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1.
  • Tjondro, Harry C., et al. (author)
  • Hyper-truncated Asn355- And Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase
  • 2021
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 296
  • Journal article (peer-reviewed)abstract
    • Myeloperoxidase (MPO) plays essential roles in neutrophil-mediated immunity via the generation of reactive oxidation products. Complex carbohydrates decorate MPO at discrete sites, but their functional relevance remains elusive. To this end, we have characterised the structure–biosynthesis–activity relationship of neutrophil MPO (nMPO). Mass spectrometry demonstrated that nMPO carries both characteristic under-processed and hyper-truncated glycans. Occlusion of the Asn355/Asn391-glycosylation sites and the Asn323-/Asn483-glycans, located in the MPO dimerisation zone, was found to affect the local glycan processing, thereby providing a molecular basis of the site-specific nMPO glycosylation. Native mass spectrometry, mass photometry and glycopeptide profiling revealed significant molecular complexity of diprotomeric nMPO arising from heterogeneous glycosylation, oxidation, chlorination and polypeptide truncation variants and a previously unreported low-abundance monoprotomer. Longitudinal profiling of maturing, mature, granule-separated and pathogen-stimulated neutrophils demonstrated that nMPO is dynamically expressed during granulopoiesis, unevenly distributed across granules and degranulated upon activation. We also show that proMPO-to-MPO maturation occurs during early/mid-stage granulopoiesis. While similar global MPO glycosylation was observed across conditions, the conserved Asn355-/Asn391-sites displayed elevated glycan hyper-truncation, which correlated with higher enzyme activities of MPO in distinct granule populations. Enzymatic trimming of the Asn355-/Asn391-glycans recapitulated the activity gain and showed that nMPO carrying hyper-truncated glycans at these positions exhibits increased thermal stability, polypeptide accessibility and ceruloplasmin-mediated inhibition potential relative to native nMPO. Finally, molecular modelling revealed that hyper-truncated Asn355-glycans positioned in the MPO-ceruloplasmin interface are critical for uninterrupted inhibition. Here, through an innovative and comprehensive approach, we report novel functional roles of MPO glycans, providing new insight into neutrophil-mediated immunity.
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2.
  • Lindberg, Frida A., et al. (author)
  • SLC38A10 knockout mice display a decreased body weight and an increased risk-taking behavior in the open field test
  • 2022
  • In: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16
  • Journal article (peer-reviewed)abstract
    • The solute carrier 38 family (SLC38) is a family of 11 members. The most commonsubstrate among these are alanine and glutamine, and members are present in a widerange of tissues with important functions for several biological processes, such as liverand brain function. Some of these transporters are better characterized than others and,in this paper, a behavioral characterization of SLC38A10−/− mice was carried out. Abattery of tests for general activity, emotionality, motor function, and spatial memorywere used. Among these tests, the elevated plus maze, Y-maze, marble burying, andchallenging beamwalk have not been tested on the SLC38A10−/− mice previously, whilethe open field and the rotarod tests have been performed by the International MousePhenotyping Consortium (IMPC). Unlike the results from IMPC, the results from this studyshowed that SLC38A10−/− mice spend less time in the wall zone in the open field testthan WT mice, implying that SLC38A10-deficient mice have an increased explorativebehavior, which suggests an important function of SLC38A10 in brain. The present studyalso confirmed IMPC’s data regarding rotarod performance and weight, showing thatSLC38A10−/− mice do not have an affected motor coordination impairment and havea lower body weight than both SLC38A10+/− and SLC38A10+/+ mice. These resultsimply that a complete deficiency of the SLC38A10 protein might affect body weighthomeostasis, but the underlying mechanisms needs to be studied further.
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3.
  • Lindberg, Frida A., et al. (author)
  • SLC38A10 Deficiency in Mice Affects Plasma Levels of Threonine and Histidine in Males but Not in Females : A Preliminary Characterization Study of SLC38A10(-/-) Mice
  • 2023
  • In: Genes. - : MDPI. - 2073-4425. ; 14:4
  • Journal article (peer-reviewed)abstract
    • Solute carriers belong to the biggest group of transporters in the human genome, but more knowledge is needed to fully understand their function and possible role as therapeutic targets. SLC38A10, a poorly characterized solute carrier, is preliminary characterized here. By using a knockout mouse model, we studied the biological effects of SLC38A10 deficiency in vivo. We performed a transcriptomic analysis of the whole brain and found seven differentially expressed genes in SLC38A10-deficient mice (Gm48159, Nr4a1, Tuba1c, Lrrc56, mt-Tp, Hbb-bt and Snord116/9). By measuring amino acids in plasma, we found lower levels of threonine and histidine in knockout males, whereas no amino acid levels were affected in females, suggesting that SLC38A10(-/-) might affect sexes differently. Using RT-qPCR, we investigated the effect of SLC38A10 deficiency on mRNA expression of other SLC38 members, Mtor and Rps6kb1 in the brain, liver, lung, muscle, and kidney, but no differences were found. Relative telomere length measurement was also taken, as a marker for cellular age, but no differences were found between the genotypes. We conclude that SLC38A10 might be important for keeping amino acid homeostasis in plasma, at least in males, but no major effects were seen on transcriptomic expression or telomere length in the whole brain.
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4.
  • Holmér, Andreas, et al. (author)
  • The factor H variant associated with age-related macular degeneration (H384) and the non-disease associated form bind differentially to C-reactive protein, fibromodulin, DNA and necrotic cells.
  • 2007
  • In: Journal of Biological Chemistry. - 1083-351X. ; 282:15, s. 10894-10900
  • Journal article (peer-reviewed)abstract
    • Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6 - 8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do not compete with FH for binding to C-reactive protein. The interaction with extracellular matrix protein fibromodulin, which we now show to be mediated, at least in part, by CCP6 - 8 of FH, occurs via the polypeptide of fibromodulin and not through its glycosaminoglycan modifications. The Tyr-384 variant of FH bound fibromodulin better than the His-384 form. Furthermore, we find that CCP6 - 8 is able to interact with DNA and necrotic cells, but in contrast the His-384 allotype binds these ligands more strongly than the Tyr-384 variant. The variations in binding affinity of the two alleles indicate that complement activation and local inflammation in response to different targets will differ between His/His and Tyr/Tyr homozygotes.
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5.
  • Lindberg, Frida A. (author)
  • The Biological Importance of the Amino Acid Transporter SLC38A10 : Characterization of a Knockout Mouse
  • 2022
  • Doctoral thesis (other academic/artistic)abstract
    • The biggest group of transporters, the solute carriers (SLCs), has more than 400 members, and about 30% of these are still orphan. In order to decipher their biological function and possible role in disease, there is a need for characterization of these. Around 25% of SLCs are estimated to have amino acids as substrates, including transporters belonging to the SLC38 family. The SLC38 members are sometimes referred to their alternative name: sodium-coupled neutral amino acid transporters (SNATs). One of these transporters, SNAT10 (or SLC38A10), has been characterized as a bidirectional transporter of glutamate, glutamine, alanine and aspartate, as well as having an efflux of serine, and is ubiquitously expressed in the body. However, its biological importance is not yet understood. The aim with this thesis was to characterize a mouse model deficient in SNAT10 protein in order to find the biological importance of this transporter. In paper I, this is done by using a series of behavioral tests, including the open field test, elevated plus maze, rotarod and Y-maze, among others. The SNAT10 knockout mouse was found to have an increased risk-taking behavior, but no motor or spatial working memory impairments. Furthermore, the knockout mouse was found to have a decreased body weight. In paper II, an additional behavioral characterization was performed by using the multivariate concentric square field™ (MCSF) test. The MCSF test is an arena with different zones associated to different behavioral traits, which generates a behavioral profile depending on where the mouse spends its time. The result from this test implies that the SNAT10 deficient mouse has a lower explorative behavior than its wild type littermates. In paper III, gene expression was studied in whole brain and some genes related to cell cycle regulation and p53 expression were found to be differentially expressed in the knockout brain. Additional gene expression was studied in kidney, liver, lung and muscle, but no changes were found. Plasma levels of histidine and threonine were altered in males, but no altered amino acid levels were found in knockout females, suggesting a possible sex-specific effect. These studies together imply that SNAT10 might be involved in processes related to risk-taking and explorative behavior in the open field and MCSF tests. SNAT10 deficiency also affected amino acid levels in plasma, indicating a disrupted amino acid homeostasis.
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6.
  • Sukhovey, Yurij G., et al. (author)
  • Functional Conjugation of the Different Regulatory Responses to the Stress Stimuli in Healthy Human Subjects
  • 2016
  • In: Open Journal of Applied Sciences. - : Scientific Research Publishing, Inc.. - 2165-3917 .- 2165-3925. ; 6, s. 489-500
  • Journal article (peer-reviewed)abstract
    • Present article discusses the physiological mechanisms of the state employees adaptation duringactive training in temporary groups. It is suggested that adaptive mechanisms to adverse effectsmay be studied basing on the concept of functional isomorphism of the psychic and immune systems.Adaptive mechanisms were studied through the monitoring of the stress factors’ impact upon thelaw enforcement officers when training outside the places of permanent deployment. The specificpurpose of present study was to evaluate the physiological indicators of the psychic, immune andendocrine systems dynamics at different stages of adaptation of the live organism to a stressfulsituation, hoping to get better insight into possible relations between psychic and immune domains.Through monitoring of the dynamics of the endocrine and immune responses to the psychic stimuli,it was possible to correlate the stages of the stress onset to the phases of specific immune reactions.Strong correlations between the parameters characterizing activation of the psychic and immuneresponses support the hypothesis of the presence of “strong cooperation” between psychic andimmune domains. It supports earlier hypothesis that we are monitoring
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7.
  • Aspholm-Hurtig, Marina, et al. (author)
  • Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
  • 2004
  • In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5683, s. 519-22
  • Journal article (peer-reviewed)abstract
    • Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.
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8.
  • Deyou, Tsegaye, et al. (author)
  • Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp teitensis
  • 2017
  • In: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:7, s. 2060-2066
  • Journal article (peer-reviewed)abstract
    • A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 mu M, respectively.
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9.
  • Mabeyo, P. E., et al. (author)
  • Selenium Accumulating Leafy Vegetables Are a Potential Source of Functional Foods
  • 2015
  • In: International Journal of Food Science. - : Hindawi Limited. - 2356-7015 .- 2314-5765. ; 2015
  • Journal article (peer-reviewed)abstract
    • Selenium deficiency in humans has been associated with various diseases, the risks of which can be reduced through dietary supplementation. Selenium accumulating plants may provide a beneficial nutrient for avoiding such illnesses. Thus, leafy vegetables such as Amaranthus hybridus, Amaranthus sp., Cucurbita maxima, Ipomoea batatas, Solanum villosum, Solanum scabrum, and Vigna unguiculata were explored for their capabilities to accumulate selenium when grown on selenium enriched soil and for use as a potential source of selenium enriched functional foods. Their selenium contents were determined by spectrophotometry using the complex of 3,3′-diaminobenzidine hydrochloride (DABH) as a chromogen. The mean concentrations in the leaves were found to range from to μg/g dry weight (DW), with C. maxima accumulating the most selenium. In stems, the accumulated selenium content ranged from μg/g in Amaranthus sp. to μg/g DW in C. maxima and was hence significantly different (). The cancer cell line MDA-MB-231 was used in cytotoxicity assays to determine the anticancer potential of these extracts. With exception of S. scabrum and S. villosum, no cytotoxicity was detected for the selenium enriched vegetable extracts up to 100μg/mL concentration. Hence, following careful evaluation the studied vegetables may be considered as selenium enriched functional foods.
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10.
  • Makungu, Marco, et al. (author)
  • Pterocarpans and isoflavones from the roots of Millettia micans and of Millettia dura
  • 2016
  • In: Advances in Drug Discovery and Development. ; 1:1, s. 1-8
  • Journal article (peer-reviewed)abstract
    • From the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia micans, a new pterocarpan, (6aR,11aR)-7,8,9-trimethoxy-3-hydroxypterocarpan (1), named micanspterocarpan, was isolated. Similarinvestigation of the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia dura gave a further new pterocarpan,3-O-prenylmaackiain (2) along with six known isoflavones (3-8) and a chalcone (9). All purifiedcompounds were identified by NMR and MS, and the absolute configuration of 1 was established by quantumchemical CD calculation. The isolated constituents, calopogonium isoflavone B (3) and isoerythrin A-4'-(3-methylbut-2-enyl) ether (4) showed marginal activities against the 3D7 and the Dd2 strains of Plasmodiumfalciparum (70-90% inhibition at 40 M). Maximaisoflavone B (5) and 7,2'-dimethoxy-4',5'-methylenedioxyisoflavone (7) were weakly cytotoxic (IC50 153.5 and 174.1 uM, respectively) against theMDB-MB-231 human breast cancer cell line. None of the tested compounds showed toxicity against theHEK-293 human embryonic kidney cell line at 40 uM.
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11.
  • Nyandoro, Stephen S., 1975, et al. (author)
  • N-Cinnamoyltetraketide Derivatives from the Leaves of Toussaintia orientalis
  • 2015
  • In: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 78:8, s. 2045-2050
  • Journal article (peer-reviewed)abstract
    • Seven N-cinnamoyltetraketides (1–7), including the new Z-toussaintine E (2), toussaintine F (6), and toussaintine G (7), were isolated from the methanol extract of the leaves of Toussaintia orientalis using column chromatography and HPLC. The configurations of E-toussaintine E (1) and toussaintines A (3) and D (5) are revised based on single-crystal X-ray diffraction data from racemic crystals. Both the crude methanol extract and the isolated constituents exhibit antimycobacterial activities (MIC 83.3–107.7 μM) against the H37Rv strain of Mycobacterium tuberculosis. Compounds 1, 3, 4, and 5 are cytotoxic (ED50 15.3–105.7 μM) against the MDA-MB-231 triple negative aggressive breast cancer cell line.
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12.
  • Nyandoro, Stephen S., 1975, et al. (author)
  • Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves
  • 2017
  • In: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:1, s. 114-125
  • Journal article (peer-reviewed)abstract
    • Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A–F (6–11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15–21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2–40 μM, and against HEK293 mammalian cells (IC50 2.7–3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03–8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.
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13.
  • Lindberg, Frida A, et al. (author)
  • SLC38A10 deficiency in male mice affect plasma levels of threonine and histidine
  • Other publication (other academic/artistic)abstract
    • Solute carriers belong to the biggest group of transporters in the human genome, but more knowledge is needed in order to fully understand their function and possible role as therapeutic targets. SLC38 is a family of amino acid transporters, commonly referred to as SNATs, consisting of 11 members. The tenth member, SLC38A10, is one of the least characterized members and is the focus of this study. By using a knockout mouse model, we studied the biological effects of SLC38A10 deficiency in vivo. We performed a transcriptomic analysis of whole brain and found seven differentially expressed genes in SLC38A10 deficient mice (Gm48159, Nr4a1, Tuba1c, Lrrc56, mt-Tp, Hbb-bt and Snord116/9). By measuring amino acids in plasma, we found lower levels of threonine and histidine in males, while no amino acids were altered in females, suggesting that SLC38A10-/- might affect sexes differently. Using RT-qPCR, we investigated the effect of SLC38A10 deficiency on mRNA expression of other SLC38 members, Mtor and Rps6kb1 in brain, liver, lung, muscle and kidney, but no differences were found. A relative telomere length measurement was also made, as a marker for cellular age, but no differences were found between the genotypes. We conclude that SLC38A10 might be important for keeping amino acid homeostasis in plasma, at least in males, but no major effects were seen on transcriptomic expression or telomere length in whole brain. 
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14.
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15.
  • Xin, D. L., et al. (author)
  • Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task
  • 2017
  • In: BMC Neuroscience. - : BioMed Central. - 1471-2202. ; 18
  • Journal article (peer-reviewed)abstract
    • Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
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16.
  • Dinér, Peter, 1976, et al. (author)
  • Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo 3,4-d pyrimidin-4-amines as RET Kinase Inhibitors
  • 2012
  • In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:10, s. 4872-4876
  • Journal article (peer-reviewed)abstract
    • A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.
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17.
  • Johansson, Staffan, 1976, et al. (author)
  • Mechanistic Proposal for the Formation of Specific Immunogenic Complexes via a Radical Pathway: A Key Step in Allergic Contact Dermatitis to Olefinic Hydroperoxides
  • 2009
  • In: Chem. Res. Toxicol.. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1774-1781
  • Journal article (peer-reviewed)abstract
    • The widespread use of scented products causes an increase of allergic contact dermatitis to fragrance compounds in Western countries today. Many fragrance compounds are prone to autoxidation, forming hydroperoxides as their primary oxidation products. Hydroperoxides are known to be strong allergens and to form specific immunogenic complexes. However, the mechanisms for the formation of the immunogenic complexes are largely unknown. We have investigated this mechanism for (5R)-5-isopropenyl-2-methyl-2-cyclohexene-1-hydroperoxide (Lim-2-OOH) by studying the formation of adducts in the reaction between this hydroperoxide and 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (Fe(III)TPPCl) in the presence of protected cysteine (NAc-Cys-OMe) or glutathione (GSH). Isolated adducts originate from the addition of the thiol group of NAc-Cys-OMe over the carbon−carbon double bonds of carvone. Furthermore, adducts between NAc-Cys-OMe and carveol as well as between GSH and carvone have been identified. The formation of these adducts most likely proceeds via the radical thiol−ene mechanism. The addition of a terpene moiety to cysteine offers an explanation of the specificity of the immune response to structurally different hydroperoxides. These results also explain the lack of cross-reactivity between carvone and Lim-2-OOH. In conclusion, we propose that immunogenic complexes of olefinic hydroperoxides can be formed via the radical thiol−ene mechanism. These complexes will be specific for the individual olefinic hydroperoxides due to the inclusion of a terpene moiety derived from the hydroperoxide.
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18.
  • Karlsson, Isabella, 1980, et al. (author)
  • Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens
  • 2009
  • In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1881-1892
  • Journal article (peer-reviewed)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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19.
  • Okroj, Marcin, et al. (author)
  • Antibodies against Kaposi sarcoma-associated herpes virus (KSHV) complement control protein (KCP) in infected individuals
  • 2007
  • In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 25:48, s. 8102-8109
  • Journal article (peer-reviewed)abstract
    • Kaposi sarcoma-associated herpesvirus (KSHV) is the most important etiopathological factor of Kaposi's sarcoma (KS) and some specific types of malignant lymphomas. One of the viral lytic genes encodes the KSHV complement control protein (KCP), which functionally mimics human complement inhibitors. Although this protein provides an advantage for evading the complement attack, it can serve as target for adaptive immune response. Herein, we identified anti-KCP IgG antibodies in patients with KS and KSHV-related lymphomas. KCP-specific antibodies were only detected in sera of those patients who had high titres of antibodies against lytic or latent KSHV antigens. Complement control protein domain 2 (CCP2) was found to be the most immunogenic part of the KCP protein. Furthermore, pre-incubation of KCP-expressing CHO cells with patient sera containing anti-KCP antibodies resulted in an increased complement deposition when incubated with human serum.
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20.
  • Okroj, Marcin, et al. (author)
  • Prevalence of antibodies against Kaposi's sarcoma associated herpes virus (KSHV) complement inhibitory protein (KCP) in KSHV-related diseases and their correlation with clinical parameters.
  • 2011
  • In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 29, s. 1129-1134
  • Journal article (peer-reviewed)abstract
    • Kaposi's sarcoma-associated herpes virus (KSHV) encodes its own inhibitor of the complement system, designated KSHV complement control protein (KCP). Previously, we detected anti-KCP antibodies in a small group of 22 patients suffering from Kaposi's sarcoma (KS) and KSHV-related lymphoproliferative diseases (Vaccine, 25:8102-9). Anti-KCP antibodies were more prevalent in individuals suffering from KSHV-related lymphomas than KS and also in those with high titer of antibodies against lytic KSHV antigens. Herein we analyze anti-KCP antibodies in 175 individuals originating from three different groups from northern Sweden or Italy, which included patients suffering from classical or HIV-associated KS, Multicentric Castleman's Disease, KSHV-associated solid lymphoma, pleural effusion lymphoma and healthy individuals with detectable KSHV immune response. Our current study confirmed previous observations concerning antibody prevalence but we also analyzed correlations between anti-KCP antibodies and classical KS evolution, clinical stage and viral load in body fluids. Furthermore, we show that patient's anti-KCP antibodies are able to decrease the ability of KCP to inhibit complement. This fact combined with results of statistical analysis suggests that KCP inactivation by specific antibodies may influence progression of classical KS.
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21.
  • Holmboe, Michael (author)
  • The bentonite barrier : microstructural aspects on colloid filtration and radiation effects on bentonite colloid stability
  • 2009
  • Licentiate thesis (other academic/artistic)abstract
    • In many countries a multi-barrier concept in a deep geological repository is planned for final disposal of nuclear waste. Many of these different concepts, for example the Swedish KBS-3 model, include an engineered barrier consisting of compacted bentonite. The compacted bentonite barrier will be positioned around copper canisters holding the nuclear waste and act as a transport barrier for various radioactive species. This is due to the compact microstructure as well as the large sorption capacity of compacted water saturated bentonite. During its required lifetime (> 100000 years) a deep geological repository and the bentonite barrier itself will be subjected to changing groundwater composition and flow, geochemistry, temperature, and large doses of ionizing irradiation. The long lifetime and significance of a deep geologic repository mean that it must be regarded as a thermodynamically open system and be assessed in terms of worst case scenarios. In case of water bearing fractures, formed by future movements in the granitic host bedrock, low ionic strength groundwater can endanger the stability of the bentonite barrier. Prolonged erosion of the bentonite barrier might cause significant loss of buffer material and jeopardize its overall functionality. This thesis deals with the microstructure of the water saturated compacted bentonite as a function of compaction, as well as effects of γ-radiation on bentonite dispersions. The microstructure was investigated both indirectly through colloid filtration experiments, as well as using low-angle XRD. Effects of γ-irradiation were investigated in terms of colloid stability and sediment behavior of bentonite (and Na-montmorillonite) dispersions. The colloid filtration experiments, using small gold colloids of different sizes as tracers, shows that the microstructural constraints of bentonite effectively filter even extremely small inorganic colloids. Colloid transport was only observed at very low compactions (i.e. dry density g/cm3) where the average interlayer distances of montmorillonite exceeded the colloid size, indicating interlayer rather than interparticle transport. From the low-angle XRD experiments the free porosity of water saturated compacted bentonite was determined by comparing its basal spacings (interlayer distances + 1 nm) with the hypothetical basal spacings assuming no free porosity. Irrespective of compaction, the maximum free porosity proved to be very low, in line with the colloid filtration experiments. The results showed that existing microstructural models sometimes exaggerate the importance of interparticle voids. The γ-irradiation experiments showed a radiation induced increase in colloid stability. This radiation induced effect also changed the sedimentation behavior of irradiated bentonite dispersions compared to unirradiated samples. The effect is attributed to an increase in surface potential of the bentonite colloids, due to reactions with the short-lived radicals formed upon water radiolysis.
  •  
22.
  • Bokarewa, Maria, 1963, et al. (author)
  • Bone remodelling: locus minori or unappreciated potential of tofacitinib?
  • 2018
  • In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 57:8, s. 1318-1320
  • Journal article (other academic/artistic)abstract
    • This editorial refers to the article "Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model" by Bruno Vidal et al. published in the same issue of Rheumatology (Oxford) doi:10.1093/rheumatology/kex258.
  •  
23.
  • Gillman, Anna, et al. (author)
  • Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards
  • 2015
  • In: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 81:7, s. 2378-2383
  • Journal article (peer-reviewed)abstract
    • Influenza A virus (IAV) has its natural reservoir in wild waterfowl and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate (OC)), stockpiled as Tamiflu® for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may there exert evolutionary pressure on avian IAV in waterfowl, resulting in development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo Mallard (Anas platyrhynchos) study we tested if an OC-resistant avian IAV strain (A(H1N1)/NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected Mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission in 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV, induced by OC exposure of the natural host, can persist in absence of the drug. Thus, there is a risk that human pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir resistant pandemic IAV would be a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment and resistance surveillance of IAV in wild birds.
  •  
24.
  • Gustafson, D, et al. (author)
  • An 18-year follow-up of overweight and risk of Alzheimer disease
  • 2003
  • In: Archives of Internal Medicine. - 0003-9926 .- 1538-3679. ; 163:13, s. 1524-1528
  • Journal article (peer-reviewed)abstract
    • Background  Overweight and obesity are epidemic in Western societies and constitute a major public health problem because of adverse effects on vascular health. Vascular factors may play a role in the development of a rapidly growing disease of late life, Alzheimer disease (AD). Using body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), we examined whether overweight is a risk factor for dementia and AD.Methods  The relationship between BMI and dementia risk was investigated in a representative cohort of 392 nondemented Swedish adults who were followed up from age 70 to 88 years, with the use of neuropsychiatric, anthropometric, and other measurements. Multivariate Cox proportional hazards regression analyses included BMI, blood pressure, cardiovascular disease, cigarette smoking, socioeconomic status, and treatment for hypertension.Results:  During the 18-year follow-up (4184.8 risk-years), 93 participants were diagnosed as having dementia. Women who developed dementia between ages 79 and 88 years were overweight, with a higher average BMI at age 70 years (27.7 vs 25.7; P = .007), 75 years (27.9 vs 25.0; P<.001), and 79 years (26.9 vs 25.1; P = .02) compared with nondemented women. A higher degree of overweight was observed in women who developed AD at 70 years (29.3; P = .009), 75 years (29.6; P<.001), and 79 years (28.2; P = .003) compared with nondemented women. For every 1.0 increase in BMI at age 70 years, AD risk increased by 36%. These associations were not found in men.Conclusions  Overweight is epidemic in Western societies. Our data suggest that overweight at high ages is a risk factor for dementia, particularly AD, in women. This may have profound implications for dementia prevention.
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25.
  • Jabbar, Karolina S., et al. (author)
  • Response.
  • 2014
  • In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 106:11
  • Journal article (other academic/artistic)
  •  
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