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| 2. |
- Albrekt, Ann-Sofie, et al.
(författare)
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Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
- 2014
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Ingår i: Bmc Pharmacology & Toxicology. - : Springer Science and Business Media LLC. - 1471-2210 .- 2050-6511. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency. Methods: Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents. Results: By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis. Conclusions: This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways.
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| 3. |
- Karlsson, Isabella, 1980, et al.
(författare)
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Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens
- 2009
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1881-1892
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Tidskriftsartikel (refereegranskat)abstract
- One of the most frequently observed photoallergens today is the sunscreen agent 4-tert-butyl-4′-methoxy dibenzoylmethane (1a). The structurally similar compound, 4-isopropyldibenzoylmethane (1b), was a common cause of sunscreen allergy in the eighties and early nineties but was removed from the market in 1993 and replaced with dibenzoylmethane 1a. We have studied the photodegradation of the dibenzoylmethane 1a, to better understand how these substances cause an immune reaction. Several expected degradation products were formed and identified. Of these, arylglyoxals and benzils were of particular interest because they were unexplored as potential contact allergens. The allergenic potential of photodegraded 1a was evaluated by screening the formed arylglyoxals and benzils for their sensitizing capacity in the murine local lymph node assay. The arylglyoxals were found to be strong sensitizers. They were also found to be highly reactive toward the nucleophile arginine, which indicates that the immunogenic hapten-protein complex could be formed via an electrophilic-nucleophilic pathway. By varying the electron-withdrawing or -donating capacity of the substituent in the para position of the arylglyoxal, the electronic effects were shown to have no significant impact on either the sensitizing or the electrophilic power of arylglyoxals. Thus, a change in the substitution pattern of the parent dibenzoylmethane will not influence the sensitizing capacity of the products formed from them upon photodegradation. Furthermore, the combined studies of benzils, using the local lymph node assay and a cell proliferation assay, indicate that the benzils are cytotoxic rather than allergenic. Taken together, this study presents strong indication that photocontact allergy to dibenzoylmethanes is caused by the arylglyoxals that are formed upon photodegradation.
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| 5. |
- Bråred Christensson, Johanna, 1965, et al.
(författare)
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Limonene hydroperoxide analogues differ in allergenic activity
- 2008
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 59:6, s. 344-352
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Tidskriftsartikel (refereegranskat)abstract
- Background: The fragrance terpene R-limonene is a very weak sensitizer but forms allergenic oxidation products upon contact with air. Oxidized (ox.) limonene is a frequent cause of contact allergy in clinical testing. Objectives: This study investigates the sensitizing potencies of ox. and non-ox. limonene and of structurally closely related limonene hydroperoxides. The clinical importance of the difference in sensitizing potency of two hydroperoxides in autoxidized limonene was studied. Patients/Methods: Ox. and non-ox. limonene were investigated in the murine local lymph node assay (LLNA). Limonene hydroperoxides were investigated using a modified LLNA involving non-pooled lymph nodes and statistical calculations; patch testing of patients with known contact allergy to ox. limonene was performed. Results: A marked increase in the sensitizing potency of ox. limonene compared with that of pure limonene was observed in the LLNA. One analogue, limonene-1-hydroperoxide, was a significantly more potent sensitizer than the other hydroperoxides and gave more positive test reactions in the allergic patients. Conclusions: The results support that hydroperoxides have a specific reactivity indicating that oxygen-centred radicals are important in hapten–protein complex formation of hydroperoxides. The primary oxidation products of ox. limonene, the hydroperoxides, have an important impact on the sensitizing capacity of the oxidation mixture.
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| 6. |
- Bråred Christensson, Johanna, 1965, et al.
(författare)
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Limonene hydroperoxide analogues show specific patch test reactions.
- 2014
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Ingår i: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 70:5, s. 291-299
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Tidskriftsartikel (refereegranskat)abstract
- The fragrance terpene R-limonene is a very weak sensitizer, but forms allergenic oxidation products upon contact with air. The primary oxidation products of oxidized limonene, the hydroperoxides, have an important impact on the sensitizing potency of the oxidation mixture. One analogue, limonene-1-hydroperoxide, was experimentally shown to be a significantly more potent sensitizer than limonene-2-hydroperoxide in the local lymph node assay with non-pooled lymph nodes.
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| 7. |
- Bäcktorp, Carina, 1964, et al.
(författare)
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Mechanism of Air Oxidation of the Fragrance Terpene Geraniol
- 2008
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Ingår i: J.Chem.Theory Comput.. - : American Chemical Society (ACS). ; 4, s. 101-106
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Tidskriftsartikel (refereegranskat)abstract
- The fragrance terpene geraniol autoxidizes upon air exposure and forms a mixture of oxidation products, some of which are skin sensitizers. Reactions of geraniol with O2 have been studied with DFT (B3LYP) and the computational results compared to experimentally observed product ratios. The oxidation is initiated by hydrogen abstraction, forming an allylic radical which combines with an O2 molecule to yield an intermediate peroxyl radical. In the subsequent step, geraniol differs from previously studied cases, in which the radical chain reaction is propagated through intermolecular hydrogen abstraction. The hydroxy-substituted allylic peroxyl radical prefers an intramolecular rearrangement, producing observable aldehydes and the hydroperoxyl radical, which in turn can propagate the radical reaction. Secondary oxidation products like epoxides and formates were also considered, and plausible reaction pathways for formation are proposed.
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| 8. |
- Bäcktorp, Carina, 1964, et al.
(författare)
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Mechanisms of Air Oxidation of Ethoxylated Surfactants - Computational Estimations of Energies and Reaction Behaviors
- 2008
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 14:31, s. 9549-9554
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Tidskriftsartikel (refereegranskat)abstract
- Pathways for formation of previously observed autoxidation products of ethoxylated surfactants have been studied by DFT (B3LYP). In addition to the established radical-chain reaction, several mechanistic possibilities for intramolecular fragmentation of the intermediate radicals have been characterized concerning reaction barriers and energies of transition states. The results can rationalize the formation of previously observed autoxidation products, including several, which have been implicated as strongly allergenic.
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| 9. |
- Bäcktorp, Carina, 1964, et al.
(författare)
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Theoretical investigation of linalool oxidation.
- 2006
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Ingår i: The journal of physical chemistry. A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 110:44, s. 12204-12
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Tidskriftsartikel (refereegranskat)abstract
- This study concerns the autoxidation of one of the most used fragrances in daily life, linalool (3,7-dimethyl-1,6-octadien-3-ol). It reacts with O2 to form hydroperoxides, which are known to be important contact allergens. Pathways for hydroperoxide formation are investigated by means of quantum mechanical electronic structure calculations. Optimized molecular geometries and harmonic vibrational frequencies are determined using density functional theory (DFT). Insight into how the addition of O2 to linalool occurs is obtained by establishing a theoretical framework and systematically investigating three smaller systems: propene, 2-methyl-2-butene, and 2-methyl-2-pentene. 2-Methyl-2-pentene was chosen as a model system and used to compare with linalool. This theoretical study characterizes the linalool-O2 biradical intermediate state, which constitutes a branching point for the further oxidation reactions pathways. Thus, the observed linalool oxidation product spectrum is discussed in terms of a direct reaction path, the ene-type mechanism, and the radical mechanism. The major hydroperoxide found in experiments is 7-hydroperoxy-3,7-dimethyl-octa-1,5-diene-3-ol, and the calculated results support this finding.
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| 10. |
- Börje, Anna, 1961, et al.
(författare)
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New luminescent and redox-active mono- and polynuclear ruthenium(II) and osmium(II) polypyridine complexes
- 2002
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Ingår i: Journal of the Chemical Society-Dalton Transactions. - 1472-7773. ; :6, s. 843-848
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Tidskriftsartikel (refereegranskat)abstract
- A series of mono and polynuclear Ru(II) and Os(II) polypyridine complexes based on the bpy-O-bpy ligand {bpy-O-bpy = bis[4-(2,2'-bipyridinyl)]ether} has been prepared. The redox, absorption and luminescence properties of these species have been measured and compared with those of the [Ru(bpy)(3)](2+) and [Os(bpy)(3)](2+) parent compounds. Electrochemical oxidation involves the metal centers, and occurs reversibly in acetonitrile at room temperature at about +1.30 and +0.85 V vs. SCE, respectively, for the Ru- and Os-based units. Reduction is ligand-centered and features a first irreversible wave followed by several reversible processes. Absorption spectra are essentially the sum of the spectra of the component monometallic species. Luminescence emission is observed both in acetonitrile solution (298 K) and in frozen matrix (77 K), originating from (MLCT)-M-3 states. Homometallic complexes display luminescence properties which are close to that featured by the parent [M(bpy)(3)](2+) species. In heterometallic species luminescence is observed only from the Os-based unit, indicating that efficient energy transfer takes place from the Ru-based to the Os-based moiety. The results indicate that the electronic communication through the bpy-O-bpy bridging ligand is so small that it doesn't substantially modify the properties of the metal units, which are those of the corresponding isolated [M(bpy)(3)](2+) units, but large enough to allow efficient energy transfer through the bridge. The bpy-O-bpy bridging ligand appears thus a promising component for the synthesis of multimetallic antenna systems.
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