| 1. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 2. |
- de Ávila, Renato Ivan, et al.
(författare)
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A proteomics dataset capturing myeloid cell responses upon cellular exposure to fungicides, adjuvants and fungicide formulations
- 2023
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 46
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells are the sentinels of the immune system, linking the innate and adaptive immune response. Myeloid and dendritic cell models have been successfully used in in vitro approaches to predict adverse outcomes such as skin sensitization. We here exposed a well-characterized human dendritic cell-like cell line to agricultural chemicals, including fungicide formulations, active ingredients, adjuvants and defined mixtures for 24 h to profile induced changes on protein levels. Cell pellets were harvested and prepared for bottom-up label-free analysis with peptide separation on an EASY-nano LC system 1200 coupled online with a QExactive HF-X mass spectrometer with data-dependent acquisition (DDA). The raw data files and processed quantitative data have been deposited to ProteomeXchange with the data identification number PXD034624 and are described here. The data in this article may serve as a resource for researchers interested in e.g. human toxicology, immunology, cell biology and pharmacology.
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| 3. |
- de Ávila, Renato Ivan, et al.
(författare)
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Adjuvants in fungicide formulations can be skin sensitizers and cause different types of cell stress responses
- 2022
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Ingår i: Toxicology Reports. - : Elsevier BV. - 2214-7500. ; 9, s. 2030-2041
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Tidskriftsartikel (refereegranskat)abstract
- New approaches based on -omics technologies can identify biomarkers and processes regulated in response to xenobiotics, and thus support toxicological risk assessments. This is vital to meet the challenges associated with “cocktail effects”, i.e. combination effects of chemicals present simultaneously in a product, our environment, and/or our body. For plant protection products (PPPs), investigations largely focus on active ingredients such as herbicides and fungicides. In this study, we have analyzed agricultural chemicals, two surfactants (poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-[2,4,6-tris(1-phenylethyl)phenoxy]-, ammonium salt, POL; N,N-dimethylcapramide, NND), and one preservative, 1,2-benzisothiazol-3(2 H)-one (BEN) used as adjuvants in PPPs, and further three fungicide PPPs, Proline EC 250, Shirlan, Folicur Xpert, containing the adjuvants, and other major individual constituents (fluazinam (FLU), prothioconazole (PRO), tebuconazole (TEB)) as well as defined mixtures (“mixes”) thereof using several in vitro approaches. All investigated single agricultural chemicals were predicted as skin sensitizers using an in vitro transcriptomic assay based on a dendritic cell model. For selected chemicals and mixes, also skin sensitization potency was predicted. The preservative BEN induced significant changes in cytokine secretion and dendritic cell activation marker CD86 expression. The surfactant NND changed cytokine secretion only and the POL only affected CD86 expression. Proteomic analyses revealed unique response profiles for all adjuvants, an oxidative stress pattern response in BEN-treated cells, and differentially abundant proteins associated with cholesterol homeostasis in response to POL. In summary, we find responses to agricultural chemicals and products consistent with the dendritic cell model reacting to chemical exposure with oxidative stress, ER stress, effects on autophagy, and metabolic changes especially related to cholesterol homeostasis. After exposure to certain mixes, novel proteins or transcripts were differentially expressed and these were not detected for any single constituents, supporting the occurrence of cocktail effects. This indicates that all chemicals in a PPP can contribute to the toxicity profile of a PPP, including their skin sensitizing/immunotoxic properties.
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| 4. |
- Forreryd, Andy, et al.
(författare)
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From genome-wide arrays to tailor-made biomarker readout – Progress towards routine analysis of skin sensitizing chemicals with GARD
- 2016
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333. ; 37, s. 178-188
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Tidskriftsartikel (refereegranskat)abstract
- Allergic contact dermatitis (ACD) initiated by chemical sensitizers is an important public health concern. To prevent ACD, it is important to identify chemical allergens to limit the use of such compounds in various products. EU legislations, as well as increased mechanistic knowledge of skin sensitization have promoted development of non-animal based approaches for hazard classification of chemicals. GARD is an in vitro testing strategy based on measurements of a genomic biomarker signature. However, current GARD protocols are optimized for identification of predictive biomarker signatures, and not suitable for standardized screening. This study describes improvements to GARD to progress from biomarker discovery into a reliable and cost-effective assay for routine testing. Gene expression measurements were transferred to NanoString nCounter platform, normalization strategy was adjusted to fit serial arrival of testing substances, and a novel strategy to correct batch variations was presented. When challenging GARD with 29 compounds, sensitivity, specificity and accuracy could be estimated to 94%, 83% and 90%, respectively. In conclusion, we present a GARD workflow with improved sample capacity, retained predictive performance, and in a format adapted to standardized screening. We propose that GARD is ready to be considered as part of an integrated testing strategy for skin sensitization.
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| 5. |
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| 6. |
- Lindberg, Tim, et al.
(författare)
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An integrated transcriptomic- and proteomic-based approach to evaluate the human skin sensitization potential of glyphosate and its commercial agrochemical formulations
- 2020
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 217
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the skin sensitization hazard of glyphosate, the surfactant polyethylated tallow amine (POEA) and two commercial glyphosate-containing formulations using different omics-technologies based on a human dendritic cell (DC)-like cell line. First, the GARD™skin assay, investigating changes in the expression of 200 transcripts upon cell exposure to xenobiotics, was used for skin sensitization prediction. POEA and the formulations were classified as skin sensitizers while glyphosate alone was classified as a non-sensitizer. Interestingly, the mixture of POEA together with glyphosate displayed a similar sensitizing prediction as POEA alone, indicating that glyphosate likely does not increase the sensitizing capacity when associated with POEA. Moreover, mass spectrometry analysis identified differentially regulated protein groups and predicted molecular pathways based on a proteomic approach in response to cell exposures with glyphosate, POEA and the glyphosate-containing formulations. Based on the protein expression data, predicted pathways were linked to immunologically relevant events and regulated proteins further to cholesterol biosynthesis and homeostasis as well as to autophagy, identifying novel aspects of DC responses after exposure to xenobiotics. In summary, we here present an integrative analysis involving advanced technologies to elucidate the molecular mechanisms behind DC activation in the skin sensitization process triggered by the investigated agrochemical materials. Significance: The use of glyphosate has increased worldwide, and much effort has been made to improve risk assessments and to further elucidate the mechanisms behind any potential human health hazard of this chemical and its agrochemical formulations. In this context, omics-based techniques can provide a multiparametric approach, including several biomarkers, to expand the mechanistic knowledge of xenobiotics-induced toxicity. Based on this, we performed the integration of GARD™skin and proteomic data to elucidate the skin sensitization hazard of POEA, glyphosate and its two commercial mixtures, and to investigate cellular responses more in detail on protein level. The proteomic data indicate the regulation of immune response-related pathways and proteins associated with cholesterol biosynthesis and homeostasis as well as to autophagy, identifying novel aspects of DC responses after exposure to xenobiotics. Therefore, our data show the applicability of a multiparametric integrated approach for the mechanism-based hazard evaluation of xenobiotics, eventually complementing decision making in the holistic risk assessment of chemicals regarding their allergenic potential in humans.
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| 7. |
- Lindberg, Tim, et al.
(författare)
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In vitro assessment of mechanistic events induced by structurally related chemical rubber sensitizers
- 2019
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333. ; 60, s. 144-153
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Tidskriftsartikel (refereegranskat)abstract
- Allergic contact dermatitis (ACD) is one of the most common forms of immunotoxicity, and increased understanding of how chemicals trigger these adverse reactions is needed in order to treat or design testing strategies to identify and subsequently avoid exposure to such substances. In this study, we investigated the cellular response induced by rubber chemicals in a dendritic cell (DC) model, focusing on the structurally similar chemicals diethylthiocarbamylbenzothiazole sulfide and dimethylthiocarbamylbenzothiazole sulfide, with regard to regulation of microRNA, and messenger RNA expression. Only a few miRNAs were found to be commonly regulated by both rubber chemicals, among them miR1973, while the overall miRNA expression profiles were diverse. Similarly, out of approximately 500 differentially regulated transcripts for each chemical, about 60% overlapped, while remaining were unique. The pathways predicted to be enriched in the cell model by stimulation with the rubber chemicals were linked to immunological events, relevant in the context of ACD. These results suggest that small structural differences can trigger specific activation of the immune system in response to chemicals. The here presented mechanistic data can be valuable in explaining the immunotoxicological events in DC activation after exposure to skin sensitizing chemicals, and can contribute to understanding, preventing and treating ACD.
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| 8. |
- Olof Olsson, P., et al.
(författare)
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Inhibition of integrin αvβ6 changes fibril thickness of stromal collagen in experimental carcinomas
- 2018
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Ingår i: Cell Communication and Signaling. - : Springer Science and Business Media LLC. - 1478-811X. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. Methods: The potential role of αVβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the αVβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Conclusion: Our data demonstrate that the αVβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.
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| 9. |
- Olsson, P. Olof, et al.
(författare)
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Inhibition of integrin alpha(V)beta(6) changes fibril thickness of stromal collagen in experimental carcinomas
- 2018
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Ingår i: Cell Communication and Signaling. - : BMC. - 1478-811X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF beta 1 and -beta 3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma.Methods: The potential role of a(v)beta(6) integrin-mediated activation of latent TGF-beta was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal a(v)beta(6) integrin-speafic monoclonal antibody 3G9 was used to inhibit the a(v)beta(6) integrin activity.Results: Both KAT-4 and Capan-2 cells expressed the a(v)beta(6) integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-beta in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-beta 1 and -beta 3 reduced collagen fibril thickness in both tumor models.Conclusion: Our data demonstrate that the a(v)beta(6)-directed activation of latent TGF-beta plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to a(v)beta(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-beta activation and the extent of desmoplasia.
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| 10. |
- Oscarsson, Elin, et al.
(författare)
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Changes in Intestinal Permeability Ex Vivo and Immune Cell Activation by Three Commonly Used Emulsifiers
- 2020
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Ingår i: Molecules (Basel, Switzerland). - : MDPI AG. - 1420-3049. ; 25:24
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Tidskriftsartikel (refereegranskat)abstract
- Food additives such as emulsifiers are used in increasing quantities in the food industry. The aim of this study was to compare three different emulsifiers (polysorbate 80 (P80), carboxymethyl cellulose (CMC), and β-lactoglobulin (β-lac) with regards to their effect on the stimulation of immune cells and intestinal permeability. The immune stimulatory effects were studied in the myeloid cell line MUTZ-3-cells, while the change in intestinal permeability was studied in the Caco-2 cell line and ex vivo in the Ussing chamber system using small intestinal fragments from rats. The tested concentrations of the emulsifiers ranged from 0.02% up to 1%, which are concentrations commonly used in the food industry. The results showed that P80 affected both the myeloid cells and the intestinal permeability more than CMC (p < 0.05) and β-lac (p < 0.05) at the highest concentration. CMC was found to neither affect the permeability in the intestine nor the MUTZ-3 cells, while β-lac changed the permeability in the total part of the small intestine in rats. These findings indicate that P80 might be more cytotoxic compared to the other two emulsifiers.
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