| 1. |
- Albrekt, Ann-Sofie, et al.
(author)
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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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In: Bmc Pharmacology & Toxicology. - : Springer Science and Business Media LLC. - 1471-2210 .- 2050-6511. ; 15
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Journal article (peer-reviewed)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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| 2. |
- Bråred Christensson, Johanna, 1965, et al.
(author)
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Limonene hydroperoxide analogues show specific patch test reactions.
- 2014
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In: Contact dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 70:5, s. 291-299
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Journal article (peer-reviewed)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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| 3. |
- Ekebergh, Andreas, 1984, et al.
(author)
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Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin
- 2011
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In: Organic Letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 13:16, s. 4458-4461
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Journal article (peer-reviewed)abstract
- The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations In Its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated In a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin.
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| 4. |
- Ekebergh, Andreas, 1984, et al.
(author)
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Total Synthesis of Nostodione A, a Cyanobacterial Metabolite
- 2012
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In: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 14:24, s. 6274-6277
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Journal article (peer-reviewed)abstract
- The first total synthesis of the mitotic spindle poison nostodione A is described. The inherent oxidative sensitivity of indoles is utilized for a late introduction of a second carbonyl to the cyclopent[b]indole-2-one system. The tricyclic system is prepared from indole-3-acetic acid and O-silylated 4-ethynylphenol, using a stereoselective intramolecular reductive Heck cyclization as the key transformation.
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| 5. |
- Hagvall, Lina, 1978, et al.
(author)
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Experimental and Theoretical Investigations of the Autoxidation of Geranial: A Dioxolane Hydroperoxide Identified as a Skin Sensitizer.
- 2011
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In: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X.
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Journal article (peer-reviewed)abstract
- The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.
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| 6. |
- Johansson, Staffan G H, et al.
(author)
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Structural Influence on Radical Formation and Sensitizing Capacity of Alkylic Limonene Hydroperoxide Analogues in Allergic Contact Dermatitis.
- 2010
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In: Chemical research in toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 23:3, s. 677-688
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Journal article (peer-reviewed)abstract
- Hydroperoxides are known to be strong contact allergens and a common cause of contact allergy. They are easily formed by the autoxidation of, for example, fragrance terpenes, compounds that are common in perfumes, cosmetics, and household products. A requirement of the immunological mechanisms of contact allergy is the formation of an immunogenic hapten-protein complex. For hydroperoxides, a radical mechanism is postulated for this formation. In our previous investigations of allylic limonene hydroperoxides, we found that the formation of carbon- and oxygen-centered radicals, as well as the sensitizing capacity, is influenced by the structure of the hydroperoxides. The aim of the present work was to further investigate the connection between structure, radical formation, and sensitizing capacity by studying alkylic analogues of the previously investigated allylic limonene hydroperoxides. The radical formation was studied in radical-trapping experiments employing 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride as an initiator and 1,1,3,3-tetramethylisoindolin-2-yloxyl as a radical trapper. We found that the investigated hydroperoxides initially form carbon- and oxygen-centered radicals that subsequently form alcohols and ketones. Trapped carbon-centered radicals and nonradical products were isolated and identified. Small changes in structure, like the omission of the endocyclic double bond or the addition of a methyl group, resulted in large differences in radical formation. The results indicate that alkoxyl radicals seem to be more important than carbon-centered radicals in the immunogenic complex formation. The sensitizing capacities were studied in the murine local lymph node assay (LLNA), and all hydroperoxides tested were found to be potent sensitizers. For two of the hydroperoxides investigated, the recently suggested thiol-ene reaction is a possible mechanism for the formation of immunogenic complexes. For the third investigated, fully saturated, hydroperoxide, the thiol-ene mechanism is not possible for immunogenic complex formation. This strongly indicates that several radical reaction pathways for immunogenic complex formation of limonene hydroperoxides are active in parallel.
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| 7. |
- Karlberg, Ann-Therese, 1947, et al.
(author)
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Activation of non-sensitizing or low-sensitizing fragrance substances into potent sensitizers - prehaptens and prohaptens
- 2013
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In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 69:6, s. 323-334
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Journal article (peer-reviewed)abstract
- Experimental and clinical studies have shown that fragrance substances can act as prehaptens or prohaptens. They form allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, thus, increasing the risk of sensitization. In the present review a series of fragrance substances with well documented abiotic and/or biotic activation are given as indicative and illustrative examples of the general problem. Commonly used fragrance substances, also found in essential oils, autoxidize on contact with air, forming potent sensitizers that can be an important source for contact allergy to fragrances and fragranced products. Some of them can act as prohaptens and be activated in the skin as well. The experimental findings are confirmed in large clinical studies. When substances with structural alerts for acting as prohaptens and/or prehaptens are identified, the possibility of generating new potent allergens should be considered. Predictive testing should include activation steps. Further experimental and clinical research regarding activation of fragrance substances is needed to increase consumer safety.
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| 8. |
- Karlsson, Isabella, 1980, et al.
(author)
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Clinical and experimental studies of octocrylene's allergenic potency
- 2011
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In: Contact Dermatitis. - : Wiley. - 1600-0536 .- 0105-1873. ; 64:6, s. 343-52
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Journal article (peer-reviewed)abstract
- Background. Reports of positive patch test and photopatch test reactions to the chemical ultraviolet filter octocrylene have increased during the last decade. Little is known about the reason for octocrylene's allergenic activity. Objectives. To present and discuss the results of patch tests and photopatch tests with octocrylene, and to investigate the possible cause of its allergenic properties. Methods. Results of patch tests and photopatch tests with octocrylene in patients with adverse skin reactions to sunscreen products and/or ketoprofen were collected. The allergenic potency of octocrylene was investigated in the murine local lymph node assay (LLNA). Chemical reactivity assays were used to mimic octocrylene's interaction with biomolecules. Results. We report 23 cases of positive test reactions to octocrylene (5 patch test and 18 photopatch). Notably, many of these patients also had positive photopatch test reactions to ketoprofen and benzophenone-3. Octocrylene was shown to be a moderate sensitizer in the LLNA, and it reacted with amines such as lysine, but not with thiols such as cysteine. Conclusions. The clinical studies show that octocrylene is both a photocontact allergen and a contact allergen. Octocrylene's ability to cause contact allergy is probably attributable to its reactivity towards lysine. To be able to understand why octocrylene causes photocontact allergy, further studies are needed.
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| 9. |
- Karlsson, Isabella, 1980, et al.
(author)
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Investigation of the Sunscreen Octocrylene's Interaction with Amino Acid Analogs in the Presence of UV Radiation
- 2012
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In: Photochemistry and Photobiology. - : Wiley. - 0031-8655 .- 1751-1097. ; 88:4, s. 904-912
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Journal article (peer-reviewed)abstract
- Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylenes interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylenes photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylenes ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols.
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| 10. |
- Karlsson, Isabella, 1980, et al.
(author)
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Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen
- 2014
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In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 27:7, s. 1294-1303
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Journal article (peer-reviewed)abstract
- Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-L-Trp ethyl ester and L-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
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