)abstract
- Iron deficiency is one of the most common micronutrient deficiencies worldwide. Food fortification can be an effective and sustainable strategy to reduce Fe deficiency but selection of iron fortificants remains a challenge. Water-soluble compounds, for example, FeSO4, usually demonstrate high bioavailability but they often cause unacceptable sensory changes in foods. On the other hand, poorly acid-soluble Fe compounds, for example FePO4, may cause fewer adverse sensory changes in foods but are usually not well bioavailable since they need to be dissolved in the stomach prior to absorption. The solubility and the bioavailability of poorly acid-soluble Fe compounds can be improved by decreasing their primary particle size and thereby increasing their specific surface area. Here, Fe oxide-based nanostructured compounds with added Mg or Ca were produced by scalable flame aerosol technology. The compounds were characterized by nitrogen adsorption, X-ray diffraction, transmission electron microscopy, and Fe solubility in dilute acid. Sensory properties of the Fe-based compounds were tested in 2 highly reactive, polyphenol-rich food matrices: chocolate milk and fruit yoghurt. The Fe solubility of nanostructured Fe2O3 doped with Mg or Ca was higher than that of pure Fe2O3. Since good solubility in dilute acid was obtained despite the inhomogeneity of the powders, inexpensive precursors, for example Fe- and Ca-nitrates, can be used for their manufacture. Adding Mg or Ca lightened powder color, while sensory changes when added to foods were less pronounced than for FeSO4. The combination of high Fe solubility and low reactivity in foods makes these flame-made nanostructured compounds promising for food fortification.
|
|
| 5. |
- Hilty, Florentine M., et al.
(författare)
-
Iron from nanocompounds containing iron and zinc is highly bioavailable in rats without tissue accumulation
- 2010
-
Ingår i: Nature Nanotechnology. - 1748-3387 .- 1748-3395. ; 5:5, s. 374-380
-
Tidskriftsartikel (refereegranskat)abstract
- Effective iron fortification of foods is difficult, because water-soluble compounds that are well absorbed, such as ferrous sulphate (FeSO(4)), often cause unacceptable changes in the colour or taste of foods. Poorly water-soluble compounds, on the other hand, cause fewer sensory changes, but are not well absorbed. Here, we show that poorly water-soluble nanosized Fe and Fe/Zn compounds (specific surface area similar to 190 m(2) g(-1)) made by scalable flame aerosol technology have in vivo iron bioavailability in rats comparable to FeSO(4) and cause less colour change in reactive food matrices than conventional iron fortificants. The addition of Zn to FePO(4) and Mg to Fe/Zn oxide increases Fe absorption from the compounds, and doping with Mg also improves their colour. After feeding rats with nanostructured iron-containing compounds, no stainable Fe was detected in their gut wall, gut-associated lymphatics or other tissues, suggesting no adverse effects. Nanosizing of poorly water-soluble Fe compounds sharply increases their absorption and nutritional value.
|
|
| 6. |
- Hurrell, T, et al.
(författare)
-
Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis
- 2020
-
Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:4
-
Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease affects approximately one billion adults worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive disease and underlies the advancement to liver fibrosis, cirrhosis, and hepatocellular carcinoma, for which there are no FDA-approved drug therapies. We developed a hetero-cellular spheroid system comprised of primary human hepatocytes (PHH) co-cultured with crude fractions of primary human liver non-parenchymal cells (NPC) from several matched or non-matched donors, to identify phenotypes with utility in investigating NASH pathogenesis and drug screening. Co-culture spheroids displayed stable expression of hepatocyte markers (albumin, CYP3A4) with the integration of stellate (vimentin, PDGFRβ), endothelial (vWF, PECAM1), and CD68-positive cells. Several co-culture spheroids developed a fibrotic phenotype either spontaneously, primarily observed in PNPLA3 mutant donors, or after challenge with free fatty acids (FFA), as determined by COL1A1 and αSMA expression. This phenotype, as well as TGFβ1 expression, was attenuated with an ALK5 inhibitor. Furthermore, CYP2E1, which has a strong pro-oxidant effect, was induced by NPCs and FFA. This system was used to evaluate the effects of anti-NASH drug candidates, which inhibited fibrillary deposition following 7 days of exposure. In conclusion, we suggest that this system is suitable for the evaluation of NASH pathogenesis and screening of anti-NASH drug candidates.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Morgantini, C., et al.
(författare)
-
Liver macrophages regulate systemic metabolism through non-inflammatory factors
- 2019
-
Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:4, s. 445-459
-
Tidskriftsartikel (refereegranskat)abstract
- Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor-binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.
|
|
| 11. |
- Posada Urrutia, Mauricio, et al.
(författare)
-
Access to long-lived room temperature phosphorescence through auration of 2,1,3-benzothiadiazole
- 2024
-
Ingår i: Dalton Transactions. - : Royal Society of Chemistry. - 1477-9226 .- 1477-9234. ; 53:12, s. 5658-5664
-
Tidskriftsartikel (refereegranskat)abstract
- A series of 2,1,3-benzothiadiazole–Au(I)–L complexes have been synthesised, structurally characterised and investigated for their photophysical properties. These are the first organometallic Au(I) complexes containing a C–Au bond on the highly electron-deficient benzothiadiazole unit. The complexes exhibit solution-phase phosphorescence at room temperature, assigned to the intrinsic triplet state of the benzothiadiazole unit that is efficently populated through its attachment to gold. Comparison with routinely reported Au(I) complexes, which include intervening alkenyl linkers, suggests that previous assignments of their phosphorescence as 1π → π*(CCR) might be incomplete. Our observations affirm that, in addition to the heavy atom effect, breaking symmetry in the involved aryl motif may be of importance in controlling the luminescence properties.
|
|
